Transferrin-Guided Polymersomal Doxorubicin for Potent and Low-Toxic Chemotherapy of Orthotopic Hepatocellular Carcinoma in Vivo

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies. The current chemotherapy with typically low tumor uptake and high toxicity reveals a poor anti-HCC efficacy. Here, we report transferrin-guided polycarbonate based polymersomal doxorubicin (Tf-Ps-Dox) as a low-toxic and potent nanotherapeutics for effective treatment of transferrin receptor (TfR)-positive human liver tumor SMMC-7721 models. Tf-Ps-Dox was facilely fabricated with small sizes of ca. 75 nm and varying Tf densities from 2.2% to 7.0%, by post-modification of maleimide-functionalized Ps-Dox (Dox loading content of 10.6 wt.%) with thiolated transferrin. MTT assays showed that Tf-Ps-Dox had an optimal Tf surface density of 3.9%. The cellular uptake, intracellular Dox level, and anticancer efficacy of Tf-Ps-Dox to SMMC-7721 cells were inhibited by supplementing free transferrin, supporting that Tf-Ps-Dox is endocytosed via TfR. Interestingly, Tf-Ps-Dox exhibited a high accumulation of 8.5% ID/g in subcutaneous SMMC-7721 tumors, which was 2 and 3-fold higher than non-targeted Ps-Dox and clinically used liposomal Dox formulation (Lipo-Dox), respectively. The median survival times of mice bearing orthotopic SMMC-7721 tumors increased from 82, 88 to 96 days when treated with Tf-Ps-Dox at Dox doses from 8, 12 to 16 mg/kg, which was significantly better than Ps-Dox at 8 mg/kg (58 days) and Lipo-Dox at 4 mg/kg (48 days) or PBS (36 days). Notably, unlike Lipo-Dox, no body weight loss and damage to major organs could be discerned for all Tf-Ps-Dox groups, indicating that Tf-Ps-Dox causes low systemic toxicity. This transferrin-dressed polymersomal doxorubicin provides a potent and low-toxic treatment modality for human hepatocellular carcinoma.