Microthrombi targeted nano-micelle synchronizing endothelial gap opening and matrix decompression for augmenting drug perfusion within pancreatic cancer

Local inhibition of the “patching” function of tumor-associated platelets against neutrophil infiltration-caused vascular breaches has been used as an “enhanced permeability and retention (EPR) amplification” strategy. Nevertheless, the vascular leakage-resulted elevation of interstitial fluid pressure (IFP) could impact tumoral perfusion and convection of nanodrugs. Especially for hypoperfused and desmoplastic pancreatic ductal adenocarcinoma (PDAC), solely relying on vascular destruction would predictably diminish tumoral drug perfusion. According to multi-thrombosis formation in PDAC, a microthrombi and matrix co-targeted dasatinib (DAS) nano-micelle (CPHD/DAS) synchronizing endothelial gap opening and matrix decompression was constructed for sustained augmentation of drug perfusion within PDAC. CPHD/DAS was composed of CREKA peptide-modified hyaluronic acid–deoxycholate conjugates co-assembled with DAS. In vitro and in vivo results demonstrated CPHD/DAS not only retarded tumor-associated platelet activation to enhance vascular permeability and expose subvascular matrix, but also inhibited pancreatic stellate cell activation to alleviate stroma barrier. Thus, the matrix decompression resisted IFP elevation caused by endothelial gap opening, facilitating sustained up-regulation of functional vessels. Based on superior tumor accumulation and penetration, CPHD/DAS exhibited favorable potency in Panc02 tumor model. This study provides a paradigm to improve the efficiency and application scope of “EPR amplification” strategy in antitumor therapy.