GE11 Peptide-Installed Chimaeric Polymersomes Tailor-Made for High-Efficiency EGFR-Targeted Protein Therapy of Orthotopic Hepatocellular Carcinoma

Cheng Zhou, Yifeng Xia, Yaohua Wei, Liang Cheng (Corresponding author), Jingjing Wei, Beibei Guo, Fenghua Meng (Corresponding author), Shoupeng Cao, Jan C.M. van Hest, Zhiyuan Zhong (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) remains a leading malignancy with a high mortality and little improvement in treatments. Protein drugs though known for their extraordinary potency and specificity have rarely been investigated for HCC therapy owing to lack of appropriate delivery systems. Here, we designed GE11 peptide-installed chimaeric polymersomes (GE11-CPs) for high-efficiency EGFR-targeted protein therapy of orthotopic SMMC 7721 HCC-bearing nude mice. GE11-CPs were assembled from poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-poly(aspartic acid) (PEG-P(TMC-DTC)-PAsp) and GE11-functionalized PEG-P(TMC-DTC), which allowed efficient loading and protection of proteins in the watery interior and fine-tuning of GE11 densities at the surface. CPs with short PAsp segments (degree of polymerization (DP) = 5, 10 and 15) exhibited a protein loading efficiency of 60%-72% and glutathione-responsive protein release. Saporin-loaded GE11-CPs had a size of 36 - 62 nm depending on GE11 densities and DP of PAsp. Notably, GE11-CPs with 10% GE11 revealed greatly enhanced uptake in SMMC 7721 cells, boosting the anticancer potency of saporin for over 3-folds compared with non-targeted control (half-maximal inhibitory concentration (IC50) = 11.0 versus 36.3 nM). The biodistribution studies using Cy5-labeled cytochrome C as a model protein demonstrated about 3-fold higher accumulation of GE11-CPs formulation than CPs counterpart in both subcutaneous and orthotopic SMMC 7721 tumor models. Notably, saporin-loaded GE11-CPs revealed low toxicity, effective tumor inhibition and significant improvement of survival rate compared with PBS and non-targeted groups (median survival time: 99 versus 37 and 42 days). EGFR-targeted chimaeric polymersomes carrying proteins appear an interesting HCC treatment modality.
Original languageEnglish
Pages (from-to)512-521
Number of pages10
JournalActa Biomaterialia
Volume113
Early online date18 Jun 2020
DOIs
Publication statusPublished - 1 Sep 2020

Keywords

  • Active targeting
  • EGFR
  • Liver cancer
  • Polymersomes
  • Protein delivery

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