Comprehensively enhanced delivery cascade by transformable beaded nanofibrils for pancreatic cancer therapy

Facing the barriers in each step of the in vivo delivery cascade, the low drug delivery efficiency remains problematic in tumor therapy. Although recently the nanofibril drug delivery systems have shown improved circulation and accumulation compared with nanoparticles, the poor deep penetration and cellular internalization hinder their application, especially for pancreatic cancer with dense stroma. To comprehensively address the hurdles in the delivery cascade, a matrix metalloproteinase 2 (MMP-2) responsive transformable beaded nanofibril, which integrates the merits of nanofibril and small-sized nanoparticles, is established. The beaded nanofibril (GD@PPF) is prepared by conjugating gemcitabine-loaded small-sized nanoparticles (GD) with fibrous PEG-PCL (PPF) via GPLGVRG, a substrate peptide of MMP-2. GD@PPF escapes the clearance of the reticuloendothelial system (RES), prolongs the circulation time, and increases the selective accumulation in the tumor as fibrous micelles. Once accumulated in the tumor, small positively-charged GD is released from the beaded nanofibrils in response to MMP-2 overexpression in the stroma of pancreatic cancer, enabling permeation in the dense tumor matrix and cellular internalization, which makes up for the shortcomings of fibrous micelles. Furthermore, the remaining fibrous PPF surround the tumor tightly to impede the efflux of drugs, leading to improved retention. GD@PPF is biocompatible and exhibits excellent antitumor effect in Pan 02 subcutaneous tumor models. Therefore, the MMP-2 responsive transformable beaded nanofibril, which enhances the delivery efficiency in multiple stage of the delivery cascade, presents a promising strategy for pancreatic cancer therapy.