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.