Table 1 Description of the main mechanisms of cancer resistance, and treatment approaches offered by multifunctional nanoparticles

Drug metabolism and drug target regulation

Anti-cancer treatments can induce the up-regulation of certain signalling pathways in order to develop resistance like amplification, drug metabolism or mutation of drug targets (Vinogradov and Wei 2012)

Drug protection and drug cocktail

Drugs can be conjugated with NP for drug delivery, which protects them from degradation. Further, when combining more than one drug in a single NP lowers the chances of resistance onset

Efflux pumps

Drug efflux transporters—first described in reference (Juliano and Ling 1976)—in the cytoplasmic membrane that expel the chemotherapeutic agents from the cell are generally found to be overexpressed in MDR cancer cells, lowering intracellular drug concentration (Kirtane et al. 2013)

Drug cocktail and drug cargo

The local release of (different) drugs from the NP increase intracellular drug concentration, which can saturate the efflux pumps minimizing their resistance effect

Tumour microenvironment

The cellular environment in which the tumour exists can alter the response of tumour cells to chemotherapy and targeted therapies. It induces the production of secreted factors, which drives tumour growth, MDR and metastasis. Also, it creates a suitable environment for treatment resistance due to the high interstitial pressure (impeding drug penetration) and hypoxia (up-regulating other resistance signalling pathways) (Iyer et al. 2013; Swartz et al. 2012; Vinogradov and Wei 2012)

Improved tumour penetration

NPs enable local hyperthermia which can contribute in (a) increasing the blood flow and tumour oxygenation, and (b) enhancing drug penetration by decreasing tumour viscosity

Quiescent phenotypes

As conventional chemotherapy agents rely on blocking cell division to induce apoptosis, quiescent cells are not affected. Once the treatment is stopped, this remaining pool of cells can grow to repopulate the tumour. A significant tumour subpopulation displaying this phenotype are CSC, which also possess other intrinsic resistant properties (Dean et al. 2005)

Radio-enhancement

Radiotherapy and hyperthermia are efficient cancer treatments irrespective of cellular type. NPs act as sensitizers in thermo and radio, increasing the local damage to kill more resistant cells

Stemness

There are several signalling pathways and genes involved in CSC maintenance. The most studied are Hedgehog, Wnt, Notch, and Nanog. Different studies showed that they provide the necessary signals to remain in the stem cell state to self-renew, to guarantee tumour growth and they have also been related to chemotherapy resistance and metastases (Vinogradov and Wei 2012)

Targeting. Side effects attenuation

(1) NPs can enable targeted therapies, which increases local damage at the targeted site while attenuating side effects in the rest of the organism. This reduces side effects and allows to fight highly resistant cells by (a) increasing doses of drugs and/or radiation (more aggressive treatment) and, (b) combining effects of chemotherapy (drug cocktails), gene therapy, and radiotherapy (overwhelming resistance and repairing mechanisms)

(2) Although these are not approaches to address these specific resistance mechanisms, is the NP which enables multimodal treatments able to fight against them

Apoptosis resistance

The up-regulation of oncogenes and the higher DNA repair capacity have been proved to make some tumoural cells more resistant to apoptosis. Additionally, the hypoxic microenvironment has been found to further induce apoptosis resistance, the hypoxia-inducible factors (HIF) up-regulate the factors of DNA-repair machinery (Milane et al. 2011)