Perspectives of nano-carrier drug delivery systems to overcome cancer drug resistance in the clinics

Abstract

Advanced cancer is still considered an incurable disease because of its metastatic spread to distal organs and progressive gain of chemoresistance. Even though considerable treatment progress and more effective therapies have been achieved over the past years, recurrence in the long-term and undesired side effects are still the main drawbacks of current clinical protocols. Moreover, a majority of chemotherapeutic drugs are highly hydrophobic and need to be diluted in organic solvents, which cause high toxicity, in order to reach effective therapeutic dose. These limitations of conventional cancer therapies prompted the use of nanomedicine, the medical application of nanotechnology, to provide more effective and safer cancer treatment. Potential of nanomedicines to overcome resistance, ameliorate solubility, improve pharmacological profile, and reduce adverse effects of chemotherapeutical drugs is thus highly regarded. Their use in the clinical setting has increased over the last decade. Among the various existing nanosystems, nanoparticles have the ability to transform conventional medicine by reducing the adverse effects and providing a controlled release of therapeutic agents. Also, their small size facilitates the intracellular uptake. Here, we provide a closer review of clinical prospects and mechanisms of action of nanomedicines to overcome drug resistance. The significance of specific targeting towards cancer cells is debated as well.

Keywords: Drug delivery systems; cancer treatment; nanomedicine; resistance.

Figure 1

Different mechanisms of cancer drug resistance. A: elevated drug efflux, B: change in the cell metabolism, C: genetic modifications of the drug target, D: enhanced DNA damage response, E: inhibition of apoptosis

Figure 2

The tumours microenvironment is a heterogenic dynamic entity. It is composed of different cell types (differentiated cancer cells, cancer stem cells, normal stromal cells like fibroblasts, mesenchymal cells, and tumour-infiltrated immune cells). It is localised near the blood vessels to obtain the nutrients needed for its continued growth and survival

Figure 3

CSCs have stem-like properties. They have self-renewal, tumour initiation capacity, and long-term repopulation potential. CSCs are capable to enter the systemic circulation and generate metastasis. CSCs: cancer stem cells

Figure 4

Strong parallels between EMT activation and CSC formation. CSC phenotype is a bidirectional dynamic process. Most of the identified CSC markers are also found in cells with mesenchymal phenotype (e.g., CD44+/CD24-, SPARK, WNT, NOTCH, and ABCG). CSCs: cancer stem cells; EMT: mesenchymal transition

Figure 5

Extravasation and cell targeting. The abnormally wide fenestrations in the blood vessels and the lack of lymphatic drainage facilitates extravasation of NPs. Once in the tumour micro environment (TME), the targeting moiety of the NPs enable its interaction with the desired cells, providing active targeting. NPs: nanoparticles