期刊
MOLECULAR PHARMACEUTICS
卷 17, 期 2, 页码 392-403出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.9b00589
关键词
drug delivery; click chemistry; pancreatic cancer; brain delivery; extracellular matrix; computer modeling
资金
- National Center for Advancing Translational Sciences (NCATS)
- National Institutes of Health [UL1TR002489]
- UNC Lineberger Comprehensive Cancer Center's University Cancer Research Fund
- University of North Carolina
- North Carolina State University
Local presentation of cancer drugs by injectable drug-eluting depots reduces systemic side effects and improves efficacy. However, local depots deplete their drug stores and are difficult to introduce into stiff tissues, or organs, such as the brain, that cannot accommodate increased pressure. We present a method for introducing targetable depots through injection of activated ester molecules into target tissues that react with and anchor themselves to the local extracellular matrix (ECM) and subsequently capture systemically administered small molecules through bioorthogonal click chemistry. A computational model of tissue-anchoring depot formation and distribution was verified by histological analysis and confocal imaging of cleared tissues. ECM-anchored click groups do not elicit any noticeable local or systemic toxicity or immune response and specifically capture systemically circulating molecules at intradermal, intratumoral, and intracranial sites for multiple months. Taken together, ECM anchoring of click chemistry motifs is a promising approach to specific targeting of both small and large therapeutics, enabling repeated local presentation for cancer therapy and other diseases.
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