Stimuli-Responsive Nanomedicines for Overcoming Cancer Multidrug Resistance

Abstract

Chemotherapy is still a main option for cancer therapy, but its efficacy is often unsatisfying due to multidrug resistance (MDR). The tumor microenvironment is considered a dominant factor causing MDR. Stimuli-responsive nanomedicines exhibit many superiorities for reversal of MDR. As smart systems, stimuli-responsive nanomedicines are desirable for achieving site-specific accumulation and triggered drug release in response to slight changes in physicochemical properties in pathological conditions or to exogenous stimuli. In this review, we highlight the current progress of various nanomedicines with different stimuli-responsive capabilities for overcoming MDR. The materials, design, construction as well as efficacy in overcoming MDR of these nanomedicines are discussed. Eventually, we look forward to forthcoming intelligent nanoparticle systems with new mechanisms to deliver drugs for practical applications in conquering cancer MDR.

The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein

“…There are many mechanisms that lead to multidrug resistance such as: (i) overexpression of transmembrane ABC transporters that efflux drugs from the cytoplasm to the extracellular environment; (ii) defective apoptosis pathways that prevent the cell from undergoing programmed death; (iii) increased DNA damage response pathways that protect the cell from damage induced by agents; (iv) overexpression of metabolism genes involved in detoxification of chemotherapy agents (e.g., cytochrome P450); (v) the tumor microenvironment features that can hinder drug penetration and distribution [80]. Over-expression of ABC drug transporters is the most frequent mechanism of MDR, which is estimated to be responsible for up to 90% of the failures in cancer chemotherapy [46]. Drug transporter proteins such as P-gp and MRP1 are often up-regulated in various types of cancer.…”

“…In the light of this issue, a recent strategy to circumvent MDR is to develop an active targeting nanosystem that would reduce or eliminate nonspecific activity in healthy cells and increase penetration in the diseased tissue. These nanosystems can carry old and new anti-cancer compounds to the neoplastic cells avoiding or reducing any possible adverse effect and killing them successfully [46].…”

“…These stimuli change the structure of the nanoparticle facilitating the release of the cargo. In addition, more than one stimulus can be exploited [46].…”

“…The strategies that has been developed and applied for years in nanosystems can be used and coupled with the ones that aim to modulate the ABC efflux function, enhancing the efficacy of today's formulations (e.g., all generations of ABC inhibitors) that still holds many issues as described before [46]. Graphene [55,56], silica mesoporous [57] and polymeric nanoparticles [58] are promising vehicles that can be built with high specificity to tumor cells, fulfilling these strategies [46].…”

“Locked” cancer cells are more sensitive to chemotherapy

“…Nanomedicines, including liposomes, [17][18][19] nanocrystals, 16,[20][21][22][23] biomimetic nanoparticles, [24][25][26][27][28] lipid drop-based nanocapsules, 29 polymer nanoparticles, [30][31][32][33][34][35] nanovaccines, 36,37 and so on, offer the promising potential to deliver the drug to the target site of interest with improved efficacy and reduced side effects. [38][39][40] Dual nanomedicinebased combinatorial therapy refers to coadministrating two separate nanomedicines.…”