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ADAM9-Responsive Mesoporous Silica Nanoparticles for Targeted Drug Delivery in Pancreatic Cancer
Etienne J Slapak1,2,3, Lily Kong4, Mouad El Mandili1,2
1Center of Experimental and Molecular Medicine, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate of all cancers. This poor prognosis results from the lack of efficient systemic treatment regimens, demanding high-dose chemotherapy that causes severe side effects. To overcome dose-dependent toxicities, we explored the efficacy of targeted drug delivery using a protease-dependent drug-release system. To this end, we developed a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSN) functionalized with an avidin-biotin gatekeeper system containing a protease linker that is specifically cleaved by tumor cells. Bioinformatic analysis identified ADAM9 as a PDAC-enriched protease, and PDAC cell-derived conditioned medium efficiently cleaved protease linkers containing ADAM9 substrates. Cleavage was PDAC specific as conditioned medium from leukocytes was unable to cleave the ADAM9 substrate. Protease linker-functionalized MSNs were efficiently capped with avidin, and cap removal was confirmed to occur in the presence of PDAC cell-derived ADAM9. Subsequent treatment of PDAC cells in vitro with paclitaxel-loaded MSNs indeed showed high cytotoxicity, whereas no cell death was observed in white blood cell-derived cell lines, confirming efficacy of the nanoparticle-mediated drug delivery system. Taken together, this research introduces a novel ADAM9-responsive, protease-dependent, drug delivery system for PDAC as a promising tool to reduce the cytotoxicity of systemic chemotherapy.
Insights
Researchers developed a novel drug delivery system for pancreatic cancer using nanoparticles that release medication only when encountering specific tumor enzymes. This targeted approach aims to reduce chemotherapy side effects by increasing drug efficacy directly at the tumor site.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits a poor prognosis due to limited effective systemic treatments and severe side effects from high-dose chemotherapy.
- Current treatment strategies necessitate high chemotherapy doses, leading to dose-dependent toxicities and limiting therapeutic efficacy.
- There is a critical need for targeted drug delivery systems to enhance treatment effectiveness and minimize systemic toxicity in PDAC.
Purpose of the Study:
- To develop and evaluate a novel protease-dependent drug delivery system for pancreatic ductal adenocarcinoma (PDAC).
- To engineer mesoporous silica nanoparticles (MSN) functionalized for tumor-specific drug release, targeting PDAC-enriched proteases.
- To assess the efficacy and specificity of the developed nanoparticle system in vitro for reducing chemotherapy-induced cytotoxicity.
Main Methods:
- Designed a drug delivery system using mesoporous silica nanoparticles (MSN) with an avidin-biotin gatekeeper system.
- Incorporated a protease linker specifically cleaved by ADAM9, a protease identified as enriched in PDAC.
- Validated protease-dependent cap removal and drug release using PDAC cell-derived conditioned medium and confirmed specificity against leukocyte-derived medium.
- Evaluated the cytotoxicity of paclitaxel-loaded MSNs against PDAC cells and white blood cell lines in vitro.
Main Results:
- Identified ADAM9 as a PDAC-specific protease capable of cleaving the engineered protease linkers.
- Demonstrated efficient cap removal of MSN by PDAC cell-derived ADAM9, confirming targeted release mechanism.
- Showcased high in vitro cytotoxicity of paclitaxel-loaded MSNs against PDAC cells.
- Confirmed minimal to no cell death in white blood cell lines, indicating high specificity and reduced off-target toxicity.
Conclusions:
- Introduced a novel ADAM9-responsive, protease-dependent drug delivery system for pancreatic ductal adenocarcinoma (PDAC).
- The developed nanoparticle system demonstrates targeted drug release, enhancing efficacy against PDAC cells.
- This targeted approach shows promise in reducing systemic chemotherapy cytotoxicity, offering a potential strategy for improved PDAC treatment.
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