MT1?MMP?Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy

ABSTRACT: Abstract Promoting tumor angiogenesis effectively and specifically to resolve tumor?associated hypoperfusion holds promise for improving pancreatic cancer therapy. Herein, a doxorubicin (DOX) loaded smart liposome, MC?T?DOX, is constructed, that carries appropriately low?density cilengitide, an ?v?3 integrin?specific Arg?Gly?Asp (RGD)?mimetic cyclic peptide, via a membrane type 1?matrix metalloproteinase (MT1?MMP) cleavable peptide. After being administered systemically in a hypoperfused pancreatic cancer mouse model at a low dose of cilengitide, the proangiogenic activity of MC?T?DOX is specifically “turned on” in tumor vessels through cleavage by MT1?MMP on tumor endothelial cells to release cilengitide. This locally released cilengitide increases tumor blood perfusion, thereby improving the accumulation and distribution of MC?T?DOX in the tumor site. The loaded?DOX then displays enhanced penetration and increased cellular uptake upon heat?triggered release from MC?T?DOX in the tumor interstitium, contributing to the improved tumor therapy efficacy. Therefore, the strategy of combining the modulation of tumor vascular promotion with smart nanodrug delivery represents a promising approach to improving drug delivery and therapeutic efficacy in a wide range of hypoperfused tumors. Low?density membrane type 1?matrix metalloproteinase (MT1?MMP)?activated cilengitide (MC) is modified onto thermosensitive liposomes loaded with doxorubicin (DOX), yielding MC?T?DOX. MC?T?DOX is activated by MT1?MMP on tumor endothelial cells to release cilengitide, which then improves tumor blood perfusion, thereby enhancing intratumoral delivery of MC?T?DOX. Subsequently, in the interstitium, heat?triggered DOX release from MC?T?DOX facilitates its bioavailability, thereby exerting improved antitumor efficacy.

SUBMITTER: Wei Y 

PROVIDER: S-EPMC7507343 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature