Codelivery of a π–π Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multidrug Resistance and Tumor Metastasis

Abstract

The multidrug resistance (MDR) of cancer cells is a major obstacle in cancer chemotherapy and very few strategies are available to overcome it. Here, a new strategy is developed to codeliver a π–π stacked dual anticancer drug combination with an actively targeted, pH‐ and reduction‐sensitive polymer micellar platform for combating multidrug resistance and tumor metastasis. In contrast to other methods, two traditional chemotherapeutics, doxorubicin (DOX) and 10‐hydroxycamptothecin with complex aromatic π–π conjugated structures, are integrated into one drug delivery system via a π–π stacking interaction, which enables the released drugs to evade the recognition of drug pumps due to a slight change in the drug's molecular structure. The micelles exhibit active targeting of DOX‐resistant human breast cancer MCF‐7 cells (MCF‐7/ADR) and have the ability to control the release of the drug in response to the microenvironmental stimuli of tumor cells. As a result, the codelivery of the π–π stacked dual anticancer drug combination displays high therapeutic efficacy in the MCF‐7/ADR tumor model and successfully prevents the lung metastasis of tumor cells. The mechanism underlying the reversal of MDR is investigated, and the results reveal that the synergistic effect of the π–π stacked dual drugs promotes mitochondria‐dependent apoptosis.

Light and pH dual‐sensitive biodegradable polymeric nanoparticles for controlled release of cargos

“…The anticancer drug DOX, interacting with DNA by intercalation and inhibition of macromolecular biosynthesis, can be encapsulated into nanoparticles . In our case, DOX was loaded in the hydrophobic cores.…”

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

“…[ 1 ] NPs are generally thought to enter tumor site via enhanced permeability and retention (EPR) effect, but the extremely complex tumor microenvironment (TME), which includes dense extracellular matrices (ECMs), high cell packing density, increased interstitial flow pressure (IFP), and slow interstitial flow velocity, constitutes a variety of barriers to NPs delivery and results in poor penetration and inadequate retention in deep tumor tissues, dramatically weakening the accumulation capability of NPs at tumor sites. [ 2 ] It was reported that the median of NPs accumulated in tumor in vivo was only ≈0.7% of the injected dose (ID), whose corresponding % ID per gram of tissue was ≈4.2%. [ 3 ] The inability of NPs to intratumoral accumulate efficiently means poor therapeutic efficacy, systemic toxicity, and possible drug resistance.…”

“…[ 3 ] The inability of NPs to intratumoral accumulate efficiently means poor therapeutic efficacy, systemic toxicity, and possible drug resistance. [ 2f ] To achieve the maximum chemotherapeutic efficacy, the accumulation of abundant NPs in tumor is of great importance. However, it is currently full of challenges to increase intratumoral accumulation of NPs.…”

pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer

“…In addition, intracellular organelle microenvironments such as low pH in endo-/lysosomal compartments are also available for triggering drug release from drug-carrier conjugates which contain acid-cleavable linkages. 25,26 In the aim to overcome the P-gp-mediated MDR, in this study we report novel surface charge-reversible polymer micelles which could cascade release PTX and DSF inside drug-resistant tumor cells (Scheme 1). The carriers were constituted with succinic anhydride-modified PTX (SA-PTX) and 2,3-dimethylmaleic anhydride (DMA)-conjugated poly(ethylene glycol)-b-poly(l-lysine).…”