Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer

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• 作者：Barbara Grü ; nwald^a ; ¹ ; Jennifer Vandooren^b ; ¹ ; Erica Locatelli^c ; ¹ ; Pierre Fiten^b ; Ghislain Opdenakker^b ; Paul Proost^b ; Achim Krü ; ger^a ; Jean Paul Lellouche^d ; Liron Limor Israel^d ; Louis Shenkman^e ; Mauro Comes Franchini^c ; ^{mauro.comesfranchini@unibo.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MMP-9 ; Nanoparticles ; Targeting ; Drug delivery ; Pancreatic cancer
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 October 2016
• 年：2016
• 卷：239
• 期：Complete
• 页码：39-48
• 全文大小：2136 K

文摘

Specific cancer cell targeting is a pre-requisite for efficient drug delivery as well as for high-resolution imaging and still represents a major technical challenge. Tumor-associated enzyme-assisted targeting is a new concept that takes advantage of the presence of a specific activity in the tumor entity. MMP-9 is a protease found to be upregulated in virtually all malignant tumors. Consequently, we hypothesized that its presence can provide a de-shielding activity for targeted delivery of drugs by nanoparticles (NPs) in pancreatic cancer. Here, we describe synthesis and characterization of an optimized MMP-9-cleavable linker mediating specific removal of a PEG shield from a PLGA-b-PEG-based polymeric nanocarrier (Magh@PNPs-PEG-RegaCP-PEG) leading to specific uptake of the smaller PNPs with their cargo into cells. The specific MMP-9-cleavable linker was designed based on the degradation efficiency of peptides derived from the collagen type II sequence. MMP-9-dependent uptake of the Magh@PNPs-PEG-RegaCP-PEG was demonstrated in pancreatic cancer cells in vitro. Accumulation of the Magh@PNPs-PEG-RegaCP-PEG in pancreatic tissues in the clinically relevant KPC mouse model of pancreatic cancer, as a proof-of-concept, was tumor-specific and MMP-9-dependent, indicating that MMP-9 has a strong potential as a specific mediator of PNP de-shielding for tumor-specific uptake. Pre-treatment of mice with Magh@PNPs-PEG-RegaCP-PEG led to reduction of liver metastasis and drastically decreased average colony size. In conclusion, the increased tumor-specific presence and activity of MMP-9 can be exploited to deliver an MMP-9-activatable NP to pancreatic tumors specifically, effectively, and safely.