SP94 peptide mediating highly specific and efficacious delivery of polymersomal doxorubicin hydrochloride to hepatocellular carcinoma in vivo

The effective treatment of hepatocellular carcinoma (HCC) requires development of novel drug formulations that selectively kill HCC cells while sparing healthy liver cells. Here, we designed and investigated HCC-specific peptide, SP94 (SFSIIHTPILPLGGC), decorated smart polymersomal doxorubicin hydrochloride (SP94-PS-DOX) for potent treatment of orthotopic human SMMC-7721 HCC xenografts. SP94-PS-DOX was fabricated by post ligand-modification, affording robust nano-formulations with a diameter of ∼ 76 nm and DOX content of 9.9 wt.%. The internalization of SP94-PS-DOX by SMMC-7721 cells showed a clear dependence on SP94 surface densities, in which 30 % SP94 resulted in ca. 3-fold better cellular uptake over non-targeted control (PS-DOX). In accordance, SP94-PS-DOX exhibited superior inhibition of SMMC-7721 cells to PS-DOX and clinical liposome injections (Lipo-DOX). Notably, a remarkable tumor deposition of 14.9 %ID/g and tumor-to-normal liver ratio of ca. 6.9 was observed for SP94-PS-DOX in subcutaneous SMMC-7721 HCC xenografts. More interestingly, SP94-PS-DOX under 10 mg DOX/kg induced far better therapeutic efficacy toward orthotopic SMMC-7721 HCC models than PS-DOX and Lipo-DOX controls giving substantial survival benefits and little adverse effects. The remarkable specificity and therapeutic outcomes lend SP94-PS-DOX promising for targeted HCC therapy.