Low-toxicity transferrin-guided polymersomal doxorubicin for potent chemotherapy of orthotopic hepatocellular carcinoma in vivo

Yaohua Wei ^a,b , Xiaolei Gu ^a , Liang Cheng ^{a,c, *}（程亮） , Fenghua Meng ^{a, *}（孟凤华） , Gert Storm ^b , Zhiyuan Zhong ^{a, *}（钟志远）

^a Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China

^b Department of Biomaterials Science and Technology, MIRA Institute for Biological Technology and Technical Medicine, University of Twente, PO Box 217, 7500AE Enschede, The Netherlands

^c Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China

Acta Biomaterialia 92 (2019) 196--204

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 nanotherapeutic agent for effective treatment of liver tumor using a transferrin receptor (TfR)-positive human liver tumor SMMC-7721 model. Tf-Ps-Dox was facilely fabricated with small size of ca. 75 nm and varying Tf densities from 2.2% to 7.0%, by postmodification 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, which supports that Tf-Ps-Dox is endocytosed through TfR. Interestingly, Tf-Ps-Dox exhibited a high accumulation of 8.5%ID/g (percent injected dose per gram of tissue) in subcutaneous SMMC-7721 tumors, which was 2- and 3-fold higher than that of nontargeted 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 longer than that of 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 caused low systemic toxicity. This transferrin-dressed polymersomal doxorubicin provides a potent and low-toxic treatment modality for human hepatocellular carcinoma.

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