Nanomedicines for combating multidrug resistance of cancer.

Chemotherapy typically involves the use of specific chemodrugs to inhibit the proliferation of cancer cells, but the frequent emergence of a variety of multidrug-resistant cancer cells poses a tremendous threat to our combat against cancer. The fundamental causes of multidrug resistance (MDR) have been studied for decades, and can be generally classified into two types: one is associated with the activation of diverse drug efflux pumps, which are responsible for translocating intracellular drug molecules out of the cells; the other is linked with some non-efflux pump-related mechanisms, such as antiapoptotic defense, enhanced DNA repair ability, and powerful antioxidant systems. To overcome MDR, intense efforts have been made to develop synergistic therapeutic strategies by introducing MDR inhibitors or combining chemotherapy with other therapeutic modalities, such as phototherapy, gene therapy, and gas therapy, in the hope that the drug-resistant cells can be sensitized toward chemotherapeutics. In particular, nanotechnology-based drug delivery platforms have shown the potential to integrate multiple therapeutic agents into one system. In this review, the focus was on the recent development of nanostrategies aiming to enhance the efficiency of chemotherapy and overcome the MDR of cancer in a synergistic manner. Different combinatorial strategies are introduced in detail and the advantages as well as underlying mechanisms of why these strategies can counteract MDR are discussed. This review is expected to shed new light on the design of advanced nanomedicines from the angle of materials and to deepen our understanding of MDR for the development of more effective anticancer strategies. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Photosensitizer-Doped and Plasma Membrane-Responsive Liposomes for Nuclear Drug Delivery and Multidrug Resistance Reversal.

Clinically approved doxorubicin (Dox)-loaded liposomes (e.g., Doxil) guarantee good biosafety, but their insufficient nuclear delivery of Dox (<0.4%) after cellular uptake significantly hampers their final anticancer efficacy. Here, we report that simply doping protoporphyrin IX (PpIX, a commonly used hydrophobic photosensitizer) into the lipid bilayers of Dox-loaded liposomes (the resultant product is termed PpIX/Dox liposomes) is a feasible way to promote the nuclear delivery of Dox. This facile strategy relies on a unique property of PpIX-it presents considerably higher affinity for the real plasma membrane over its liposomal carrier, which drives the doped PpIX molecules to detach from the liposomes when encountering cancer cells. We demonstrate that this process can trigger the efficient release of the loaded Dox molecules and allow them to enter the nuclei of MCF-7 breast cancer cells without being trapped by lysosomes. Regarding the drug-resistant MCF-7/ADR cells, the aberrant activation of the efflux pumps in the plasma membranes expels the internalized Dox. However, we strikingly find that the robust drug resistance can be reversed upon mild laser irradiation because the photodynamic effect of PpIX disrupts the drug efflux system (e.g., P-glycoprotein) and facilitates the nuclear entry of Dox. As a proof-of-concept, this PpIX doping strategy is also applicable for enhancing the effectiveness of cisplatin-loaded liposomes against both A549 and A549/DDP lung cancer cells. In vivo experimental results prove that a single injection of PpIX/Dox liposomes completely impedes the growth of MCF-7 tumors in nude mice within 2 weeks and, in combination with laser irradiation, can synergistically ablate MCF-7/ADR tumors. Biosafety assessments reveal no significant systemic toxicity caused by PpIX/Dox liposomes. This work exemplifies a facile method to modulate the subcellular fate of liposomal drugs and may inspire the optimization of nanopharmaceuticals in the near future.