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Nanomedicine review: clinical developments in liposomal applications

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

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
figure2

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)

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
figure3

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)

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

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

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

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

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
Table 6 Toxicity of the clinical trials with doxorubicin
Table 7 Efficacy of recent clinical trials with liposomal daunorubicin in mono or combined therapy

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
Table 9 Efficacy of recent clinical trials with liposomal paclitaxel in mono or combined therapy

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
Table 11 Characteristics of recent clinical trials with liposomal amphotericin B in mono or combined therapy

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

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

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Acknowledgements

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

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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.

Correspondence to Alba A Vallejo-Cardona.

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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