RGD-directed 24 nm micellar docetaxel enables elevated tumor-liver ratio, deep tumor penetration and potent suppression of solid tumors.

Nanomedicines while showing a great potential in improving the performance of chemotherapeutics like docetaxel (DTX) are distressed by a high liver deposition and poor tumor penetration, which might not only cause liver toxicity but also moderate therapeutic effect. Herein, we report that cRGD-directed 24 nm disulfide-crosslinked micellar docetaxel (cRGD-MDTX) presents low liver accumulation, high tumor uptake, and deep tumor penetration, leading to the potent suppression of different solid tumors. cRGD-MDTX was optimized with a cRGD density of 4% and DTX loading of 10 wt%. Interestingly, cRGD-MDTX enabled an extraordinary tumor-liver ratio of 2.8/1 with a DTX uptake of 8.3 %ID/g in αvβ3 over-expressing PC3 prostate tumor. The therapeutic studies demonstrated striking antitumor effects of cRGD-MDTX toward PC3 prostate tumor, prostate cancer patient-derived xenografts (PDX), orthotopic A549-Luc lung cancer and orthotopic SKOV3-Luc ovarian tumor models, in which tumor growth was effectually inhibited and 6-8 times better improvement of median survival time over free DTX was observed. This small disulfide-crosslinked micellar drug capable of relegating liver deposition opens a new avenue to nanomedicines for targeted therapy.