Morphology/Interstitial Fluid Pressure-Tunable Nanopomegranate Designed by Alteration of Membrane Fluidity under Tumor Enzyme and PEGylation.

ABSTRACT

Up to now, insufficient drug accumulation in tumor remains a major challenge for nanochemotherapy. However, the spherical nanocarriers with large diameter, which are beneficial for blood circulation and tumor extravasation, cannot travel deep in a tumor. Additionally, high tumor interstitial fluid pressure (IFP) in the tumor microenvironment may promote the efflux of the penetrable nanodrugs. Therefore, the size and shape of nanocarriers as well as the tumoral IFP can be regulated synchronously for improved tumor penetration and combined chemotherapy. Herein, a novel dual-functional polymer-polypeptide (Biotin-PEG2000-GKGPRQITITK) for both verified tumor targeting and responsiveness was synthesized to construct the "peel" of nanopomegranate-like nanovectors (DI-MPL), in which docetaxel-loaded micelles was encapsulated as "seeds". Interestingly, DI-MPL was endowed multi-abilities of tunable size/shape switch and controlled release of IFP alleviator imatinib (IM), which were developed with one and the same strategy-alteration of membrane fluidity under the cleavage of polymer-polypeptide and PEGylation. As a result, the peel of DI-MPL could turn into small pieces with the seed scattered out in response to matrix metalloproteinase-9 (MMP-9), making nanopomegranate (180 nm) switch into spheres/disks (40 nm), during which IM is released to reduce IFP synchronously. With prominent tumor penetration ability in both multicellular tumor spheroids (MCTS) and tumor tissue, DI-MPL exhibited optimal inhibition of MCTS growth and the enhanced chemotherapy in comparison to other preparations. Meanwhile, the improved penetrability of DI-MPL in tumor tissue was found to be related to the reduced IFP, which is achieved via inhibiting expression of phosphorylated platelet-derived growth factor receptor-ß (p-PDGFR-ß) by IM. Altogether, the bilateral adjusting strategies from nanocarrier size/shape and tumoral IFP with a single enzyme-responsive material could provide a potential combined chemotherapy to improve tumor penetration.