Highly permeable and tumor-selective killing Doxil for efficient cancer therapy

Poly(ethylene glycol)-modified (PEGylated) liposomal doxorubicin (Doxil), a clinically used long-circulating liposomal delivery system of doxorubicin for the treatment of various malignancies, is bottlenecked by its therapeutic outcome due to insufficient tumor penetration, suboptimal drug release within the tumor microenvironment, and non-selective toxicities to normal cells. To address these limitations, we developed poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)-b-poly(ε-caprolactone) (OPDEA-PCL)-functionalized Doxil (OP-Doxil) via a one-step engineering strategy using amphiphilic block copolymer, OPDEA-PCL. The decoration of OPDEA-PCL endowed Doxil with enhanced tumor penetration, cellular uptake, and pH-responsive drug release. Furthermore, OP-Doxil facilitated both nuclear and mitochondrial co-localization, thereby promoting tumor cell apoptosis while minimizing cytotoxicity to normal cells, realizing tumor-cell selective killing due to the distinct cellular uptake and pH-responsive doxorubicin (DOX) release between tumor cells and normal cells. In the orthotopic hepatocellular carcinoma model, a single injection of OP-Doxil showcased potent anti-tumor activity, achieving a tumor inhibition rate of 97.2%, compared to 68.4% in the Doxil-treated group. Additionally, OP-Doxil spared fibroblasts in the tumor microenvironment, while downregulating WNT16B expression and preventing tumor metastasis, with reduced cardiotoxicity. OP-Doxil also effectively inhibited lung metastasis and cancer embolus formation in the 4T1 breast cancer model. These results highlighted OP-Doxil as a safe, efficient, and clinically translatable therapeutic strategy for primary and metastatic tumors.