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Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitrosimulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.

The development of versatile antitumor agents with tumor-imaging, targeting and therapeutic activity is promising for clinical cancer therapy. Prostate cancer is still the one of the leading threats to males. Current therapies have restricted clinical efficiency for patients with advanced and metastatic prostate cancer. Recent studies demonstrate that monoamine oxidase A (MAOA) levels elevate with prostate cancer aggression and metastasis. In addition, MAOA inhibitor therapies have been reported as an effective means to reduce the metastasis of prostate cancer and extend mouse survival. Thus, these findings provide evidence that MAOA is promising for the treatment of metastatic and advanced prostate cancer. Herein, three isoniazid (INH)–dye conjugates were synthesized by conjugating MAOA inhibitor INH with mitochondria-targeting NIRF heptamethine dyes to improve the therapeutic efficacy of prostate cancer. These INH–dye conjugates could accumulate in PC-3 cellular mitochondria viaorganic anion transport peptide (OATP), increase ROS generation, and induce cancer cells apoptosis. In prostate cancer bearing xenografts, INH–dye conjugates showed significantly improved tumor-homing characteristics, resulting in potent antitumor activity viaa reduction in MAOA activity. These results suggest that INH–dye conjugates have great potential to be used as versatile antitumor agents with prostate cancer targeting, NIR imaging, and potent antitumor efficacy.

Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized viadifferent redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivocompared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.