Long-Circulating Amphiphilic Doxorubicin for Tumor Mitochondria-Specific Targeting

Abstract

The mitochondria have emerged as a novel target for cancer chemotherapy primarily due to their central roles in energy metabolism and apoptosis regulation. Here, we report a new molecular approach to achieve high levels of tumor- and mitochondria-selective deliveries of the anticancer drug doxorubicin. This is achieved by molecular engineering, which functionalizes doxorubicin with a hydrophobic lipid tail conjugated by a solubility-promoting poly(ethylene glycol) polymer (amphiphilic doxorubicin or amph-DOX). In vivo, the amphiphile conjugated to doxorubicin exhibits a dual function: (i) it binds avidly to serum albumin and hijacks albumin’s circulating and transporting pathways, resulting in prolonged circulation in blood, increased accumulation in tumor, and reduced exposure to the heart; (ii) it also redirects doxorubicin to mitochondria by altering the drug molecule’s intracellular sorting and transportation routes. Efficient mitochondrial targeting with amph-DOX causes a significant increase of reactive oxygen species levels in tumor cells, resulting in markedly improved antitumor efficacy than the unmodified doxorubicin. Amphiphilic modification provides a simple strategy to simultaneously increase the efficacy and safety of doxorubicin in cancer chemotherapy.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…Due to its high affinity toward membrane bilayer, diacyl lipid‐immunostimulatory oligonucleotide conjugates were designed to target Toll‐like receptor (TLR) 9, which are exclusively expressed within the endosomal compartments of APCs . The enhanced cellular uptake and intracellular targeting by amphiphilic modification have been applied to overcome the drug‐resistance, one of the major challenges in current cancer chemotherapy . This is achieved by amphiphilic conjugation which alters the internalization pathways, or delivers and anchors the drug to intracellular organelles where the P‐glycoprotein efflux pump cannot access …”

“…C) Molecular structure and confocal image of mitochondria‐targeting amphiphilic doxorubicin. Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…conjugated the amine group of doxorubicin to 1,2‐Distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE) linked with a polyethylene glycol linker (amph‐dox, Figure 4D). Interestingly, this simple molecular conjugate achieved high levels of tumor‐ and mitochondria‐selective accumulation of doxorubicin. Although it is not clear how amphiphilic modification impacts doxorubicin's cellular uptake and intracellular trafficking, it is concluded that amphiphilic modification altered the physicochemical properties of doxorubicin, which in turn retargets it to mitochondria …”

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“…Recently, mitochondria have emerged as a hot target in cancer therapy due to their central roles in regulating cell metabolism and apoptosis. Delivery of anticancer drugs to mitochondria may bypass the classical resistance pathways while maintaining or improving their therapeutic efficacy 32,33. In addition, induction of mitochondria-mediated apoptosis could also enhance the efficiency of cancer therapy 34.…”

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“…Recent studies have revealed that LIFU sonication can accurately steer drug release, meanwhile, locally facilitate the diffusion and penetration of drugs 15,16. Among the chemotherapeutics regularly used in clinical GC treatment, DNA-binding medicine, doxorubicin (DOX) has always been widely used due to its excellent anti-proliferation and apoptosis-promoting effect 17. However, with the defect of non-specific distribution in organs and the high blood concentration needed to fulfill the therapeutic dose, DOX will indiscriminately attack proliferating tumor and normal tissue cells, sequentially leading to severe systemic toxicity, such as myelosuppression and cardiotoxicity, thus greatly limiting its therapeutic potential 18.…”