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Nanomedicine review: clinical developments in liposomal applications

Cancer Nanotechnology volume 10, Article number: 11 (2019) Cite this article

Abstract

Background

In recent years, disease treatment has evolved strategies that require increase in pharmaceutical agent’s efficacy and selectivity while decreasing their toxicity in normal tissues. These requirements have led to the development of nanoscale liposome systems for drug release. This review focuses on lipid features, pharmacological properties of liposomal formulations and the clinical studies of their application.

Main body

Several lipids are available, but their properties could affect pharmacological or clinical efficiency of drug formulations. Many liposomal formulations have been developed and are currently on the market. Proper selection of lipid is essential for the pharmacological effect to be improved. Most of the formulations use mainly zwitterionic, cationic or anionic lipids, PEG and/or cholesterol, which have different effects on stability, pharmacokinetics and delivery of the drug formulation. Clinical trials have shown that liposomes are pharmacologically and pharmacokinetically more efficient than drug-alone formulations in treating acute myeloid leukemia, hepatitis A, pain management, ovary, gastric breast and lung cancer, among others.

Conclusion

Liposomal formulations are less toxic than drugs alone and have better pharmacological parameters. Although they seem to be the first choice for drug delivery systems for various diseases, further research about dosage regimen regarding dose and time needs to be carried out.

Background

Many conventional drugs exhibit poor pharmacokinetics, limited bioavailability and a high toxicity, all of which restrain their use. To overcome these issues and improve the therapeutic indexes of the drug, the emergent fields of nanotechnology and nanomedicine have made significant progress in detection, diagnosis and treatment of several diseases at clinical level (Li et al. 2014; Yingchoncharoen et al. 2016; Signorell et al. 2018). In fact, thanks to nanoparticles and liposomes, it has been possible to decrease the toxicity and improve the pharmacokinetics parameters, such as distribution, increased circulation time, targeted controlled release, increased intracellular concentration, and enhanced solubility and stability of drugs in the organism (Medina-Alarcón et al. 2017; Ventola 2017). All these advantages have been reached by using drug delivery systems with 1–100 nm diameter nanoparticles, where a large surface leads to an increase in cellular interactions and multiple alterations of surface properties (Ud Din et al. 2017; Senapati et al. 2018; Gonda et al. 2019). Moreover, by co-delivering multiple drugs, treatments with NPs have also facilitated synergistic therapies and avoided drug resistance (Casals et al. 2017). For example, in CPX-351, a liposomal formulation, cytarabine and daunorubicin are packed together at a 5:1 molar ratio within 100-nm-diameter liposomes (Gergis et al. 2013; Cortes et al. 2015; Lancet et al. 2014).

Liposomes were discovered by Alec D. Bangham in 1965 (Allen and Cullis 2013) and were the first approved class of therapeutic NPs for cancer treatment. They still represent a large proportion of clinical-stage nanotherapeutics (Shi et al. 2017; Bourquin et al. 2018) due to their biodegradable, biocompatible, non-toxic, and non-immunogenic composition (Bozzuto and Molinari 2015; Zamani et al. 2018). The amphiphilic phospholipid bilayer of liposomes has close resemblance to the mammalian cell membrane, enabling efficient interactions between liposomes and cell membrane and subsequently effective cellular uptake (Gonda et al. 2019). In addition, liposomes may be added with ligands to increase efficiency and specifically target damaged cells, thus improving liposome pharmacokinetics and their ability to pass through target membranes, reaching high concentrations inside cells while reducing toxicity and enhancing treatment efficacy (Li et al. 2014; Ud Din et al. 2017; Zamani et al. 2018; Hussain et al. 2017; Lombardo et al. 2016; Fouladi et al. 2017; Maranhão et al. 2017; Miller et al. 2016). For instance, MM-302, an antibody–liposomal doxorubicin conjugate, specifically targets HER2 overexpressing cells (Miller et al. 2016). Liposome encapsulation may reduce drug clearance by the immune and renal systems, extending circulation time in the blood and increasing their availability (Bulbake et al. 2017). Another advantage of liposomes in their thermosensitive feature, i.e., an increase of temperature (to 40–41 °C) causes packing changes in the bilayer favoring the release of the encapsulated drug. These thermo-devices favor the specific release of a large amount of the cytotoxic agent to a heat-treated tumor site when using an external heat source, avoiding damage to the surrounding normal tissue (Nardecchia et al. 2019).

The first nanosized liposomal product to obtain regulatory approval in the US was Doxil®, which was approved in 1995 for the treatment of ovarian cancer and AIDS-related Kaposi’s sarcoma. Later, in 1996 the US FDA approved DaunoXome®, manufactured by NeXstar Pharmaceuticals, for the delivery of daunorubicin to treat advanced HIV-associated Kaposi sarcoma. Subsequently, more products have become available for the treatment of cancer and different diseases (Bulbake et al. 2017).

The most commonly investigated nanoparticles are phospholipids-based carriers, micelles, polymeric nanoparticles based on poly(lactide-coglycolide) (PLGA), polybutylcyanoacrylate, poly(isohexyl cyanoacrylate), poly(amine-co-ester), chitosan nanoparticles (Chaudhuri and Straubinger 2019; van Rijt et al. 2014), cellulose nanocrystals systems (Mohanta et al. 2019), viral vectors (Gomes et al. 2017), self-assemble proteins (Colton et al. 2014), carbon nanotubes (Kaur et al. 2019), dendrimers (Hudson 2001), core–shell and metallic NPs (Wu et al. 2008), Fig. 1. However, for nanomaterial-based therapeutics, liposomes have been the most successful formulation for clinical application to date (Gonda et al. 2019), and the sterically stabilized liposomal formulations currently dominate the clinical landscape with FDA-approved products (Chaudhuri and Straubinger 2019). The success of liposomes in clinics is based on their versatility and their characteristics, such as their structural similarity to mammalian cell membranes and their capability to encapsulate either hydrophobic or hydrophilic drugs (Gonda et al. 2019), among the other features described above.

Fig. 1
figure1

Nanoparticles commonly used as drug delivery systems. a Liposomes: biomimetic structure, encapsulate hydrophobic and hydrophilic drugs. Schematic image done with Adobe® Photoshop® CS6. b Viral vector: schematic representation of viral adenovirus. From Gomes et al. (2017). c Self-assembled proteins: ribbon diagram representing the structure of the ferritin protein. From Colton et al. (2014). d Polymeric nanoparticle [image from van Rijt et al. (2014)]. e Metallic nanoparticle: magnetic and non-immunogenic sphere, rod or cage nanoparticles (schematic image done with Paint 3D®). f Single-walled carbon nanotube: efficient drug-loading capacity because of ultrahigh surface area. Diameter range from 0.4 to 2 nm for SWCN and 2–100 nm for MWCN. From Kaur et al. (2019). g Astruc’s 54-ferrocene dendrimer. From Hudson (2001). h Polystyrene-coated magnetic NPs with core/shell structure. Modified from Wu et al. (2008). i Micelle formulation as drug delivery system. Public domain

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In recent years, many clinical trials using liposome as a drug delivery system to treat several diseases have been published. This review discusses the emerging research and clinical developments in liposome therapeutics, as well an overview of the liposome characteristics and the distribution of liposomal clinical trials worldwide.

Liposomes: an overview

Liposomes are bilayer spherical vesicles composed by phospholipids and cholesterol that in water create at least one lipid bilayer surrounding an aqueous core, which may encapsulate both hydrophilic drugs (e.g., Doxil®, encapsulated doxorubicin in the aqueous core) and hydrophobic compounds (e.g., AmBisome®, trapped amphotericin B) immersed in the lamellae by Van der Waals forces (Senapati et al. 2018; Gonda et al. 2019; Gao et al. 2018), see Fig. 2.

Fig. 2
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Schematic structure of a stable antibody–liposome encapsulating hydrophobic and hydrophilic drugs. Hydrophilic drugs like doxorubicin can be encapsulated in the aqueous compartment. Hydrophobic drugs like amphotericin B, paclitaxel, and docetaxel, can be encapsulated in the non-polar compartment. Liposome size varies between 20 nm to several hundred microns. Pharmacokinetics depends directly of the size (schematic image done with Adobe® Photoshop® CS6)

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Phospholipids are amphiphilic lipids that consist of a glycerol molecule bound to a phosphate group (PO42−) and to two fatty acid chains that may be saturated or unsaturated (Pinot et al. 2014). The phosphate has also an ester bound with an organic molecule, e.g., choline or ethanolamine (Monteiro et al. 2014) (Fig. 3). Phospholipids are key components and provide specific characteristics to liposomes, i.e., the way of encapsulating the compounds and the functionalization into the organism (Hussain et al. 2017). Since phospholipids are the main biological cell membrane components, both liposomal and cell membranes can coexist during the release mechanism (Rothfield 1971).

Fig. 3
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a Chemical structure of hydrogenated soybean phosphatidylcholine (HSPC), a phospholipid used in Doxil®, the first approved liposomal nanoformulation. Brackets indicate the polar and non-polar portions of the phospholipid. b Scheme of the membrane permeability of liposomes with unsaturated phospholipids. Blue figures represent charged compounds while orange ones have no charge: the circles represent the polar head of phospholipids; bars, the fatty acid chains; hexagons, hydrophobic drugs; and triangles, the hydrophilic drugs (schematic image done with Adobe® Photoshop® CS6)

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As we seen, liposome properties are affected not only by its composition, but also by size, surface charge, number of lamellae, rigidity of the bilayer, surface modification and method of preparation (Olusanya et al. 2018). For instance, the ammonium sulfate method would render a high concentration of amphipathic drugs, such as doxorubicin, similar to the pH gradient method for vincristine (Senapati et al. 2018). Another important parameter for preparing self-aggregating amphiphiles such as surfactants, lipids and liposomes, is the critical micelle concentration (CMC), i.e., the relatively narrow concentration range over which amphiphile dispersions show an abrupt change in physical properties. At concentrations below the CMC, the phospholipids are in monomeric form; at the CMC, aggregation of the molecules produce micelles, and the physical properties of the dispersion show changes. The CMC values depend on intrinsic factors such as structure of the hydrophobic and hydrophilic parts of the amphiphile molecule and external factors such as medium temperature and composition (ionic strength, dielectric constant, pH) (Priev et al. 2002). For the purpose of this review, only the physicochemical parameters of phospholipids affecting liposomes characteristics will be discussed.

The transition temperature of phospholipids (TC) (the temperature at which phospholipids shift from gel to liquid crystalline phase), is one of the main parameters in the manufacture of liposomes (Zamani et al. 2018). TC depends on the length of the fatty acid chains, their degree of saturation, charge and head group species, as shown in Table 1 (Li et al. 2014; Hussain et al. 2017; Monteiro et al. 2014). TC determines the fluidity and permeability of the liposome bilayer. In fact, at temperatures lower than TC the phospholipids are in gel phase, which has low fluidity and low permeability. In contrast, at temperatures higher than TC, phospholipids are in liquid-crystalline phase, having greater fluidity and permeability but low permeability to certain particles. Also, as shown in Table 1, the longer the chain the higher the TC is. The TC decreases, the more double bonds. Thus, when compared at certain temperatures, bilayers with long and saturated hydrocarbon chains are more rigid and less permeable than bilayers with shorter and unsaturated chains (Monteiro et al. 2014; Lin and Gu 2014; Murthy et al. 2016; Kraft et al. 2014) (Fig. 2). The transition temperature and lipid composition influence the curvature of liposomes, i.e., a liposome whose diameter varies between 100 and 200 nm can be appreciated as a sphere whose curvature will be defined by a homogeneous surface perimeter. However, the surface of the liposome can actually present a ripple phase depending mainly on the lipid composition and temperature that are directly related to the aggregate state of the liposome. Therefore, the ripple phase can be considered as domains of ordered phases of liquid crystalline phase with the gel phase. Other compound that can also modify the ripple phase is cholesterol, which directly affects the fluidity of the liposome bilayer increasing fluidity in the core of the bilayer, but increasing viscosity close to phospholipid headgroups. Thus, cholesterol produces similar phases to liquid crystalline and gel phases, the so-called disordered and ordered phases. Further studies on membrane fluidity of the liposomal dosage forms and their impact on drug delivery may improve formulations and their efficacy. Therefore, the phase transition behavior of the lipid bilayers has been exploited to improve liposome aggregation, curvature of membrane (ripple phase), lipid transfer and drug release. Proper lipid compositions preserve the bilayer structure, as well as physical properties at body temperature (37 °C), which are key considerations for liposome design (Rühling et al. 2017; Vallejo et al. 2007).

Table 1 Phospholipids characteristics
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Modifications of polar and non-polar regions of natural phospholipids have allowed researchers to create a wide variety of synthetic phospholipids, which have proved to be more stable (Monteiro et al. 2014; Agassandian and Mallampalli 2013). The surface charge in liposomes depends on the phospholipid headgroup, and it can be negative, neutral or positive. This may alter liposome stability, pharmacokinetics, biodistribution and cellular uptake, see Table 1. Negatively charged phospholipids, such as DMPG or DOPS, are recognized by macrophages and enter the cell via endocytosis at a faster rate than neutral phospholipids, like HSPC and DOPE, resulting in a shorter circulation time. A small negative charge may stabilize neutral liposomes increasing the electrostatic repulsive forces, affecting the aggregation-dependent phagocytic uptake mechanism (Olusanya et al. 2018; Kraft et al. 2014). On the other hand, cationic liposomes interact with plasma proteins enhancing the uptake by the phagocytic system that promotes clearance by the lung, liver or spleen. Moreover, uptake of liposomes with a positive charge appears to be much higher than negative liposomes. Thus, negatively charged lipid liposomes are common to most FDA-approved liposome formulations (Bourquin et al. 2018; Zamani et al. 2018; Kraft et al. 2014; Merino et al. 2018).

Liposomes have a diameter ranging from 20 nm to more than several hundred micrometers, as shown in Table 2. Particle size affects their pharmacokinetics, tissue extravasation, tissue diffusion, hepatic uptake, kidney excretion, and clearance rate from the site of injection (Zamani et al. 2018; Gao et al. 2018; Olusanya et al. 2018; Kraft et al. 2014). Only liposomes of a mean diameter between 100 and 150 nm are able to enter fenestrated vessels in the liver endothelium, secondary lymphoid structures, or tumor microenvironments (Bourquin et al. 2018; Gao et al. 2018; Kraft et al. 2014). Only liposomes with such a diameter can easily escape from blood vessel capillaries that perfuse tissues, such as lung, heart, and kidney. On the other hand, particles less than 10 nm undergo renal filtration through the glomerular capillary wall and are not reabsorbed (Gao et al. 2018; Kraft et al. 2014; Merino et al. 2018). Furthermore, cell uptake is most relevant to liposomes of 100–150 nm diameter. The immune system phagocytosis is also important, since reduction of liposome diameter to 50 nm or below greatly reduces phagocytosis clearance (Kraft et al. 2014; Merino et al. 2018). Thus, liposomes within 50–100 nm, such as DaunoXome, avoid phagocytosis and have long blood circulation time (Olusanya et al. 2018; Kraft et al. 2014). Therefore, the optimal range-size is between 80 and 150 nm (Olusanya et al. 2018; Kraft et al. 2014; Merino et al. 2018; Riaz et al. 2018). It has been demonstrated that larger liposomes can persist longer in the injection site (Bourquin et al. 2018), such as Exparel® and DepoDur™, which are used for pain control.

Table 2 Liposomal formulation present in clinical trials
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Cholesterol has an important role in the preparation and chemical properties of liposomes. This molecule accommodates itself along with the phospholipid chain, with its hydroxyl group close to the hydrophilic region and its aromatic rings parallel to the fatty acid chain within the bilayer (Fig. 1) due to hydrophobic interactions. Fluidity and water permeability decrease because of the increase in mechanical rigidity caused by the dense rings (Yingchoncharoen et al. 2016; Monteiro et al. 2014; Sinatra et al. 2014). Various clinically approved liposomal formulations incorporating cholesterol are already in the market (Table 2). Cholesterol acts as a cell membrane stabilizer: in its absence, liposomes often interact with proteins, including albumin, transferrin, macroglobulin and high-density lipoproteins. Such interaction destabilizes the structure of the liposomes and consequently decreases their capacity as drug delivery systems (Yingchoncharoen et al. 2016; Maranhão et al. 2017; Lu et al. 2013). Cholesterol is also crucial for the structural stability of liposome membranes against intestinal environment stress (Olusanya et al. 2018; Kraft et al. 2014).

Although their biocompatibility, biodegradability, and ability to encapsulate hydrophilic, hydrophobic, and amphiphilic compounds are important advantages, one of the major drawbacks of conventional liposomes is their rapid clearance from the bloodstream (Senapati et al. 2018; Gangadaran et al. 2018), which shortens the blood circulation time. To overcome this drawback, several approaches have been used. Small fractions of hydrophilic polymers, such as polyethylene glycol (PEG), are used as surface coatings in order to extend blood circulation half-life from few minutes (conventional liposomes) to several hours (stealth liposomes). In fact, PEGylated liposomes with a mean 100–150 nm diameter reduce the interaction of liposomes with plasma proteins such as opsonins (Yingchoncharoen et al. 2016; Senapati et al. 2018; Bourquin et al. 2018; Kraft et al. 2014; Lamichhane et al. 2018). Thus, PEG prevents liposome opsonization and consumption by the reticuloendothelial system (RES) since it entangles 2–3 molecules of water per oxyethylene unit, which may increase 5–10 times the apparent molecular weight. This improves solubility and decreases the aggregation and the immunogenicity of the drug, leading to 10 times longer circulation time and an increase of liposome accumulation in damaged tissues (Yingchoncharoen et al. 2016; Maranhão et al. 2017; Li et al. 2013). This PEG-technology has been successfully proven in Doxil® (Bulbake et al. 2017) and there are various clinically approved stealth and non-stealth liposomal formulations with or without cholesterol in the market (Table 2), as compared in the following section.

In summary, the properties of the membrane and general structure of liposomes depend on (a) the nature of the lipid, either natural or synthetic; (b) the phospholipid polar headgroup and its charge; (c) the length and degree of unsaturation of the fatty acids; (d) the TC, the temperature before and after the liposome synthesis, and (e) the addition of other compounds to the membrane or surface of the liposome such as cholesterol, PEG, proteins, ligands and/or antibodies (Bozzuto and Molinari 2015; Maranhão et al. 2017; Sercombe et al. 2015). The manipulation and design of all the factors mentioned above make liposomes versatile and capable of a wide range of functions. This has made liposomes one the most explored and used release system to address different functions and specific purposes for the treatment of cancer and other diseases (Yingchoncharoen et al. 2016; Maranhão et al. 2017; Monteiro et al. 2014; Meng et al. 2016; Rose et al. 2014). Currently, there is a wide variety of liposome formulations that are in preclinical and clinical trials, while some others are already being used as approved therapies, as will be discussed in the next section.

Clinical trials: efficacy and toxicity

A literature search regarding clinical studies was carried out in PubMed during April and May 2018 using the search term “liposome”. The sort function and the filters were used to show only the most recent clinical trials in the PubMed search.

The inclusion criteria were:

  • The study must be a phase I, II or III clinical trial.

  • The study must report either the side effects or the efficacy of the liposomal formulation.

  • The article publishing date must be after 2013.

Pain management: bupivacaine

Liposomal bupivacaine (Exparel®, Pacira Pharmaceuticals, San Diego, CA) was approved for local surgical site injection for postoperative pain after haemorrhoidectomy and bunionectomy by the US FDA in 2011 (Yeung et al. 2018). Each liposomal bupivacaine particle (DepoFoam®, Pacira Pharmaceuticals, Parsippany, NJ) is composed of a honeycomb-like structure of internal aqueous chambers containing encapsulated bupivacaine (Mazloomdoost et al. 2017). A single dose (266 mg) of encapsulated bupivacaine amide-based local anesthetic is injected directly into the surgical site. A slow-release mechanism involving reorganization of the barrier lipid membranes is sustained for up to 92 h with concomitant pain control for up to 72 h, as compared to 7–12 h with standard bupivacaine. Studies show bupivacaine decreased pain compared to placebo, the use of opioids and the hospital costs (Yeung et al. 2018; Mazloomdoost et al. 2017; Sabesan et al. 2017; Declaire et al. 2017; Smith et al. 2017; Mcgraw-tatum et al. 2017; Abildgaard et al. 2017; Alijanipour et al. 2016; Davidovitch et al. 2017). Although the liposomal bupivacaine is not a nanoparticle (3–30 μm mean diameter), it is mentioned here because it is one of the most recent liposomal formulations approved. Characteristics and efficacy of the last 13 clinical studies with liposomal bupivacaine (LB) for pain management are summarized in Table 3. In 2017, Rice et al. (2017) published the pharmacokinetic and safety profiles of LB. When administered in two doses (266 mg each) immediately, 24, 48, 72 h after the first one, the mean maximum concentration (Cmax) of bupivacaine in plasma was higher than with only one dose, but did not reach the double of the Cmax from a single dose. The highest Cmax was observed in an individual taking the second dose 24 h after the first, but was below toxic levels for central nervous system and cardiac. In general, LB was well tolerated and revealed no clinically relevant unsafety signs (Rice et al. 2017), provided excellent pain scores, lower opioids consumption, and at a lower cost (Mazloomdoost et al. 2017; Sabesan et al. 2017; Mcgraw-tatum et al. 2017; Davidovitch et al. 2017; Johnson et al. 2017; Barron et al. 2016). Thus, liposome formulation of the anesthetic rendered longer therapeutic times with no adverse effects.

Table 3 Evaluation of liposomal bupivacaine (LB) effect on pain scores and narcotic consumption
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Cancer treatment

In this section, the most recent clinical studies using different liposomal drugs for the treatment of various solid cancers are described. The meaning of the endpoints in the clinical trials described here go as follows: complete response (CR): disappearance of all clinical evidences of disease or all target lesions; partial response (PR), at least 30% reduction in size of the target lesions; stable disease (SD), a 30% reduction or less than 25% increase in the size of all detectable disease; objective response rate (ORR) refers to the percentage of patients with partial or complete response to therapy (tumor reduction); “effects” refers to those effects that are attributable directly to the drug and not the natural history of the disease; progression-free survival (PFS) means the time between treatment assignments and disease progression or death, not affected by crossover or subsequent therapies and generally based on objective and quantitative assessment; events-free survival (EFS): time from treatment assignments to disease progression, death, or discontinuation of treatment for any reason (e.g., toxicity, patient preference, or initiation of a new treatment without documented progression); overall survival (OS): time from treatment assignments to patient death, irrespective of cause. Patients who are alive or missed to follow-up at the cut-off date are excluded (Fiteni et al. 2014; Villaruz and Socinski 2013; Roever 2016). Table 4 describes the phases of a clinical trial.

Table 4 Description of clinical trial phases
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Doxorubicin and daunorubicin

Doxil® is the first drug delivery system based on PEGylated liposome technology. It consists of encapsulated doxorubicin hydrochloride, an anticancer drug of the anthracycline family that induces caspase-dependent apoptosis in cancer cells through oxidative DNA damage by blocking topoisomerase IIα, an enzyme needed by cancer cells to divide and grow (Table 5). This enzyme also generates free radicals (reactive oxygen species) that can lead to lipid peroxidation and membrane impairment (Yingchoncharoen et al. 2016; Medina-Alarcón et al. 2017; Bozzuto and Molinari 2015; Lombardo et al. 2016). The composition of different liposomal doxorubicin formulations (Doxil, LipoDox, Myocet, Thermodox, and Caelix), as well as their therapeutic indications and other relevant characteristics are presented in Table 2. Characteristics and efficacy of the reviewed studies with liposomal doxorubicin therapy are presented in Table 6. The major toxicities are presented in Table 7.

Table 5 Efficacy of recent clinical trials with liposomal doxorubicin in mono and combination therapy
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Table 6 Toxicity of the clinical trials with doxorubicin
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Table 7 Efficacy of recent clinical trials with liposomal daunorubicin in mono or combined therapy
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The major drawback of non-liposomal or conventional anthracyclines, such as doxorubicin and daunorubicin, is their related cardiotoxicity (Kaspers et al. 2013; Thorn et al. 2011). This is because cardiac muscle is enriched with mitochondria, which contains a high level of anionic diphosphatidylglycerol (cardiolipin) that interacts strongly with positively charged doxorubicin, and can lead to lipid peroxidation within cardiac tissue (Yingchoncharoen et al. 2016; Chang and Yeh 2012). Therefore, encapsulated doxorubicin in liposomes (PLD) was developed to overcome the challenges associated with the use of free doxorubicin (Miller et al. 2016; Chang et al. 2018; Coltelli et al. 2017; Rocca et al. 2017; Zhao et al. 2017; Luminari et al. 2017; Fridrik et al. 2016). In addition, PLD showed a reduced cardiac toxicity compared to non-liposomal doxorubicin. Few cardiac events were found in most of the clinical trials described in Table 5 (Coltelli et al. 2017; Rocca et al. 2017; Luminari et al. 2017; Fridrik et al. 2016; Tampaki et al. 2018).

As previously described, PEGylation may extend the blood circulation time of liposomes and improve accumulation in tumor tissues, hence reducing related adverse effects (e.g., cardiotoxicity). However, PLD causes specific side effects, such as hand–foot syndrome (HFS), hypersensitivity reaction, stomatitis and mucositis (Bozzuto and Molinari 2015; Chang and Yeh 2012; Zhao et al. 2017; Casadei et al. 2018; Jung et al. 2017; Bun et al. 2018). PLDs are small enough to pass through the vasculature in both tumor and healthy organs, including the skin (Bun et al. 2018). Thus, PLDs are secreted in sweat after intravenous infusion. This causes an oxidant/antioxidant imbalance in the skin, since doxorubicin and the Cu(II) ions that are abundant in skin tissue generate reactive oxygen species, leading to HFS lesions (Jung et al. 2017; Bun et al. 2018). As Table 7 shows, only > 3rd grade stomatitis/mucositis and HFS appeared in the PLD studies, but not in the three studies that used Myocet®, a non-PEGylated version of liposomal doxorubicin formulation (NPLD). In addition, Volgger et al. in 2015 reported no > 3rd grade stomatitis/mucositis, HFS, or cardiac toxicity in a phase II trial (n = 39) with NPLD conducted by AGO (Volgger et al. 2015). Also, Baselga et al. reported that 9% of NPLD-treated patients showed > 3 grade stomatitis and a higher heart safety in a phase III clinical trial (n = 179) than with doxorubicin (Pharmachemie B.V.) (Baselga et al. 2014). Nevertheless, NPLD exhibits a short half-life compared to PLD, leading to use higher NPLD doses than PLD (50–70 mg/m2 Q3W, Table 6) (Zhao et al. 2017).

Other liposomal formulations with doxorubicin designed to be more tolerable and more effective than free doxorubicin have been developed, such as MM-302 and ThermoDox®. The MM-302 formulation is a HER2-targeted antibody–liposomal doxorubicin conjugate that specifically targets HER2 overexpressing cells, increasing the delivery of doxorubicin to tumor cells and limiting exposure to healthy cells, such as cardiomyocytes. Lipid compositions are shown in Table 2. In 2016, Miller et al. (2016) used the MM-302 formulation plus trastuzumab (30 mg/m2 + 14 mg/kg IV Q3W, respectively) in a phase II trial in patients with HER2-positive locally advanced/metastatic breast cancer. ThermoDox® is a specially formulated and long-circulating lyso-thermosensitive liposomal doxorubicin that has been used clinically combined with radiofrequency ablation (RFA) to remove the core of the tumor. In a phase I trial, (Oxford.) Lyon et al. (2017) explored the safety and feasibility of using an extracorporeal ultrasound-guided focus ultrasound (FU), a non-invasive clinical treatment modality, to induce highly localized hyperthermia in liver tumors in order to trigger the release of doxorubicin and enhance the delivery of systemically circulating ThermoDox® (50 mg/m2). No results have been reported in the study.

DaunoXome® was the first liposomal daunorubicin formulation developed by NeXstar Pharmaceuticals in 1996 for the management of HIV-associated Kaposi’s sarcoma (Table 2). Because of their small size (45–80 nm), the reticulo-endothelial system (RES) uptake of DaunoXome is diminished, leading to extensive drug circulation. DaunoXome has a half-life of between 4 and 5.6 h, longer than that of free daunorubicin ≈ 0.77 h (Bulbake et al. 2017). Moreover, as described previously, liposomally entrapped anthracyclines cause less cardiotoxicity than conventional anthracyclines, such as doxorubicin and daunorubicin (Kaspers et al. 2013; Thorn et al. 2011). CPX-351 is also a liposomal daunorubicin formulation encapsulating cytarabine at a 5:1 molar ratio within 100-nm-diameter liposomes, which was found to be maximally synergistic and minimally antagonistic. Each unit of CPX-351 is composed of 0.1 mg of cytarabine and 0.44 mg of daunorubicin. It also increases the plasma’s half-life and leads to drug accumulation within the bone marrow (Gergis et al. 2013; Cortes et al. 2015; Lancet et al. 2014).

In a PubMed search covering 2013–2018, only six clinical studies using liposomal daunorubicin were found. The studies’ characteristics and toxicity indexes are, respectively, shown in Tables 7 and 8. The study by Creutzig et al. (2013), using liposomal daunorubicin, achieved the larger percentage of patients with a complete response (89%), followed by the study of Gergis et al. (2013), which uses CPX-351 (72.2%) (Cortes et al. 2015), which uses CPX-351 (72.2%) (Gergis et al. 2013). The two studies showed low toxicity levels, as same as the study by Kaspers et al. (2013), as shown in Table 9. However, thanks to a phase III study that demonstrated better overall survival rate (Kraft et al. 2014), FDA recently approved the liposomal combination of daunorubicin and cytarabine, CPX-351 (Vyxeos™), for the treatment of acute myeloid leukemia (AML), as shown in Table 8. In general, liposomal daunorubicin proved to be effective with a low cardiac toxicity profile in an increased anthracycline dose in older patients, children, and adolescents (Gergis et al. 2013; Lancet et al. 2014; Kaspers et al. 2013; Creutzig et al. 2013).

Table 8 Toxicity of the clinical trials with daunorubicin
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Table 9 Efficacy of recent clinical trials with liposomal paclitaxel in mono or combined therapy
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Irinotecan

Irinotecan, also known as CPT-11, is a water-soluble semi-synthetic analogue of the natural alkaloid camptothecin. It prevents DNA from unwinding and replicating by inhibition of topoisomerase-I. It is used as antineoplastic agent to treat various types of cancers, diarrhea, and myelosuppression. Onivyde® (nal-IRI) is a nanoliposomal hydrochloride irinotecan formulation approved by the FDA in the US and the European Medicines Agency for the treatment of metastatic pancreatic adenocarcinoma (mPAC) in combination with 5-FU/LV, a fluoropyrimidine-based agent, in patients previously treated with gemcitabine-based therapy (Pelzer et al. 2017; Clarke et al. 2017; Wang-gillam et al. 2016; Chiang et al. 2016). In 2017, Clarke et al. (2017) published a phase I trial of nal-IRI in patients with recurrent high-grade glioma to assess the safety and pharmacokinetics (PKs) of nal-IRI and to determine the maximum tolerated dose (MTD). Patients homozygous WT for UGT1A1 (a genotype reported as toxicity predictor when heterozygous) were initially dosed at 120 mg/m2 IV Q3W and with 60 mg/m2 dose increments, while heterozygous (WT/*28 UGT1A1) patients were started at 60 mg/m2 with dose increments of 30 mg/m2. In the WT cohort (n = 16), the MTD was 120 mg/m2; in the HT cohort (n = 18), the MTD was 150 mg/m2. Nal-IRI had no unexpected toxicities. PFS-6 was 2.9%, median PFS was 42 days and median OS was 107 days. The terminal half-life for nal-IRI did not change with dosage. In 2016, Chiang et al. (2016) (PharmaEngine, Inc.) published a phase I dose escalation study of nal-IRI in patients with advanced solid tumors. In this study, the dose-limiting toxicity (DLT), MTD and PKs were investigated. Three individuals were dosed with 60 mg/m2, six with 80 mg/m2, five with 100 mg/m2, and two with 120 mg/m2 on day 1, followed by 5-FU 2000 mg/m2 and LV 200 mg/m2 on days 1 and 8 IV Q3W. Four patients showed DLT: two at the 100 mg/m2 dosage level, and two at the 120 mg/m2. The MTD was 80 mg/m2, which, after the study, has been the recommended dosage. The most common observed adverse effects were nausea (81%), diarrhea (75%), and vomiting (69%). Only four individuals had stable disease, one showed partial response, and the other, a progressive disease. The irinotecan liposome injection increased the bioavailability. Maximum plasma concentration decrease and half-life increased. The area under the plasma concentration–time curve from zero to infinity of SN-38 (the active metabolite of irinotecan) was higher than irinotecan itself at a similar dosage level. Thus, liposomal dosage form improved pharmacokinetic parameters of the chemotherapeutic drug, without adding more adverse effects than the drug itself.

The US FDA approved nal-IRI + 5-FU/LV based on results from the NAPOLI-1 clinical trial (Pelzer et al. 2017). This phase III trial of Wang-Gillam et al. (2016) (Merrimack Pharmaceuticals) was published in 2016 and demonstrated that the combination of nal-IRI + 5-FU/LV (80 mg/m2 + 2400 mg/m2 + 400 mg/m2, respectively) improved median overall survival (6.1 vs. 4.2 months) and median progression-free survival (3.1 vs. 1.5 months) compared with 5-FU/LV therapy alone in metastatic pancreatic cancer after previous gemcitabine-based therapy. The grade 3 or 4 adverse events that most frequently occurred in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). It can be concluded that nanoliposomal irinotecan, in combination with 5-FU/LV, extends survival rates with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma.

Paclitaxel and docetaxel

Paclitaxel inhibits tumor endothelial cells growth, through combination with beta microtubules (Qu et al. 2017; Xu et al. 2013; Slingerland et al. 2017). Because of the paclitaxel’s (PTX) insolubility in water, polyethoxylated castor oil (Cremophor EL) and dehydrated ethanol in a 1:1 (v/v) ratio are used as formulation vehicles, although it has toxic effects, such as hypersensitivity reactions, hyperlipidemia and neurotoxicity (Bulbake et al. 2017; Xu et al. 2013; Slingerland et al. 2017; Ahn et al. 2014; Graziani et al. 2017; Strieth et al. 2013). To avoid these drawbacks, many Cremophor-free liposomal paclitaxel (LPTX) formulations have been approved by FDA, such as (1) LEP-ETU, a conventional cationic nanosome with a size of about 150 nm (Slingerland et al. 2017); (2) EndoTAG™-1, a cationic liposome formulation of lipid-embedded paclitaxel, which interacts with negatively charged tumor endothelial cells lessening their tumor blood supply (Strieth et al. 2013; Awada et al. 2014; Haas et al. 2012; Ignatiadis et al. 2016); and (3) Lipusu® (Sike Pharmaceutical Co. Ltd., Nanjing, Jiangsu, P.R. China), a formulation approved in China prepared by using film dispersion methods followed by a lyophilization technique (Xu et al. 2013; Slingerland et al. 2017; Ahn et al. 2014; Graziani et al. 2017; Strieth et al. 2013; Awada et al. 2014; Haas et al. 2012; Ignatiadis et al. 2016; Ye et al. 2013). Even Cremophor-free liposome-like formulations, such as Genexol-PM, a polymeric micelle formulation of paclitaxel (Samyang Co., Seoul Korea) (Ahn et al. 2014), and PTX–LDE, a lipid core nanoparticle with encapsulated paclitaxel that binds to low-density lipoprotein receptors of cancer cells and concentrates in the tumor tissues (Graziani et al. 2017). Compositions of liposomal and non-liposomal formulations are shown in Table 2.

Table 10 shows the characteristics of the most recent liposomal PTX formulation, which include clinical trials, liposomal formulation, number of patients, dosage, and treatment efficacy. In Table 11, a toxicity map is provided. As shown in the non-small-cell lung carcinoma (NSCLC) treatment, the study of Lu et al. (2015) had the highest endpoint outputs (ORR 81%, PFS 16.5 months, OS 23.2 months), while the study of Wang and Zhang (2014) had the lowest (ORR 44%, PFS 6 months). This may be caused by the addition of gemcitabine. Ahn’s et al. study also combined gemcitabine with paclitaxel encapsulated within a non-liposomal formulation (polymeric micelle). The results were similar to those of Wang et al. (2014) and Hu et al. (2013) used L-PTX plus cis-platin for the treatment of NSCLC but did not report any results. The study of Lu et al. was the most effective in the treatment of NSCLC, but it also showed the highest toxicity levels, as shown in Table 11.

Table 10 Toxicity of the clinical trials to paclitaxel
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Table 11 Characteristics of recent clinical trials with liposomal amphotericin B in mono or combined therapy
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Docetaxel is a semi-synthetic taxane analogue and an antimitotic agent which binds itself to the beta subunit of tubulin and causes stabilization of tubulin polymerization. This stabilization results in a microtubule disrupting and cell cycle arrests at the G2/M phase, thus inhibiting mitosis. It is poorly soluble in water, and is commonly used in the treatment of a variety of solid tumors (Mahalingam et al. 2014; Deeken et al. 2013). Due to its insolubility, the currently marketed docetaxel (Taxotere) is formulated in Tween 80 and ethanol. However, this compound has been implicated in infusion-related toxicity, acute hypersensitivity reactions, as well as cumulative fluid retention. To avoid such undesirable side effects, several Tween 80-free and ethanol delivery systems have been developed and clinically tested, such as nanosomes, polymeric micelles, protein, and nanospheres (Deeken et al. 2013; Ahmad et al. 2014). For instance, in the phase I clinical trial of Mahalingam et al. (2014) (University of Texas Health Science Center), 15–110 mg/m2 of ATI-1123, a liposomal formulation of docetaxel that uses protein-stabilized nanoparticles encapsulating docetaxel in the liposome, was administered Q3W to 29 adult patients with advanced solid tumors (lung, pancreas, prostate, cervix, and ovarian). The partial response and stable disease percentages were 3% and 75%, respectively. The grade > 3 toxicities were as follows: 65% neutropenia, 28% anemia, 7% nausea, 7% vomiting, 3% asthenia, 14% fatigue, and 10% febrile neutropenia. Ahmad et al. (2014) administered 75 mg/m2 of a nanosomal docetaxel lipid suspension in 49 patients with metastatic breast cancer where no > 3 grade toxicities were reported. The complete and partial responses were 4.2% and 31.3%, respectively. Deeken et al. (2013) used a liposomal docetaxel formulation with a mean diameter of 100 nm composed by DOPC, cholesterol, cardiolipin, and alpha-tocopheryl acid succinate to 24 patients (50–132 mg/m2 IV Q3W) with advanced solid tumors. The partial response and stable disease percentages were 8% and 33%, respectively. Only a 38% of > 3 grade neutropenia was reported. In conclusion, liposomal docetaxel shows an acceptable tolerance, improves clinical efficacy without any premedication and thus, a beneficial treatment for solid tumors (Mahalingam et al. 2014; Deeken et al. 2013; Ahmad et al. 2014).

Other liposomal formulations for cancer treatment

Mepact® is a liposomal mifamurtide formulation (liposomal muramyl tripeptide phosphatidylethanolamine) approved by European Union, Switzerland, and other countries for the treatment of osteosarcoma (Venkatakrishnan et al. 2013). In the PubMed search for publications on the subject carried out, no recent results were found. In 2014, Venkatakrishnan et al. (2013) published an evaluation of the pharmacokinetics and pharmacodynamics after a single dose of Mepact® (4 mg IV) in adult subjects with hepatic impairment in comparison with healthy subjects. In 2009, Chou et al. (2009) (IDM Pharma) published a phase III trial (n = 91) of liposomal mifamurtide addition to chemotherapy (cis-platin, doxorubicin, methotrexate and ifosfamide) for patients with osteosarcoma. The 5-year event-free survival rate for patients who received liposomal mifamurtide (n = 46) was 42% vs. the 26% of those who did not (n = 45). The 5-year overall survival rate for patients who received Mepact compared to those who did not received Mepact was 53% and 40%, respectively. Moreover, data suggest that liposomal mifamurtide might provide a benefit when added to chemotherapy for the treatment of osteosarcoma.

Vincristine sulfate, a semi-synthetic chemotherapeutic agent, has been encapsulated in sphingomyelin/cholesterol nanoliposomes to overcome the dosing, pharmacokinetic, and pharmacodynamic limitations of non-liposomal vincristine. This vincristine injection dosage form (VSLI, Marqibo®) has been approved by FDA, since it has proved to be safe. It also showed tolerability, enhanced vincristine cell uptake, penetration and concentration in tissues and organs with fenestrated vasculature or involved in the mononuclear phagocyte system, including non-Hodgkin lymphomas. It did not show toxic effects, but high ORR. Thus, it provides encouraging PFS and OS when substituted for standard vincristine in polytherapy (Shah et al. 2016; Kaplan et al. 2014; Hagemeister et al. 2013). In a phase I study carried out in 2016 with 21 patients suffering of refractory solid tumors or leukemias, no subjects experienced dose-limiting toxicity (DLT) at the first dosage level (1.75 mg/m2/dose). Even though, at 2.25 mg/m2, one subject had transient dose-limiting grade 4 transaminase elevation, no additional DLT was observed when the dose level was increased. A stable disease was observed in nine patients, although in one subject with leukemia, a minimal residual disease and a negative complete remission was observed. Children were able to tolerate adult dosages (2.25 mg/m2/dose of weekly VSLI) with no evidence of neurotoxicity (Shah et al. 2016). In a phase II study of Marqibo and rituximab (Therapeutics Inc.), the ORR was 59%: 27% of complete response, and 32% of partial response in 22 patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). Median response duration was 147 days, TTP was 121 days, and overall survival was 322 days. Nevertheless, patients reported adverse effects like Grade 3 peripheral neuropathy, febrile neutropenia, and constipation. Thus, VSLI + rituximab provokes a durable response in those lymphomas. Adverse effects were manageable (Kaplan et al. 2014). In a phase II study, 72 patients with untreated and aggressive non-Hodgkin lymphomas, including 60 with DLBCL, were treated with Marqibo® plus cyclophosphamide, doxorubicin, and prednisone (2 mg/m2 + 750 mg/m2 + 50 mg/m2 IV + 100 mg PO Q3W, respectively), with or without rituximab (375 mg/m2 IV Q3W). Of them, 96% showed complete response and 3% were unconfirmed. The 5-year and 10-year PFS and OS were 75% and 63%; and 87% and 77%, respectively. Although exposure was up to 35 mg, this multidrug treatment (Marqibo plus cyclophosphamide, doxorubicin, and prednisone ± rituximab) was as safe as the same therapy with non-liposomal vincristine. As for the adverse effects, grade 3 peripheral neuropathy was reported in 3% of the patients and there was no reported Grade 3/4 constipation. All this demonstrates that the encapsulation does not alter the safety properties of the drug. Moreover, Marqibo was well tolerated and showed a higher activity, probably due to the pharmacokinetic optimization and the enhanced delivery (Hagemeister et al. 2013).

Liposomal cytarabine (Depocyt®) is a slow-release dosage form of cytarabine that results in cytotoxic cytarabine concentrations in the cerebrospinal fluid for at least 1 week, while non-liposomal cytarabine is maintained for only 24 h (Levinsen et al. 2016; Ferreri et al. 2015; Peyrl et al. 2014). In 2016, Levinsen et al. (2016) published a phase II trial (n = 40) that investigated the efficacy and toxicity of intrathecal liposomal cytarabine in comparison with conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. Depocyt® showed acceptable toxicity when administered as first-line therapy with concomitant use of dexamethasone, which suggests that it could play a future role in improving outcomes in children with acute lymphoblastic leukemia. Peyrl et al. (2014) studied the pharmacokinetics and toxicity of intrathecal liposomal cytarabine in sixteen children and adolescents with malignant brain tumors. In general, liposomal cytarabine was well tolerated, with relevant but manageable toxicities that showed sufficient drug exposure for at least 1 week (Peyrl et al. 2014).

Molecular therapy

Patisiran (ONPATTRO®) is a siRNA-delivering liposome developed and marketed by Alnylam, for the silencing of a specific gene responsible for expression of transthyretin (TTR), which can cause hereditary transthyretin amyloidosis (Anselmo and Mitragotri 2019). The composition of this liposomal formulation is in Table 2. Actually, ONPATTRO is the newest approved liposomal formulation here described. It is also the first clinically approved example of an RNAi therapy-delivering nanoparticle administered intravenously, and it is actually the first therapeutic RNAi approved by the FDA as well, independent of the nanoparticle delivery vehicle (Anselmo and Mitragotri 2019; Adams et al. 2018), which was the major milestone in the biotech and nanomedicine industry (Anselmo and Mitragotri 2019). RNA interference is a cellular process that controls gene expressions, in which small interfering RNAs (siRNAs) mediate the cleavage of specific messenger RNAs (mRNAs). Patisiran comprises a TTR mRNA-specific siRNA formulated (Anselmo and Mitragotri 2019; Adams et al. 2018; Suhr et al. 2015). Clinical data have shown a potent and sustained knockdown of TTR expression and, while there have been side effects, there has been little evidence of safety concerns about platelets, renal function or liver enzyme elevations. The results were published in July 2018 (Adams et al. 2018) and found that the drug reduced TTR production by about 81%. The following month, patisiran was approved by both the US Food and Drug Administration and the European Medicines Agency (EMA). The efficacy was shown in a clinical trial involving 225 patients, 148 received an patisiran infusion once every 3 weeks for 18 months, The patients who received the RNA had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions (Minamisawa et al. 2019), additional investigation suggests that patisiran may stop or possibly reverse the progression of hATTR (Solomon et al. 2019).

MRX34 mimics miR-34a, a miRNA suppressor of more than 30 oncogenes. It is the first-in-class drug. It is encapsulated in a liposomal nanoparticle with ≈ 110 nm diameter. The liposomal component contains amphiphilic lipids, which display a positive charge under acidic conditions, ensuring the efficient encapsulation of the negatively charged miR-34a mimic, and a negative charge in vivo at neutral pH to minimize aggregation and electrostatic adherence to the cell membrane of endothelial cells. miR-34a shows interesting pharmacological properties in mice and non-human primates: it has a long residence time in blood, inhibits growth of primary tumors, blocks metastasis, and extends survival (Beg et al. 2016; Li et al. 2013). In a phase I trial with 47 patients showing refractory advanced solid tumors, MRX34 dosage (escalating twice-weekly) showed evidence of antitumor activity. In 2016, a phase I clinical trial of miRNA cancer therapy was carried out, in these study, 47 patients were treated twice a week with escalating doses of MRX34 IV (BAYER®) (Davidovitch et al. 2017). MRX34 treatment with dexamethasone premedication was associated with acceptable safety indexes. Remarkably, it demonstrated that MRX34 has in vivo antitumor activity even in patients with refractory advanced solid tumors, including hepatocellular carcinoma (HCC). The MTD for non-HCC patients was 110 mg/m2. Two patients experienced DLT of grade 3 hypoxia and enteritis at 124 mg/m2. A patient with HCC achieved a prolonged confirmed partial response lasting 48 weeks, and four patients experienced stable disease for more than 4 cycles (Beg et al. 2016; Li et al. 2013).

In 2016, a phase I clinical trial was carried out with 20 patients with multiple sclerosis (MS) (Pharmsynthez OJSC). Treatment was performed with myelin basic protein, the structural component of the myelin membrane. It was coencapsulated in CD206-targeted small monolamellar mannosylated liposomes prepared from egg phosphatidylcholine and monomannosyl dioleoyl glycerol with α-tocopherol and lactose (Xemys; Pharmsynthez, St. Petersburg, Russia). Patients were dosed weekly with subcutaneous injections of Xemys at escalating doses of 50, 150, 225, 450 and 900 μg, over 6 weeks (2.675 mg). Dendritic cells uptake was significantly enhanced by mannosylation of liposomes. Administration of Xemys was safe and well tolerated in patients with MS. Mild-to-moderate severe adverse effects were observed mainly after submaximal and maximal doses. Although no concomitant medication was required, no abnormalities in blood or other safety problems were observed (Jr et al. 2016).

Other molecular treatments target the normal human p53 gene, which is a well-known tumor suppressor gene. Over 60% of cancers are related to the loss of p53 suppressor function. Up to 80% of cancer cases show p53 mutations. Moreover, cells lacking p53 are more resistant to chemotherapy. In contrast, p53 restoration enhances sensitivity to standard therapies. SGT-53 has been designed as an immunoliposome nanocomplex designed for systemic, tumor-targeting delivery. This nanodelivery system targets transferrin receptor (TFR), a highly expressed receptor on tumor cells, via a single-chain antibody fragment (termed as TFRscFv). The complex with the receptor is internalized into the tumor cells via endocytosis. In 2016, a trial with 14 patients with advanced cancer was administered with escalating doses of a combination of SGT-53 and docetaxel. The combination was well tolerated. Three of 12 patients showed partial responses with tumor reduction of 47%, 51% and 79%, while the others showed stable disease (Pirollo et al. 2016).

Fungal and bacterial infections

Amphotericin B

Invasive fungal infections (IFI) are considered opportunistic since they occur when the patient is predisposed to medical treatments (Sánchez et al. 2016) because of cancer, malignant hematological neoplasms (cryptococcosis), bone marrow transplants, or hematopoietic progenitors, immunosuppressive treatments (fusarosis), prolonged neutropenia, and immunodeficiencies in cells (zygomycosis or mucormycosis), as well as hepatic dysfunction (invasive candidiasis), injured mucous membranes (invasive aspergillosis), among others (Tacke et al. 2014).

Amphotericin B is used for the treatment of invasive fungal infections (Delattin et al. 2014) and acts by binding itself to sterols in the cell membrane of susceptible fungi, with a resulting change in membrane permeability. The first liposomal formulations were presented as AmBisome® from NeXstar Pharmaceuticals, Inc. (now Astellas Pharma, Inc.); lipid complexes such as Abelcet® from Enzon Pharmaceuticals (now Sigma Tau Pharmaceuticals, Inc. and Amphotec® from InterMune, Inc. (now Kadmon Pharmaceuticals, Inc.) (Table 2). Since the 1970s, more than 353 patents have been registered, some of which protect the formulation of liposomes under specific characteristics, e.g., liposomes and lipid complexes intercalating amphotericin B (Verma et al. 2005).

Table 11 shows the characteristics of recent studies using amphotericin B to treat fungal infections as described below. In the study of Cornely et al. (2017), the primary endpoint was the rate of proven/probable IFI: 7.9% to liposomal amphotericin B (AmBisome) group, and 11.7 to placebo group, suggesting that AmBisome is not as effective as prophylaxis against invasive fungal diseases (IFD) in these patients, which is difficult to explain since AmBisome is effective against IFD. The chosen dose to minimize toxicity represented a major limitation of the study. However, more patients in the AmBisome group than in the placebo group had adverse effects (AE). This resulted in the interruption of treatment with the drug (20.3% versus 7.6%). They also experienced serious AE considered to be related to the drug. Mortality was very similar in both groups (7.2% and 6.8%, respectively). The complete remission rate was 72.8%, which was lower than expected. The low efficacy of AmBisome was attributed to the patients’ baseline characteristics and the diagnostic strategy of IFI. Romero et al. (2017) evaluated the efficacy and safety of AmBisome and the combination of AmBisome + meglumine antimoniate (MA). The final analyses showed a CR at 6 months of 87.2% for AmBisome, 83.9% for AmBisome + MA, and 77.5% for MA alone. AmBisome monotherapy was safer than MA, as measured by the frequency of treatment-related adverse events, proportion of patients presenting at least one severe AE, and the proportion of AE resulting in definitive treatment discontinuation. In the study of Rahman et al. (2017), a 35-year-old female patient presented high-grade fever, rash, and swelling of arms and legs in the AmBisome + miltefosine (Milt) group. Treatment was interrupted and she was later diagnosed with rickettsial fever with concomitant nutritional edema. Approximately, 34% of AE were related to the treatment. The proportion of patients that experienced any treatment-related side effects was the highest in the AmBisome + Milt group, and the lowest in the AmBisome group (Table 12). None of the other non-fatal AE reported were related to the treatment. No drug-related deaths occurred either in the AmBisome group, or in the combination groups. In the intention-to-treat (ITT) population, the CR at month 6 was 98.1% for the AmBisome group, 99.4% to AmBisome + paromomycin, and 94.4% to AmBisome + Milt. Although not statistically significant, AmBisome + paromomycin was the most effective treatment. In the low-dosage study of Miyao et al. (2016), the most frequent events were electrolyte abnormalities, most of which involved hypokalemia (7.5% of grade 3 and 3.75% grade 4 cases). AE related with AmBisome that necessitated protocol discontinuation occurred in only one case that involved grade 4 glutamate pyruvate transaminase elevation. No patient deaths related to the treatment occurred during the study.

Table 12 Toxicity of the clinical trials to amphotericin B
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In a more recent study by Wasunna et al. (2016), the authors reported the percentage of patients cured in day 210 of the treatment as follows: 87% to the AmBisome + sodium stibogluconate (SSG) group, and 77% to the AmBisome + Milt group. There were two AE related to the studied drug. In the AmBisome + SSG group, severe anemia resulted in death at day 20 (the only death considered drug related), and in the AmBisome + Milt group, renal failure at day 3 was resolved. 73% and 78% of patients in the AmBisome + SSG and AmBisome + Milt had at least one adverse drug reaction. In the AmBisome + SSG and in the AmBisome + Milt groups, all non-serious drug-related events were categorized as mild to moderate. The only group that contained SSG (combined with AmBisome) showed low levels of cardiac disorders (< 5%), which were similar to those of the AmBisome + MF group. The authors concluded that a multiple daily dose of 3 mg/kg AmBisome may be more beneficial to eliminate fungi than a single 10 mg/kg dose at day 1, suggesting that a more frequent administration could result in a higher efficacy of AmBisome.

Amikacin

Pulmonary nontuberculous mycobacterial disease is a chronic infection with necrotizing inflammation, bronchiectasis, and cavitation with irreversible lung damage and increased mortality. To improve efficacy and reduce toxicity, a liposomal amikacin for inhalation (LAI) (Arikace®, ≈ 300 nm), composed of DPPC and cholesterol, has been developed. The liposomes are taken up by lung macrophages, allowing for intracellular delivery of high levels of amikacin into nontuberculous mycobacterial cells (Rose et al. 2014; Olivier et al. 2017). In 2018, Caimmi et al. (2018) reported the effect of LAI (590 mg daily) on five patients with Mycobacterium abscessus in cystic fibrosis. None of the five patients showed any side effects related to the treatment, while three patients showed improvement of their pulmonary function test values and their clinical symptoms. Moreover, LAI showed to be active against both P. aeruginosa and M. abscessus. In 2017, Olivier et al. (2017) (LAI NTM Study Group) reported the efficacy and safety of LAI (590 mg daily) in 44 patients (phase II study) with refractory pulmonary mycobacterial nontuberculous (Mycobacterium avium complex or Mycobacterium abscessus). A greater proportion of the LAI group demonstrated at least one negative sputum culture (32% vs. 9%), and improvement in a 6-min-walk test (+ 20.6 m vs. − 25.0 m) with limited systemic toxicity. In 2013, Clancy et al. (2013) published a phase II study of LAI (70, 140, 280, and 560 mg; n = 7, 5, 21, and 36) in cystic fibrosis patients chronically infected with P. aeruginosa. The adverse event profile was similar among Arikace and placebo subjects, but the lung function was higher in the 560 mg dose group. Also, the sputum P. aeruginosa density decreased in the 560 mg group against placebo.

Conclusions

Traditional pharmacological agents have to cross many barriers and hostile environments in the body that degrade them in the way, such as acidic stomach, intestinal wall barrier, liver, proteins, and enzymes in the bloodstream and the blood brain barrier to be able to reach the site where they are needed. Thus, they have to be ingested over and over again to be effective in the body. However, if ingestion exceeds certain doses, the therapeutic agent may become toxic and severely damage one or several organs in the body. Nanomedicine emerges as a potential solution to these problems, where liposomes are one of the most effective, healthy, and safe nanoparticle structures developed thus far. Liposomes can go through the body and function like a vehicle that can reach the specific tissue, organ or receptor of interest. This is achieved by adding molecules on the liposome surface that function like molecular “keys”. As described above, the therapeutically benefits of encapsulating anticancer drugs such as daunorubicin, doxorubicin and cytarabine in liposomes have been demonstrated. To achieve that, the liposome formulation should be carefully and properly designed. This may reduce the toxicity while maintaining or improving treatment efficacy. Physicochemical properties and surface composition of liposomes can be easily adjusted and highly personalized, thus dictating the biological destiny of liposomes for each individual or disease. Although this is not a simple task, it may represent a turning point in the application of nano-membrane technology in personalized cancer therapy and other diseases.

Availability of data and materials

Not applicable.

Abbreviations

A:

anemia

Abelcet® :

amphotericin B

AC:

advance cancer

AE:

adverse effects

AGC:

atypical glandular cells

AmBisome® :

amphotericin B

AML:

acute myeloid leukemia

Amphotec® :

amphotericin B

AP:

abdominal pain

ARF:

acute renal failure

Arikace® :

amikacin

Ast:

asthenia

AUC:

area under curve

B:

bacteremia

BC:

breast cancer

C:

cardiotoxicity

C:U:

number of carbons:number of unsaturation

CIATEJ:

Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco

Cmax:

maximum concentration

CPX-351:

daunorubicin + cytarabine

CPM:

cyclophosphamide

CR:

complete response

CR:

complete remission

Cyt:

cytarabine

D:

diarrhea

DAP:

diacyl dimethylammonium-propane

DaunoXome® :

daunorubicin

Depocyt® :

cytarabine

DepoDur™:

morphine sulfate

DLBCL:

diffuse large B-cell lymphoma

DLPA:

dilauroyl phosphatidic acid

DLPC:

dilauroyl phosphatidylcholine

DLPE:

dilauroyl phosphatidylethanolamine

DLPG:

dilauroyl phosphatidylglycerol

DLPS:

dilauroyl phosphatidylserine

DLT:

the dose-limiting toxicity

DLin-MC3-DMA:

(6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate

DMPA:

dimyristoyl phosphatidic acid

DMPC:

dimyristoyl phosphatidylcholine

DMPE:

dimyristoyl phosphatidylethanolamine

DMPG:

dimyristoyl phosphatidylglycerol

DMPS:

dimyristoyl phosphatidylserine

DNA:

deoxyribonucleic acid

DOPA:

dioleoyl phosphatidic acid

DOPC:

dioleoyl phosphatidylcholine

DOPE:

dioleoyl phosphatidylethanolamine

DOPG:

dioleoyl phosphatidylglycerol

DOPS:

dioleoyl phosphatidylserine

DOTAP:

dioleoyl trimethylammonium-propane

Doxil® :

doxorubicin

DPPA:

dipalmitoyl phosphatidic acid

DPPC:

dipalmitoyl phosphatidylcholine

DPPE:

dipalmitoyl phosphatidylethanolamine

DPPG:

dipalmitoyl phosphatidylglycerol

DPPS:

dipalmitoyl phosphatidylserine

DSPA:

distearoyl phosphatidic acid

DSPC:

distearoyl phosphatidylcholine

DSPE:

distearoyl phosphatidylethanolamine

DSPG:

distearoyl phosphatidylglycerol

DSPS:

distearoyl phosphatidylserine

EFS:

events-free survival

EndoTAG® :

paclitaxel

EOC:

epithelial ovarian carcinoma

Epaxal® :

inactivated hepatitis A virus

EPC:

ethylphosphocholine

EPG:

esterified propoxylated glycerol

Exparel® :

bupivacaine

F:

fatigue

FDA:

Food and Drug Administration

FN:

febrile neutropenia

FU:

focus ultrasound

GC:

gastric cancer

Gem:

gemcitabine

GEN:

IL-12 plasmid

Genexol-PM:

PEG–PLA polymeric micelle

H:

hypotension

HCC:

hepatocellular carcinoma

HER2:

human epidermal growth factor receptor 2

HFS:

hand–foot syndrome

Hk:

hypokalemia

HNC:

head and neck cancer

HSPC:

hydrogenated soy phosphatidylcholine

Ht :

hypertension

HT:

the heterotype

IFD:

invasive fungal diseases

IFI:

invasive fungal infections

Inflexal V® :

inactivated hemagglutinin, and A or B influenza virus

ITT:

the intention-to-treat

IU:

investigational use

L:

leukopenia

LAI:

liposomal amikacin for inhalation

LB:

liposomal bupivacaine

Ld:

liver dysfunction

LEP-ETU:

paclitaxel

LF:

liposomal formulation

Lipo-Dox® :

doxorubicin

Lipusu® :

paclitaxel

LPTX:

liposomal paclitaxel

Marqibo® :

vincristine

MBC:

metastatic breast cancer

MCL:

mantle cell lymphoma

Mepact® :

mifamurtide

MGC:

metastatic gastric cancer

MHL:

multirelapsed Hodgkin lymphoma

Mil:

miltefosine

Milt:

milt

MM:

multiple myeloma

MM-302:

doxorubicin

mPAC:

metastatic pancreatic adenocarcinoma

m-PFS:

median progression-free survival

MRX34:

Mir-34a

MS:

multiple sclerosis

MSPC:

monostearoyl phosphatidylcholine

MTD:

maximum tolerated dose

Myocet® :

doxorubicin + cyclophosphamide

n:

number of patients

N:

neutropenia

Na:

nauseas

nal-IRI:

nanoliposomal hydrochloride irinotecan

NPs:

nanoparticles

NPLD:

liposomal doxorubicin formulation

NRS:

numerical rating scale

NSCLC:

the non-small-cell lung carcinoma

OC:

ovarian cancer

Onivyde® :

irinotecan + fluorouracil + folinic acid

ORR:

objective response rate

OS:

overall survival

P:

pneumonia

Par:

paromycin

PC:

phosphatidylcholine

PDAC:

pancreatic cancer

PEG:

polyethylene glycol

PEG2000-C-DMG:

α-(30-{[1,2-di(myristyloxy)propanoxy]carbonylamino}propyl)-ω-methoxy-polyoxyethylene

PEI:

polyethylenimine

PFS:

progression-free survival

PFS:

median radiologic

PKs:

pharmacokinetics

PLA:

polylactic acid

PLD:

doxorubicin in liposomes

PO4 2− :

phosphate group

POD:

postoperative day

POTO:

postoperative total opiates consumption

PR:

partial response

PTX:

paclitaxel

PTX–LCN:

paclitaxel lipid core nanoparticle

PTX–LDE:

paclitaxel a lipid core nanoparticle with encapsulated paclitaxel

Q3W:

every 3 weeks

R:

rash

RBGB:

regulator of G protein signaling rgsb

RES:

reticuloendothelial system

RF:

respiratory failure

RFA:

radiofrequency ablation

RFN:

refractory febrile neutropenia

RMM:

relapse or refractory multiple myeloma

RNA:

ribonucleic acid

ROC:

recurrent ovarian cancer

S:

sepsis

S/M:

stomatitis/mucositis

SD:

stable disease

siRNA:

small interfering RNA

SSG:

sodium stibogluconate

T:

thrombocytopenia

TC :

the transition temperature of phospholipids

TFR:

targets transferrin receptor

Thermodox® :

doxorubicin

TNBC:

triple-negative breast cancer

TTP:

time to progression

US:

United States

UTI:

urinary tract infection

V:

vomiting

VAS:

visual analogue scale

Visudyne® :

verteporphin

VL:

visceral leishmaniasis

VSLI:

vincristine sulfate liposomes injection

Vyxeos™:

daunorubicin and cytarabine liposomal

Xemys:

myelin basic proteins

WT:

the wild-type

References

  1. Abildgaard JT, Lonergan KT, Tolan SJ, Kissenberth MJ, Hawkins RJ, Iii RW, et al. Liposomal bupivacaine versus indwelling interscalene nerve block for postoperative pain control in shoulder arthroplasty: a prospective randomized controlled trial. J Shoulder Elb Surg. 2017;26(7):1175–81. https://doi.org/10.1016/j.jse.2017.03.012.

  2. Adams D, Duarte AG, O’Riordan WD, Yang C, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.

  3. Agassandian M, Mallampalli RK. Surfactant phospholipid metabolism. Biochim Biophys Acta Mol Cell Biol Lipids. 2013;1831(3):612–25.

  4. Ahmad A, Sheikh S, Taran R, Srivastav SP, Prasad K, Rajappa SJ, et al. Therapeutic efficacy of a novel nanosomal docetaxel lipid suspension compared with taxotere in locally advanced or metastatic breast cancer patients. Clin Breast Cancer. 2014;14(3):177–81. https://doi.org/10.1016/j.clbc.2013.09.011.

  5. Ahn KH, Jung M, Sym SJ, Shin DB, Kang SM, Kyung SY et al. A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2014;74(2):277–82.

  6. Alijanipour P, Tan TL, Matthews CN, Jessica R, Purtill JJ, Rothman RH, et al. Peri-articular injection of liposomal bupivacaine offers no benefit over standard bupivacaine in total knee arthroplasty: a prospective, randomized, controlled trial. J Arthroplasty. 2016;32(2):628–34. https://doi.org/10.1016/j.arth.2016.07.023.

  7. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013;65(1):36–48.

  8. Amundson AW, Johnson RL, Abdel MP, Mantilla CB, Panchamia JK, Taunton MJ, et al. A three-arm randomized clinical trial comparing continuous femoral plus single-injection sciatic peripheral nerve blocks versus periarticular injection with ropivacaine or liposomal bupivacaine for patients undergoing total knee arthroplasty. Anesthesiology. 2017;126(6):1139–50.

  9. Anselmo AC, Mitragotri S. Nanoparticles in the clinic : an update. Bioeng Transl Med. 2019. https://doi.org/10.1002/btm2.10143.

  10. Awada A, Bondarenko IN, Bonneterre J, Nowara E, Ferrero JM, Bakshi AV, et al. A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC). Ann Oncol. 2014;25(4):824–31.

  11. Banerjee S, Oza AM, Birrer MJ, Hamilton EP, Hasan J, Leary A, et al. Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study. Ann Oncol. 2018;29(4):917–923. https://doi.org/10.1093/annonc/mdy023

  12. Barron KI, Lamvu GM, Schmidt RC. Wound infiltration with extended-release versus short-acting bupivacaine before laparoscopic hysterectomy: a randomized controlled trial. J Minim Invasive Gynecol. 2016;24(2):286–92. https://doi.org/10.1016/j.jmig.2016.11.002.

  13. Baselga J, Manikhas A, Cortés J, Llombart A, Roman L, Semiglazov VF, et al. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer. Ann Oncol. 2014;0:1–7.

  14. Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, et al. Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. JAMA Oncol. 2016:1–7.

  15. Becker PS, Gooley TA, Burwick N, Kim TY, Kojouri K, Inoue Y, et al. A phase 2 study of bortezomib, cyclophosphamide, pegylated liposomal doxorubicin and dexamethasone for newly diagnosed multiple myeloma. Blood Cancer J. 2016;6(5):e422.

  16. Beg MS, Brenner AJ, Sachdev J, Borad M, Kang Y, Stoudemire J, et al. Phase I study ofMRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig New Drugs. 2016;35(2):180–8. https://doi.org/10.1007/s10637-016-0407-y.

  17. Bourquin J, Milosevic A, Hauser D, Lehner R, Blank F, Petri-Fink A, Rothen-Rutishauser B. Biodistribution, clearance, and long-term fate of clinically relevant nanomaterials. Adv Mater. 2018;30(19):1–31.

  18. Bozzuto G, Molinari A. Liposomes as nanomedical devices. Int J Nanomedicine. 2015;10:975–99.

  19. Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9(2):1–33.

  20. Bun S, Yunokawa M, Tamaki Y, Shimomura A, Shimoi T, Kodaira M, et al. Symptom management: the utility of regional cooling for hand-foot syndrome induced by pegylated liposomal doxorubicin in ovarian cancer. Support Care Cancer. 2018;26(7):2161–6. https://doi.org/10.1007/s00520-018-4054-z.

  21. Caimmi D, Martocq N, Trioleyre D, Guinet C, Godreuil S, Daniel T, et al. Positive effect of liposomal amikacin for inhalation on mycobacterium abscessus in cystic fibrosis patients. Open Forum Infect Dis. 2018;5(3):34–6.

  22. Cancer.org. What are the phases of clinical trials? 2018. https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html. Accessed 4 Apr 2019.

  23. Carvalho B, Roland LM, Chu LF, Campitelli VA, Riley ET. Single-dose, extended-release epidural morphine (DepoDur) compared to conventional epidural morphine for post-cesarean pain. Anesth Analg. 2007;105(1):176–83. https://doi.org/10.1213/01.ane.0000265533.13477.26.

  24. Casadei B, Pellegrini C, Tonialini L, Argnani L, Zinzani PL. Interesting activity of pegylated liposomal doxorubicin in primary refractory and multirelapsed Hodgkin lymphoma patients: bridge to transplant. Hematol Oncol. 2018:1–3.

  25. Casals E, Gusta MF, Cobaleda-Siles M, Garcia-Sanz A, Puntes VF. Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles. Cancer Nanotechnol. 2017;8(1):7. https://doi.org/10.1186/s12645-017-0030-4

  26. Chang H-I, Yeh M-K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomedicine. 2012;7:49–60.

  27. Chang AE, Wu QV, Jenkins IC, Specht JM, Gadi VK, Gralow JR, et al. Phase I/II trial of combined pegylated liposomal doxorubicin and cyclophosphamide in metastatic breast cancer. Clin Breast Cancer. 2018;18(1):e143–9. https://doi.org/10.1016/j.clbc.2017.10.005.

  28. Chaudhuri TR, Straubinger RM. Nanoparticles for brain tumor delivery. Nerv Syst Drug Deliv. 2019:229–50. https://doi.org/10.1016/B978-0-12-813997-4.00012-8

  29. Chiang N, Chao T, Hsieh R, Wang C, Wang Y, Yeh CG, et al. A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors. BMC Cancer. 2016. https://doi.org/10.1016/s0140-6736(15)00986-1.

  30. Chou AJ, Kleinerman ES, Krailo MD, Chen Z, Betcher DL, Healey JH, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma. Cancer. 2009;115:5339–48.

  31. Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax. 2013;68:818–25.

  32. Clarke JL, Molinaro AM, Cabrera JR, Desilva AA, Rabbitt JE, Prey J, et al. A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma. Cancer Chemother Pharmacol. 2017;79(3):603–10.

  33. Clemons KV, Stevens DA. Comparative Efficacies of four amphotericin B formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against systemic murine aspergillosis. Antimicrob Agents Chemother. 2004;48(3):1047–50. https://doi.org/10.1128/AAC.48.3.1047-1050.2004.

  34. Cohen A, Spektor TM, Bessudo A, Peter J, Klein LM, Flam M, et al. Safety and efficacy of pomalidomide, dexamethasone and pegylated liposomal doxorubicin for patients with relapsed or refractory multiple myeloma. Br J Haematol. 2018;180:60–70.

  35. Coltelli L, Fontana A, Lucchesi S, Ginocchi L, Bocci G, Filidei M, et al. Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients. Breast. 2017;31:186–91. https://doi.org/10.1016/j.breast.2016.11.006.

  36. Colton JS, Erickson SD, Smith TJ, Watt RK. Sensitive detection of surface- and size-dependent direct and indirect band gap transitions in ferritin. Nanotechnology. 2014;25:135703.

  37. Cornely OA, Leguay T, Maertens J, Vehreschild MJGT, Anagnostopoulos A, Castagnola C, et al. Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia. J Antimicrob Chemother. 2017;72(8):1–9.

  38. Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, Kolitz JE. Phase II, multicenter, randomized trial of CPX-351 (Cytarabine:Daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015;121(2):234–42.

  39. Creutzig U, Zimmermann M, Bourquin J, Dworzak MN, Graf N, Klingebiel T, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013;122(1):37–43.

  40. Davidovitch R, Goch A, Driesman A, Konda S, Pean C, Egol K. The use of liposomal bupivacaine administered with standard bupivacaine in ankle fractures requiring open reduction internal fixation: a single-blinded randomized controlled trial. J Orthop Trauma. 2017;31(8):434–9.

  41. Declaire JH, Aiello PM, Warritay O, Freeman C. Effectiveness of bupivacaine liposome injectable suspension for postoperative pain control in total knee arthroplasty: a prospective, randomized, double blind, controlled study. J Arthroplasty. 2017. https://doi.org/10.1016/j.arth.2017.03.062.

  42. Deeken JF, Slack R, Weiss GJ, Ramanathan RK, Pishvaian MJ, Hwang J, et al. A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 2013;71:627–33.

  43. Delattin N, De Brucker K, Vandamme K, Meert E, Marchand A, Chaltin P, et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. J Antimicrob Chemother. 2014;69(4):1035–44. https://doi.org/10.1093/jac/dkt449.

  44. Eitan R, Fishman A, Meirovitz M, Goldenberg H, Amit A, Koren C, et al. Liposome-encapsulated doxorubicin citrate (Myocet) for treatment of recurrent epithelial ovarian cancer. Anticancer Drugs. 2014;25(1):101–5.

  45. Ferreri AJM, Donadoni G, Cabras MG, Patti C, Mian M, Zambello R, et al. High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: final results of a multicenter phase II trial. J Clin Oncol. 2015;33(33):3903–10. https://doi.org/10.1200/JCO.2015.61.1236.

  46. Fiteni F, Westeel V, Pivot X, Borg C, Vernerey D, Bonnetain F. Endpoints in cancer clinical trials. J Visc Surg. 2014;151:17–22. https://doi.org/10.1016/j.jviscsurg.2013.10.001.

  47. Fouladi F, Steffen KJ, Mallik S. Enzyme-responsive liposomes for the delivery of anticancer drugs. Bioconjug Chem. 2017;28(4):857–68.

  48. Fridrik MA, Jaeger U, Petzer A, Willenbacher W, Keil F, Lang A, et al. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma. Eur J Cancer. 2016;58:112–21. https://doi.org/10.1016/j.ejca.2016.02.004.

  49. Gangadaran P, Hong CM, Ahn B. An update on in vivo imaging of extracellular vesicles as drug delivery vehicles. Front Pharmacol. 2018;9:169.

  50. Gao Y, Wijewardhana C, Mann JFS. Virus-like particle, liposome, and polymeric particle-based vaccines against HIV-1. Front Immunol. 2018;9:345.

  51. Gasparini R, Amicizia D, Lai PL, Rossi S, Panatto D. Effectiveness of adjuvanted seasonal influenza vaccines (Inflexal V® and Fluad®) in preventing hospitalization for influenza and pneumonia in the elderly. Hum Vaccine Immunother. 2013;9(1):144–52. https://doi.org/10.4161/hv.22231.

  52. Gergis U, Roboz G, Shore T, Ritchie E, Mayer S, Wissa U, Feldman E. A phase I study of CPX-351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia. Biol Blood Marrow Transplant. 2013;19(7):1040–5.

  53. Gomes AC, Mohsen M, Bachmann MF. Harnessing nanoparticles for immunomodulation and vaccines. Vaccines. 2017;5:6.

  54. Gonda A, Zhao N, Shah J, Calvelli HR, Kantamneni H, Francis N, Ganapathy V. Engineering tumor-targeting nanoparticles as vehicles for precision nanomedicine. Med One. 2019. https://doi.org/10.20900/mo.20190021.

  55. Graziani SR, Vital CG, Morikawa AT, Van Eyll BM, Fernandes Junior HJ, Filho RK, et al. Phase II study of paclitaxel associated with lipid core nanoparticles (LDE) as third-line treatment of patients with epithelial ovarian carcinoma. Med Oncol. 2017;34(151).

  56. Haas SL, Bechstein W, Bodoky G, Cwiertka K, Fischbach W, Ja D, et al. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol. 2012;23(5):1214–22.

  57. Hagemeister F, Alma M, Deitcher SR, Younes A, Fayad L, Goy A, et al. Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo?) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive. Br J Haematol. 2013;162:631–8.

  58. Harbeck N, Saupe S, Ja E, Shmidt M, Kreienberg R, Muller L, et al. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017;161(1):63–72.

  59. Herzog TJ, Bidzi ÞM, Symanowski J, Nguyen B, Rangwala RA, Naumann RW. Adverse event profile by folate receptor status for vintafolide and pegylated liposomal doxorubicin in combination, versus pegylated liposomal doxorubicin alone, in platinum-resistant ovarian cancer: exploratory analysis of the phase II PRECEDENT trial. Int J Gynecol Cancer. 2016;26(9):1580–5.

  60. Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems—a review (part 1). Trop J Pharm Res. 2013;12(2):255–64.

  61. Hu L, Liang G, Yuliang W, Bingjing Z, Xiangdong Z, Rufu X. Assessing the effectiveness and safety of liposomal paclitaxel in combination with cisplatin as first-line chemotherapy for patients with advanced NSCLC with regional lymph-node metastasis: study protocol for a randomized controlled trial (PLC-GC trial). Trials. 2013;14(1):45.

  62. Hudson RDA. Ferrocene polymers: current architectures, syntheses and utility. J Organomet Chem. 2001;637–639:47–69.

  63. Hussain A, Singh S, Sharma D, Webster TJ, Shafaat K, Faruk A. Elastic liposomes as novel carriers: recent advances in drug delivery. Int J Nanomedicine. 2017;12:5087–108.

  64. Ignatiadis M, Zardavas D, Lemort M, Wilke C, Vanderbeeken C, Hondt VD, et al. Feasibility study of EndoTAG-1, a tumor endothelial targeting agent, in combination with paclitaxel followed by FEC as induction therapy in HER2-negative breast cancer. PLoS ONE. 2016;11(7):1–11. https://doi.org/10.1371/journal.pone.0154009.

  65. Jain M, Zellweger M, Frobert A, Valentin J, van den Bergh H, Wagnières G, et al. Intra-arterial drug and light delivery for photodynamic therapy using Visudyne®: implication for atherosclerotic plaque treatment. Front Physiol. 2016. https://doi.org/10.3389/fphys.2016.00400/abstract.

  66. Jehn CF, Hemmati P, Lehenbauer-dehm S, Kümmel S, Flath B, Schmid P. Biweekly pegylated liposomal doxorubicin (Caelyx) in heavily pretreated metastatic breast cancer: a phase 2 study. Clin Breast Cancer. 2016. https://doi.org/10.1016/j.clbc.2016.06.001.

  67. Jin Z, Lv Y, Cao H, Yao J, Zhou J, He W, et al. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting. Sci Rep. 2016;6:27559.

  68. Johnson RL, Amundson AW, Abdel MP, Sviggum HP, Mabry TM, Mantilla CB, et al. Continuous posterior lumbar plexus nerve block versus periarticular injection with ropivacaine or liposomal bupivacaine for total hip arthroplasty. J Bone Jt Surg Am. 2017;99:1836–45.

  69. Jr AB, Zakharov K, Lomakin Y, Surkov K, Avtushenko S, Kruglyakov P, et al. CD206-targeted liposomal myelin basic protein peptides in patients with multiple sclerosis resistant to first-line disease-modifying therapies: a first-in-human, proof-of-concept dose-escalation study. Neurotherapeutics. 2016;13(4):895–904. https://doi.org/10.1007/s13311-016-0448-0.

  70. Jung S, Sehouli J, Chekerov R, Kluschke F, Patzelt A, Fuss H, et al. Prevention of palmoplantar erythrodysesthesia in patients treated with pegylated liposomal doxorubicin (Caelyx ®). Support Care Cancer. 2017;25(11):3545–9.

  71. Kaplan LD, Deitcher SR, Silverman JA, Morgan G. Phase II study of vincristine sulfate liposome injection (Marqibo) and rituximab for patients with relapsed and refractory diffuse large B-cell lymphoma or mantle cell lymphoma in need of palliative therapy. Clin Lymphoma Myeloma Leuk. 2014;14(1):37–42. https://doi.org/10.1016/j.clml.2013.09.009.

  72. Kaspers GJL, Zimmermann M, Reinhardt D, Gibson BES, Tamminga RYJ, Aleinikova O, et al. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the international BFM Study Group. J Clin Oncol. 2013;31(5):599–607.

  73. Kaur J, Gill GS, Jeet K. Chapter 5—applications of carbon nanotubes in drug delivery: a comprehensive review. In: Characterization and biology of nanomaterials for drug delivery. 2019. p. 113–35. https://doi.org/10.1016/b978-0-12-814031-4.00005-2.

  74. Kim KH, Jelovac D, Armstrong DK, Schwartz B, Weil SC, Schweizer C, et al. Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer. Gynecol Oncol. 2015. https://doi.org/10.1016/j.ygyno.2015.11.031.

  75. Kohli AG, Kivimäe S, Tiffany MR, Szoka FC. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan. J Control Release. 2014;191:105–14.

  76. Kolašinac R, Kleusch C, Braun T, Merkel R, Csiszàr A. Deciphering the functional composition of fusogenic liposomes. Int J Mol Sci. 2018;19:346.

  77. Kraft JC, Freeling JP, Wang Z, Ho RJY. Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci. 2014;103(1):29–52.

  78. Krauss AC, Gao X, Li L, Manning ML, Patel P, Fu W, et al. FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia. Clin Cancer Res. 2019;25(9):2685–90. https://doi.org/10.1158/1078-0432.CCR-18-2990.

  79. Lamichhane N, Udayakumar T, D’Souza W, Simone C II, Raghavan S, Polf J, et al. Liposomes: clinical applications and potential for image-guided drug delivery. Molecules. 2018;23(2):288.

  80. Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Yeager AM. Phase 2 trial of CPX-351, a fixed 5: 1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239–46.

  81. Landrum LM, Brady WE, Armstrong DK, Moore KN, Disilvestro PA, Malley DMO, et al. A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2016;140(2):204–9. https://doi.org/10.1016/j.ygyno.2015.11.024.

  82. Lee Y-J, Kim Y-M, Lee S-W, Park J-Y, Kim D-Y, Suh D-S, et al. The efficacy and safety of pegylated liposomal doxorubicin monotherapy and combination therapy with carboplatin in Korean patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer: a single-institution experience. Obstet Gynecol Sci. 2017;60(5):433–9. https://doi.org/10.5468/ogs.2017.60.5.433.

  83. Levinsen M, Harila-Saari A, Grell K, Jonsson OG, Taskinen M, Abrahamsson J, et al. Efficacy and toxicity of intrathecal liposomal cytarabine in first-line therapy of childhood acute. J Pediatr Hematol Oncol. 2016;38(8):602–9.

  84. Li W, Zhan P, De Clercq E, Lou H, Liu X. Current drug research on PEGylation with small molecular agents. Prog Polym Sci. 2013a;38(3–4):421–44.

  85. Li L, Yuan L, Luo J, Gao J, Guo J, Xie X. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin Exp Med. 2013b;13(2):109–17. https://doi.org/10.1007/s10238-012-0186-5.

  86. Li J, Wang X, Zhang T, Wang C, Huang Z, Luo X, Deng Y. A review on phospholipids and their main applications in drug delivery systems. Asian J Pharm Sci. 2014;10(2):81–98.

  87. Li M, Du C, Guo N, Teng Y, Meng X, Sun H, et al. Composition design and medical application of liposomes. Eur J Med Chem. 2019. https://doi.org/10.1016/j.ejmech.2019.01.007.

  88. Lim J, Song Y-J, Park W-S, Sohn H, Lee M-S, Shin D-H, et al. The immunogenicity of a single dose of hepatitis A virus vaccines (Havrix® and Epaxal®) in Korean young adults. Yonsei Med J. 2014;55(1):126. https://doi.org/10.3349/ymj.2014.55.1.126.

  89. Lin X, Gu N. Surface properties of encapsulating hydrophobic nanoparticles regulate the main phase transition temperature of lipid bilayers: a simulation study. Nano Res. 2014;7(8):1195–204. https://doi.org/10.1007/s12274-014-0482-3.

  90. Lindemann K, Gibbs E, Åvall-lundqvist E, Christensen RD, Woie K, Auranen A, et al. Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer: a phase III, randomised, multicentre trial (Ovaresist). Br J Cancer. 2017. https://doi.org/10.1038/bjc.2016.435.

  91. Lombardo D, Calandra P, Barreca D, Magazù S, Kiselev M. Soft interaction in liposome nanocarriers for therapeutic drug delivery. Nanomaterials. 2016;6(7):125.

  92. Lu R-M, Chen M-S, Chang D-K, Chiu C-Y, Lin W-C, Yan S-L, et al. Targeted drug delivery systems mediated by a novel peptide in breast cancer therapy and imaging. PLoS ONE. 2013;8(6):e66128. https://doi.org/10.1371/journal.pone.0066128.

  93. Lu B, Sun L, Yan X, Ai Z, Xu J. Intratumoral chemotherapy with paclitaxel liposome combined with systemic chemotherapy: a new method of neoadjuvant chemotherapy for stage III unresectable non-small cell lung cancer. Med Oncol. 2015;32:345.

  94. Lu M, Wang T, Wang J. Effects of paclitaxel liposome and capecitabine in the treatment of advanced gastric cancer by clinical observation. Int J Clin Pharmacol Ther. 2016;54(09):693–7.

  95. Luminari S, Viel E, José A, Ferreri M, Zaja F, Chimienti E, et al. Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B—cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi. Hematol Oncol. 2017:1–8.

  96. Lyon PC, Griffiths LF, Lee J, Chung D, Carlisle R, Wu F, et al. Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours. J Ther Ultrasound. 2017;5:28.

  97. Ma Y, Poole K, Goyette J, Gaus K. Introducing membrane charge and membrane potential to T cell signaling. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.01513/full.

  98. Mahalingam D, Nemunaitis JJ, Malik L, Sarantopoulos J, Weitman S, Sankhala K, et al. Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;74:1241–50.

  99. Maranhão RC, Vital CG, Tavoni TM, Graziani SR. Clinical experience with drug delivery systems as tools to decrease the toxicity of anticancer chemotherapeutic agents. Expert Opin Drug Deliv. 2017. https://doi.org/10.1080/17425247.2017.1276560.

  100. Marth C, Vergote I, Scambia G, Oberaigner W, Clamp A, Berger R, et al. ENGOT-ov-6/TRINOVA-2: randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer. Eur J Cancer. 2017;70:111–21. https://doi.org/10.1016/j.ejca.2016.09.004.

  101. Mazloomdoost D, Pauls RN, Hennen EN, Yeung Y, Smith BC, Kleeman SD, et al. Liposomal bupivacaine decreases pain following retropubic sling placement: a randomized placebo-controlled trial. Am J Obstet Gynecol. 2017. https://doi.org/10.1016/j.ajog.2017.07.001.

  102. Mcgraw-tatum M, Groover MT, George NE, Urse JS, Heh V. A prospective, randomized trial comparing liposomal bupivacaine versus fascia iliaca compartment block for postoperative pain control in total hip arthroplasty. J Arthroplasty. 2017. https://doi.org/10.1016/j.arth.2017.02.019.

  103. Medina-Alarcón KP, Voltan AR, Fonseca-Santos B, Moro IJ, de Oliveira Souza F, Chorilli M, Fusco-Almeida AM. Highlights in nanocarriers for the treatment against cervical cancer. Mater Sci Eng C. 2017;80:748–59.

  104. Meng J, Guo F, Xu H, Liang W, Wang C, Yang X-D. Combination therapy using co-encapsulated resveratrol and paclitaxel in liposomes for drug resistance reversal in breast cancer cells in vivo. Sci Rep. 2016;6(1):22390.

  105. Merino M, Zalba S, Garrido MJ. Immunoliposomes in clinical oncology: State of the art and future perspectives. J Control Release. 2018;275:162–76.

  106. Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, Yardley DA. HERMIONE: a randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 2016;16(1):1–11.

  107. Minamisawa M, Claggett B, Adams D, Kristen AV, Merlini G, Slama MS, et al. Association of patisiran, an RNA interference therapeutic, with regional left ventricular myocardial strain in hereditary transthyretin amyloidosis the APOLLO study. JAMA Cardiol. 2019;4(5):466–72.

  108. Miyao K, Sawa M, Kurata M, Suzuki R, Sakemura R, Sakai T, et al. A multicenter phase 2 study of empirical low-dose liposomal amphotericin B in patients with refractory febrile neutropenia. Int J Hematol. 2016;105(1):79–86.

  109. Mohanta V, Madras G, Patil S. Layer-by-layer assembled thin films and microcapsules of nanocrystalline cellulose for hydrophobic drug delivery. ACS Appl Mater Interfaces. 2019;6(22):20093–101.

  110. Monk BJ, Brady MF, Aghajanian C, Lankes HA, Rizack T, Leach J, et al. A phase 2, randomized, double-blind, placebo-controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study. Ann Oncol. 2017;0:1–9.

  111. Monteiro N, Martins A, Reis RL, Neves NM. Liposomes in tissue engineering and regenerative medicine. J R Soc Interface. 2014;11(101):20140459. https://doi.org/10.1098/rsif.2014.0459.

  112. Murthy AVR, Guyomarc’h F, Lopez C. The temperature-dependent physical state of polar lipids and their miscibility impact the topography and mechanical properties of bilayer models of the milk fat globule membrane. Biochim Biophys Acta Biomembr. 2016;1858(9):2181–90.

  113. Nagao S, Iwasa N, Kurosaki A, Nishikawa T, Hanaoka T, Hasegawa K, et al. The efficacy of low-dose paclitaxel added to combination chemotherapy of carboplatin and gemcitabine or pegylated liposomal doxorubicin. Int J Gynecol Cancer. 2016;26(3):443–8.

  114. Namdari S, Nicholson T, Abboud J, Lazarus M, Steinberg D, Williams G. Randomized controlled trial of interscalene block compared with injectable liposomal bupivacaine in shoulder arthroplasty. J Bone Jt Surg Am. 2017;99:550–6. https://doi.org/10.2106/JBJS.16.00296.

  115. Nardecchia S, Sánchez-Moreno P, Vicente J, Marchal J, Boulaiz H. Clinical trials of thermosensitive nanomaterials: an overview. Nanomaterials. 2019;9(2):191.

  116. Olivier KN, Grif DE, Eagle G, Ii JPM, Micioni L, Liu K, et al. Randomized trial of liposomal amikacin for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med. 2017;195(6):814–23.

  117. Olusanya T, Haj Ahmad R, Ibegbu D, Smith J, Elkordy A. Liposomal drug delivery systems and anticancer drugs. Molecules. 2018;23(4):907.

  118. Orlowski RZ, Nagler A, Sonneveld P, Bladè J, Hajek R, Spencer A, et al. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016;122(13):2050–6.

  119. Pelzer U, Chen L, Siveke JT, Wan Y, Solem CT, Botteman MF, et al. Quality-adjusted survival with combination nal-IRI þ 5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. Br J Cancer. 2017;1–7.

  120. Peyrl A, Sauermann R, Chocholous M, Azizi AA, Jager W, Hoferl M, et al. Pharmacokinetics and toxicity of intrathecal liposomal cytarabine in children and adolescents following age-adapted dosing. Clin Pharmacokinet. 2014;53:165–73.

  121. Phuphanich S, Maria B, Braeckman R, Chamberlain M. A pharmacokinetic study of intra-CSF administered encapsulated cytarabine (DepoCyt®) for the treatment of neoplastic meningitis in patients with leukemia, lymphoma, or solid tumors as part of a phase III study. J Neurooncol. 2006;81(2):201–8. https://doi.org/10.1007/s11060-006-9218-x.

  122. Pinot M, Vanni S, Pagnotta S, Lacas-Gervais S, Payet L-A, Ferreira T, et al. Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins. Science. 2014;345(6197):693–7. https://doi.org/10.1126/science.1255288.

  123. Pirollo KF, Nemunaitis J, Leung PK, Nunan R, Chang EH, Pirollo KF, et al. Safety and efficacy in advanced solid tumors of docetaxel in combination with a targeted nanocomplex carrying the p53 gene: a phase Ib study. Mol Ther. 2016;24(9):1697–706.

  124. Priev A, Zalipsky S, Cohen R, Barenholz Y. Determination of critical micelle concentration of lipopolymers and other amphiphiles: comparison of sound velocity and fluorescent measurements. Langmuir. 2002;18(3):612–7. https://doi.org/10.1021/la0110085.

  125. Qu C, Sun G, Yang S, Tian J, Si J, Wang Y. Toxicities of different first-line chemotherapy regimens in the treatment of advanced ovarian cancer. Medicine. 2017. https://doi.org/10.1097/md.0000000000005797.

  126. Rahman R, Goyal V, Haque R, Jamil K, Faiz A, Samad R, et al. Safety and efficacy of short course combination regimens with Am Bisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh. PLoS Negl Trop Dis. 2017;11(5):e0005635.

  127. Riaz MK, Riaz MA, Zhang X, Lin C, Wong K, Chen X, et al. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: a review. Int J Mol Sci. 2018;19(1):195.

  128. Rice D, Heil JW, Biernat L. Pharmacokinetic profile and tolerability of liposomal bupivacaine following a repeated dose via local subcutaneous infiltration in healthy volunteers. Clin Drug Investig. 2017;37(3):249–57.

  129. Rocca A, Cecconetto L, Passardi A, Melegari E, Andreis D, Monti M, et al. Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer. Cancer Chemother Pharmacol. 2017;79:863–71.

  130. Roever L. Evidence based medicine and practice endpoints in clinical trials: advantages and limitations. Evid Based Med Pract. 2016;1(2):1–2.

  131. Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, et al. Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. PLoS Negl Trop Dis. 2017;11(6):e0005706. https://doi.org/10.1371/journal.pntd.0005706.

  132. Rose SJ, Neville ME, Gupta R, Bermudez LE. Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection. PLoS ONE. 2014;9(9):e108703.

  133. Rothfield LI, editor. Structure and function of biological membranes. 1st ed. Cambridge: Academic Press; 1971.

  134. Rühling A, Wang D, Ernst JB, Wulff S, Honeker R, Richter C, et al. Influence of the headgroup of azolium-based lipids on their biophysical properties and cytotoxicity. Chem Eur J. 2017;23(25):5920–4. https://doi.org/10.1002/chem.201604182.

  135. Runnebaum IB, Reichert D, Ringsdorf U, Kuther M, Hesse T, Sehouli J, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study. J Cancer Res Clin Oncol. 2018;144(6):1185–95. https://doi.org/10.1007/s00432-018-2637-1.

  136. Sabesan VJ, Shahriar R, Petersen-fitts GR, Whaley JD, Bou-akl T, Sweet M, et al. A prospective randomized controlled trial to identify the optimal postoperative pain management in shoulder arthroplasty: liposomal bupivacaine versus continuous interscalene catheter. J Shoulder Elb Surg. 2017;26:1810–7. https://doi.org/10.1016/j.jse.2017.06.044.

  137. Sánchez DR, Vaca LB, Linares MY, Giraldo CM, Erazo JR, Beltrán SL, et al. Infección fúngica invasiva en pacientes inmunosuprimidos atendidos en un hospital de tercer nivel. Rev Colomb Neumol. 2016;28(1):10.

  138. Sehouli J, Chekerov R, Reinthaller A, Richter R, Harter P, Woopen H, et al. Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria. Ann Oncol. 2016;00:1–6.

  139. Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct Target Ther. 2018;3(1):7.

  140. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286.

  141. Shah NN, Merchant MS, Cole DE, Jayaprakash N, Bernstein D, Delbrook C, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo): results from a phase I study in children, adolescents, and young adults with refractory solid tumors or leukemias. Pediatr Blood Cancer. 2016;63:997–1005.

  142. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37.

  143. Shoji T, Takatori E, Omi H, Kagabu M, Honda T, Futagami M, et al. A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study) Tadahiro. Cancer Chemother Pharmacol. 2017;80:355–61.

  144. Signorell RD, Luciani P, Brambilla D, Leroux JC. Pharmacokinetics of lipid-drug conjugates loaded into liposomes. Eur J Pharm Biopharm. 2018;128:188–99.

  145. Silverman JA, Deitcher SR. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol. 2013;71(3):555–64. https://doi.org/10.1007/s00280-012-2042-4.

  146. Sinatra ST, Teter BB, Bowden J, Houston MC, Martinez-Gonzalez MA. The saturated fat, cholesterol, and statin controversy a commentary. J Am Coll Nutr. 2014;33(1):79–88. https://doi.org/10.1080/07315724.2014.878633.

  147. Slingerland M, Guchelaar H, Rosing H, Scheulen ME, Van Warmerdam LJC, Beijnen JH, et al. Bioequivalence of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: a randomized, two-period crossover study in patients with advanced cancer. Clin Ther. 2017;35(12):1946–54. https://doi.org/10.1016/j.clinthera.2013.10.009.

  148. Smith JA, Mathew L, Burney M, Nyshadham P, Coleman RL. Equivalency challenge: evaluation of Lipodox® as the generic equivalent for Doxil® in a human ovarian cancer orthotropic mouse model. Gynecol Oncol. 2016;141(2):357–63.

  149. Smith EB, Kazarian GS, Maltenfort MG, Lonner JH, Sharkey PF, Good RP. Periarticular liposomal bupivacaine injection versus intra-articular bupivacaine infusion catheter for analgesia after total knee arthroplasty. J Bone Jt Surg Am. 2017;99:1337–44. https://doi.org/10.2106/JBJS.16.00571.

  150. Solomon SD, Adams D, Kristen A, Grogan M, González-duarte A, Maurer MS, et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis: an analysis of the APOLLO study running. Circulation. 2019;139(4):431–43.

  151. Strieth S, Dunau C, Michaelis U, Jager L, Gellrich D, Wollenberg B, et al. Phase I/II clinical study on safety and antivascular effects of paclitaxel encapsulated in cationic liposomes for targeted therapy in advanced head and neck cancer. Head Neck. 2013;36(7):976–84.

  152. Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015:10(109).

  153. Tacke D, Buchheidt D, Karthaus M, Krause SW, Maschmeyer G, Neumann S, et al. Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Ann Hematol. 2014;93(9):1449–56. https://doi.org/10.1007/s00277-014-2108-y.

  154. Tampaki EC, Tampakis A, Alifieris CE, Kikelis D, Pazaiti A, Kontos M, et al. Efficacy and safety of neoadjuvant treatment with bevacizumab, liposomal doxorubicin, cyclophosphamide and paclitaxel combination in locally/regionally advanced, HER2-negative, grade III at premenopausal status breast cancer: a phase II study. Clin Breast Cancer. 2018. https://doi.org/10.1007/s40261-018-0655-z.

  155. Thaker PH, Brady WE, Lankes HA, Odunsi K, Bradley WH, Moore KN, et al. A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal. Gynecol Oncol. 2017. https://doi.org/10.1016/j.ygyno.2017.08.001.

  156. Thorn CF, Oshiro C, Marsh S, Hernandez-boussard T, Mcleod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharm Genomics. 2011;21:440–6.

  157. Tran S, Degiovanni PJ, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clin Transl Med. 2017;6(1):44. https://doi.org/10.1186/s40169-017-0175-0.

  158. Tsermentseli S, Kontogiannopoulos K, Papageorgiou V, Assimopoulou A. Comparative study of PEGylated and conventional liposomes as carriers for shikonin. Fluids. 2018;3(2):36.

  159. Ud Din F, Aman W, Ullah I, Qureshi OS, Mustapha O, Shafique S, Zeb A. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomedicine. 2017;12:7291.

  160. U.S. Food and Drug Administration. Step 3: clinical research. 2018. https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm%0A. Accessed 4 Apr 2018.

  161. Vallejo AA, Velázquez JB, Fernández MS. Lateral organization of mixed, two-phosphatidylcholine liposomes as investigated by GPS, the slope of Laurdan generalized polarization spectra. Arch Biochem Biophys. 2007;466:145–54. https://doi.org/10.1016/j.abb.2007.06.031.

  162. van Rijt SH, Bein T, Meiners S. Medical nanoparticles for next generation drug delivery to the lungs. Eur Respir J. 2014:1–10.

  163. Venkatakrishnan K, Liu Y, Noe D, Mertz J, Bargfrede M, Marbury T, et al. Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment. Br J Pharmacol. 2013;77(6):998–1010.

  164. Ventola CL. Progress in nanomedicine: approved and investigational nanodrugs. Pharm Ther. 2017;42(12):742.

  165. Verma JN, Verma L, Tripathi KK. Sterol enriched mixed lammelarity amphotericin intercalating liposomes in saline and the process for their preparation. WO/2005/120460, 2005.

  166. Villaruz LC, Socinski MA. The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement. Clin Cancer Res. 2013;19(10):2629–36. https://doi.org/10.1158/1078-0432.CCR-12-2935.

  167. Volgger B, Zeimet ÞAG, Reinthaller A, Petru E, Schauer C, Klein M, et al. Carboplatin and nonpegylated liposomal doxorubicin in primary advanced or recurrent endometrial cancer a phase 2 trial conducted by AGO Austria. Int J Gynecol Cancer. 2015;25(2):257–62.

  168. Voorhees PM, Gasparetto C, Moore DT, Winans D, Robert Z, Hurd DD. Final results of a phase I study of vorinostat, pegylated liposomal doxorubicin and bortezomib in relapsed or refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2017. https://doi.org/10.1016/j.clml.2017.05.007.

  169. Wang H, Zhang X. Comparison of efficacy and safety between liposome-paclitaxel injection plus carboplatin and paclitaxel plus carboplatin as first line treatment in advanced non-small cell lung cancer. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2014;36(3):305–8.

  170. Wang-gillam A, Li C, Bodoky G, Dean A, Shan Y, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–57. https://doi.org/10.1016/S0140-6736(15)00986-1.

  171. Wasunna M, Njenga S, Balasegaram M, Alexander N, Omollo R, Edwards T, et al. Efficacy and safety of am bisome in combination with sodium stibogluconate or miltefosine and miltefosine monotherapy for African visceral leishmaniasis: phase II randomized trial. PLoS Negl Trop Dis. 2016;10(9):e0004880.

  172. Wu W, He Q, Jiang C. Magnetic iron oxide nanoparticles: synthesis and surface functionalization strategies. Nanoscale Res Lett. 2008;3(11):397–415.

  173. Xu X, Wang L, Xu H, Huang X, Qian Y, Xiang J. Clinical comparison between paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac J Cancer Prev. 2013;14(4):2591–4. https://doi.org/10.7314/APJCP.2013.14.4.2591.

  174. Ye L, He J, Hu Z, Dong Q, Wang H, Fu F, et al. Antitumor effect and toxicity of Lipusu in rat ovarian cancer xenografts. Food Chem Toxicol. 2013;52:200–6. https://doi.org/10.1016/j.fct.2012.11.004.

  175. Yeung J, Crisp CC, Pauls RN, Mazloomdoost D, Kleeman SD. Liposomal bupivacaine during robotic colpopexy and posterior repair: a randomized controlled trial. Obstet Gynecol. 2018;0:1–8.

  176. Yingchoncharoen P, Kalinowski DS, Richardson DR. Lipid-based drug delivery systems in cancer therapy: what is available and what is yet to come. Pharmacol Rev. 2016;68(3):701–87. https://doi.org/10.1124/pr.115.012070.

  177. Zamani P, Momtazi-Borojeni AA, Nik ME, Oskuee RK, Sahebkar A. Nanoliposomes as the adjuvant delivery systems in cancer immunotherapy. J Cell Physiol. 2018;233(7):5189–99. https://doi.org/10.1002/jcp.26361.

  178. Zhao W, Song Zhuang XR. Comparative study of the in vitro and in vivo characteristics of cationic and neutral liposomes. Int J Nanomedicine. 2011;6:3087–3098. https://doi.org/10.2147/IJN.S25399.

  179. Zhao M, Ding X, Shen J, Zhang X, Ding X, Xu B. Use of liposomal doxorubicin for adjuvant chemotherapy of breast cancer in clinical practice. J Zhejiang Univ Sci B Biomed Biotechnol. 2017;18(1):15–26.

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Acknowledgements

The authors are grateful CIATEJ by project 2546 CATEDRAS-CONACYT and project Glucolipids.

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  1. Departamento de Biotecnología Médica Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Jalisco, Mexico
    • Esteban Beltrán-Gracia
    •  & Adolfo López-Camacho
  2. Departamento de Tecnología Alimentaria, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Jalisco, Mexico
    • Inocencio Higuera-Ciapara
  3. Departamento de Tecnología Ambiental, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CONACYT-CIATEJ), Guadalajara, Jalisco, Mexico
    • Jesús B Velázquez-Fernández
  4. Departamento de Biotecnología Médica Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CONACYT-CIATEJ), A. C., Av. Normalistas 800, Col. Colinas de la Normal, 44270, Guadalajara, Jalisco, Mexico
    • Alba A Vallejo-Cardona
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EBG, ALC, JBVF, IHC and AAVC wrote the manuscript, AAVC, JBVF and IHC analyzed, discussed and reviewed the manuscript. All authors agreed to submission of the present work. All authors read and approved the final manuscript.

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Beltrán-Gracia, E., López-Camacho, A., Higuera-Ciapara, I. et al. Nanomedicine review: clinical developments in liposomal applications. Cancer Nano 10, 11 (2019). https://doi.org/10.1186/s12645-019-0055-y

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Keywords

  • Drug delivery systems
  • Nanoscale
  • Liposomal nanotechnology
  • Recent clinical trials

Cancer Nanotechnology

ISSN: 1868-6966

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