Actively targeted nanomedicines though conceptually attractive for tumor therapy are extremely hard to realize due to problems of premature drug leakage, excessive liver accretion, inadequate tumor uptake, and/or retarded drug release inside tumor cells. Here, we systemically studied the influence of disulfide crosslinking on the in vitro and in vivo performance of integrin-targeted micellar docetaxel (t-MDTX). Of note, t-M5DTX with a high disulfide content was clearly advantageous in terms of stability, intracellular drug release and anti-tumor activity toward αβ-overexpressing A549 cells, and circulation and therapeutic efficacy in orthotopic A549-luc lung tumor-bearing mice. t-MDTX induced extraordinary tumor targetability with tumor-to-normal tissue ratios of 1.7-8.3. Further studies indicated that t-M5DTX could effectively eradicate αβ-overexpressing lung and prostate cancer patient-derived xenografts (PDX), in which ca. 80% mice became tumor-free. This integrin-targeting disulfide-crosslinked micellar docetaxel emerges as a promising actively targeted nanoformulation for tumor therapy. STATEMENT OF SIGNIFICANCE: Nanomedicines have a great potential in treating advanced tumor patients; however, their tumor-targeting ability and therapeutic efficacy remain unsatisfactory. In addition to PEGylation and ligand selection, particle size, stability and drug release behavior are also critical to their performance in vivo. In this paper, we find that small and cRGD-guided disulfide-crosslinked micellar docetaxel (t-MDTX) induces superior tumor uptake and retention but without increasing liver burden, leading to extraordinary selectivity and inhibition of αβ overexpressing lung tumors. t-MDTX is further shown to effectively treat αβ-positive patient-derived tumor models, lending it a high potential for clinical translation.
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