In situ hydrogelation of bicalutamide-peptide conjugates at prostate tissue for smart drug release based on pH and enzymatic activity.

Tissue-specific self-assemblies of supramolecular hydrogels have attracted great interest in material design and biomedical applications, for in situ-formed hydrogels serve as an excellent local depot with tunable release of drug therapeutics. Here we report the design and syntheses of a novel class of histidine-containing hexapeptide derivatives (Nap-1 and ID-1) for in situ hydrogelation at the zinc ion-rich prostate tissue. Thanks to the efficient co-ordination between zinc and histidine, both Nap-1 and ID-1 displayed excellent self-assembly capability with a high sensitivity to zinc ions at ∼0.1 equivalency. To foster a prostate-specific drug delivery system (DDS), ID-1 was chosen for further conjugation with bicalutamide (BLT), a clinically used drug for prostate cancer. The as-synthesized ID-1-BLT retained the self-assembly capability with zinc ions, and conferred supramoelcular hydrogels at the prostate site. Interestingly, ID-1-BLT hydrogels demonstrated tunable drug release profiles in a typical tumor microenvironment, with acidic pH and esterase activity regulating the drug release in a dose dependent manner. Consequently, the hydrogel-based DDS demonstrated enhanced potency and selective cytotoxicity against prostate cancer cell DU145 over normal fibroblast cell NIH3T3, plausibly due to differential cellular uptake of drugs as well as the elevated esterase activities in cancer cells. Finally, the biocompatible hydrogel system demonstrated sustained delivery of drugs at the prostate gland of rats, with a superior in situ drug distribution profile compared to that of aqueous solution of BLT alone.