EGFR and CD44 Dual-Targeted Multifunctional Hyaluronic Acid Nanogels Boost Protein Delivery to Ovarian and Breast Cancers In Vitro and In Vivo
Abstract
Protein drugs with intracellular targets like Granzyme B (GrB) have demonstrated great proliferative inhibition activity in cancer cells. Their clinical translation, however, relies on the development of safe, efficient, and selective protein-delivery vehicles. Here, we report that epidermal growth factor receptor (EGFR) and CD44 dual-targeted multifunctional hyaluronic acid nanogels (EGFR/CD44-NGs) boost protein delivery to ovarian and breast cancers in vitro and in vivo. EGFR/CD44-NGs obtained via nanoprecipitation and photoclick chemistry from hyaluronic acid derivatives with tetrazole, GE11 peptide/tetrazole, and cystamine methacrylate groups had nearly quantitative loading of therapeutic proteins like cytochrome C (CC) and GrB, a small size of ca. 165 nm, excellent stability in serum, and fast protein release under a reductive condition. Flow cytometry assays showed that EGFR/CD44-NGs exhibited over 6-fold better uptake in CD44 and EGFR-positive SKOV-3 ovarian cancer cells than CD44-NGs. In accordance, GrB-loaded EGFR/CD44-NGs (GrB-EGFR/CD44-NGs) displayed enhanced caspase activity and growth inhibition in SKOV-3 cells as compared to GrB-loaded CD44-NGs (GrB-CD44-NGs) control. Intriguingly, the therapeutic studies in SKOV-3 human ovarian carcinoma and MDA-MB-231 human breast tumor xenografted in nude mice revealed that GrB-EGFR/CD44-NGs at a low dose of 3.85 nmol GrB equiv/kg induced nearly complete growth suppression of both tumors, which was obviously more effective than GrB-CD44-NGs, without causing any adverse effects. EGFR and CD44 dual-targeted multifunctional hyaluronic acid nanogels have appeared as a safe and efficacious platform for cancer protein therapy.
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Dual targeting approaches with EGFR and CD44 are effective for enhancing EPR-based drug delivery and may decrease uncertainty of a single targeting strategy.
“Dual targeting approaches with EGFR and CD44 are also effective for enhancing EPR-based drug delivery, which may decrease the uncertainty of a single targeting strategy [54,55].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [54]
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- Authors
- Chen, J., Ouyang, J., Chen, Q., Deng, C., Meng, F., Zhang, J., Cheng, R., Lan, Q., & Zhong, Z.
- Affiliations
- Soochow University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Corresponding author
- Deng, Chao
- Zhong, Zhiyuan
- Venue
- ACS Applied Materials & Interfaces
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-07-10
- Volume
- 9
- Issue
- 28
- Pages
- 24140-24147
- ISSN
- 1944-8244 (ISSN-L)
- 1944-8252
- OpenAlex
- W2732191012
- Cited by
- 124
- References
- 59
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 15 · 2022: 14 · 2021: 12 · 2020: 16 · 2019: 24 · 2018: 20 · 2017: 3
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Applied Materials & Interfaces (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (51403147, 51473110, 51633005)
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- hyaluronic acid nanogels, EGFR, CD44, dual-targeted drug delivery, protein delivery, granzyme B, cytochrome c, ovarian cancer, breast cancer, SKOV3 cells, MDA-MB-231 cells, photoclick chemistry, tetrazoles, tumor xenografts
- MeSH terms
- Animals, Breast Neoplasms, Female, Humans, Hyaluronic Acid, Mice, Nude, Ovarian Neoplasms, Hyaluronan Receptors, Cell Line, Tumor, Mice, Nanoparticles, ErbB Receptors
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