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Synthesis and characterization of a PDMS-PMOXA based polymersomes sensitive to MMP-9 for application in breast cancer
Journal
Molecular pharmaceutics
Volume
15
Number
11
Pages / Article-Number
4884-4897
Mesh terms
Animals; Antineoplastic Agents, Phytogenic, pharmacokinetics; Breast Neoplasms, pathology; Drug Carriers, chemical synthesis; Drug Liberation; Embryo, Nonmammalian; Female; Humans; MCF-7 Cells; Matrix Metalloproteinase 9, metabolism; Nanoparticles, chemistry; Oxazoles, chemical synthesis; Paclitaxel, pharmacokinetics; Polymers, chemical synthesis; Treatment Outcome; Xenograft Model Antitumor Assays; Zebrafish
Abstract
Cytotoxic compounds used to treat cancer are often associated with adverse events. The development of formulations activated by tumor-specific triggers would allow a reduction of systemic exposure while maintaining therapeutic concentrations in the tumor. One enzyme with proteolytic activity reported to be involved in tumor progression and assumed to be enhanced in the tumor environment is the matrixmetalloproteinase 9 (MMP-9). In our study, we aimed to develop surface modified PDMS-PMOXA polymersomes able to release their cytotoxic payload upon digestion by MMP-9. To test the applicability of such a system in breast cancer, this tumor entity was assessed for MMP-9 expression, supporting breast cancer as a potential target. The surface-modified polymersomes were synthesized and formulated resulting in paclitaxel loaded particles of about 320 ± 153.15 nm in size with a surface potential of 0.04 ± 0.007 mV. After verifying expression and activity of MMP-9 in MCF7 cells, this cell line was used for further analysis. Treatment of MCF7 cells with the polymersomes significantly reduced cell viability, this effect was abolished after addition of MMP-inhibitors, suggesting proteolytic activation. In zebrafish embryos, the polymersomes were observed in the circulation with some enrichment in liver and agglomerates in the caudal veins. Importantly, in zebrafish embryos xenografted with mKate2-expressing MCF7 cells the amount of tumor cells, quantified by detecting the copies of the heterologously expressed fluorescent protein, significantly decreased after treatment with PDMS-PMOXA-SRL paclitaxel polymersomes. Taken together our data suggest that polymersomes modified with an MMP-9 labile peptide and loaded with paclitaxel can be formulated, and that these particles exert pharmacological activity upon enzymatic digestion.
