A cooperative polymeric platform for tumor-targeted drug delivery† †Electronic supplementary information (ESI) available: Materials, experimental description of preparation of FITC-labeled fibrinogen, histopathological analyses at varied doses of DMXAA, preparation of RhoB- and IR830-labeled A15-PGA-CisPt, characterization of the prepared A15-PGA-CisPt conjugates, in vitro release, cytotoxicity, cellular uptake, stability test in plasma, and pharmacokinetic test. Schemes of syntheses of RhoB- or IR830-labeled PGA-g-mPEG/MAL-PEG, macroscopic observation of hemorrhages, histopathological analysis of fibrin localization, H&E and histopathological analysis of heart, liver, spleen, lung and kidney, 1H NMR spectrum and GPC curves of PGA-g-mPEG/MAL-PEG, DLS, TEM image, XPS spectra, in vitro release, cytotoxicity, CLSM images of cellular uptake, sizes and surface bound proteins measurement, pharmacokinetic results, UV-spectrum of IR830-labeled A15-PGA-CisPt in water, platinum biodistribution. See DOI: 10.1039/c5sc01698c Click here for additional data file

A tumor-targeted drug delivery system with small-molecule vascular disrupting agents inducing coagulation environment inside tumor and coagulation-targeted nanoparticles accumulating there.
In the pursuit of effective treatments for cancer, an emerging strategy is “active targeting”, where nanoparticles are decorated with targeting ligands able to recognize and bind specific receptors overexpressed by tumor cells or tumor vasculature so that a greater fraction of the administered drugs are selectively trafficked to tumor sites. However, the implementation of this strategy has faced a major obstacle. The interpatient, inter- and intra-tumoral heterogeneity in receptor expression can pose challenges for the design of clinical trials and result in the paucity of targetable receptors within a tumor, which limits the effectiveness of “active targeting” strategy in cancer treatment. Here we report a cooperative drug delivery platform that overcomes the heterogeneity barrier unique to solid tumors. The cooperative platform comprises a coagulation-inducing agent and coagulation-targeted polymeric nanoparticles. As a typical small-molecule vascular disrupting agent (VDA), DMXAA can create a unique artificial coagulation environment with additional binding sites in a solid tumor by locally activating a coagulation cascade. Coagulation-targeted cisplatin-loaded nanoparticles, which are surface-decorated with a substrate of activated blood coagulation factor XIII, can selectively accumulate in the solid tumor by homing to the VDA-induced artificial coagulation environment through transglutamination. In vivo studies show that the cooperative tumor-selective platform recruits up to 7.5-fold increases in therapeutic cargos to the tumors and decreases tumor burden with low systemic toxicity as compared with non-cooperative controls. These indicate that the use of coagulation-targeted nanoparticles, in conjunction with free small-molecule VDAs, may be a valuable strategy for improving standard chemotherapy.