Redox Sensitive Shell and Core Crosslinked Hyaluronic Acid Nanocarriers for Tumor-Targeted Drug Delivery
Abstract
The purpose of the present study was to develop a robust and redox-sensitive nanocarrier based on amphiphilic hyaluronic acid nanoparticles, in which the hydrophobic core was crosslinked by photo-crosslinking and the hyaluronic acid shell was crosslinked via a bioreducible disulfide linkage. Dynamic light scattering showed that the shell and core crosslinked nanocarriers were obviously more stable than core crosslinked or non-crosslinked nanoparticles. Moreover, the particle size changed as the glutathione concentration was altered, exhibiting obvious redox sensitivity. Transmission electron microscopy showed that the nanoparticle structure was denser after crosslinking. Additionally, methotrexate was effectively encapsulated into nanoparticles with high drug-loading efficiency. In vitro methotrexate release assays showed that the methotrexate-loaded bioreducible hyaluronic acid nanoparticles greatly suppressed drug release in phosphate-buffered saline (pH 7.4) without or with 20 μM glutathione. In contrast, in phosphate-buffered saline (pH 7.4) with higher glutathione concentrations (2, 5, or 10 mM), methotrexate was released more rapidly and completely from the nanocarriers in 24 h. Furthermore, methotrexate was released completely and rapidly from the nanoparticles under simulated tumor cell conditions (pH 5.0 with 10 mM glutathione), suggesting potential applications in tumor-specific drug release. In vitro anticancer activity tests showed that the inhibition rate of methotrexate-loaded nanoparticles in HeLa cells reached 94%. However, excess hyaluronic acid decreased cell toxicity. Cellular uptake studies suggested that the prepared nanoparticles were probably internalized into the cancer cells via receptor-mediated endocytosis. Overall, our data demonstrated that the bio-reducible shell and core crosslinked nanoparticles could be used as a potential carrier for cancer therapy.
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The nanosized structure of micelles contributes to diffusion through leaky blood vessels to accumulate drugs in tumor tissues, known as the enhanced permeability and retention effect.
“The nanosized structure of micelles contributes to the diffusion of micelles through the leaky blood vessels to accumulate drugs in the tumor tissues, also known as enhanced permeability and retention (EPR) effect.40,41”
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- Authors
- Zheng, H., Yin, L., Zhang, X., Zhang, H., Hu, R., Yin, Y., Qiu, T., Xiong, X., & Wang, Q.
- Venue
- Journal of Biomedical Nanotechnology
- Publisher
- American Scientific Publishers
- Published
- 2016-08-01
- Volume
- 12
- Issue
- 8
- Pages
- 1641-1653
- ISSN
- 1550-7033 (ISSN-L)
- OpenAlex
- W2482918599
- Cited by
- 64
- References
- 0
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 12 · 2019: 14 · 2018: 16 · 2017: 8
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Biomedical Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- hyaluronic acid nanoparticles, photocrosslinking, disulfide bonds, glutathione-responsive release, methotrexate, anticancer drug delivery, tumor microenvironment, receptor-mediated endocytosis, HeLa cells, anticancer activity
- MeSH terms
- Antineoplastic Agents, Cross-Linking Reagents, Drug Carriers, Glutathione, HeLa Cells, Humans, Hyaluronic Acid, Methotrexate, Oxidation-Reduction, Particle Size, Cell Proliferation, Nanoparticles, Hydrophobic and Hydrophilic Interactions
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