GE11 peptide-installed chimaeric polymersomes tailor-made for high-efficiency EGFR-targeted protein therapy of
Cheng Zhou1, Yifeng Xia1, Yaohua Wei1
1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Soochow University, Suzhou, 215123, PR China.
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.
Insights
Researchers developed GE11 peptide-installed chimaeric polymersomes (GE11-CPs) for targeted protein therapy in hepatocellular carcinoma (HCC). This novel delivery system enhanced protein drug delivery and efficacy, significantly improving survival rates in mice with HCC tumors.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited therapeutic advancements.
- Protein drugs offer high potency and specificity but lack effective delivery systems for HCC treatment.
Purpose of the Study:
- To design and evaluate GE11 peptide-functionalized chimaeric polymersomes (GE11-CPs) for targeted protein delivery in HCC.
- To assess the efficacy of GE11-CPs loaded with saporin for treating orthotopic HCC in a mouse model.
Main Methods:
- GE11-CPs were synthesized using PEG-P(TMC-DTC)-PAsp polymers, enabling protein encapsulation and surface functionalization.
- Protein loading efficiency, release kinetics (glutathione-responsive), and particle characteristics were analyzed.
- In vitro cellular uptake and in vivo biodistribution, anti-tumor efficacy, and survival rates were evaluated in HCC models.
Main Results:
- GE11-CPs demonstrated efficient protein loading (60-72%) and controlled release.
- GE11-CPs showed enhanced cellular uptake and a 3-fold increase in saporin's anti-cancer potency.
- In vivo studies revealed 3-fold higher tumor accumulation, significant tumor inhibition, and improved median survival (99 days vs. 37-42 days).
Conclusions:
- GE11-CPs represent a promising platform for targeted protein delivery in HCC therapy.
- This EGFR-targeted approach enhances therapeutic efficacy and reduces toxicity, offering a potential new treatment modality for HCC.
