Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch-doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (∼2 μM) but released DOX quickly under intracellular GSH level (2-10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity as compared to free DOX in the in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy.

In this work, we rationally combined novel ICG@HES-OA NPs with PEITC for potent PDT. The combination of ICG@HES-OA NPs and PEITC results in synergistic PDT efficacy.

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Paclitaxel (PTX) is an effective antineoplastic agent and shows potent antitumor activity against a wide spectrum of cancers. Yet, the wide clinical use of PTX is limited by its poor aqueous solubility and the side effects associated with its current therapeutic formulation. To tackle these obstacles, we report, for the first time, α-amylase- and redox-responsive nanoparticles based on hydroxyethyl starch (HES) for the tumor-targeted delivery of PTX. PTX is conjugated onto HES by a redox-sensitive disulfide bond to form HES-SS-PTX, which was confirmed by results from NMR, high-performance liquid chromatography-mass spectrometry, and Fourier transform infrared spectrometry. The HES-SS-PTX conjugates assemble into stable and monodispersed nanoparticles (NPs), as characterized with Dynamic light scattering, transmission electron microscopy, and atomic force microscopy. In blood, α-amylase will degrade the HES shell and thus decrease the size of the HES-SS-PTX NPs, facilitating NP extravasation and penetration into the tumor. A pharmacokinetic study demonstrated that the HES-SS-PTX NPs have a longer half-life than that of the commercial PTX formulation (Taxol). As a consequence, HES-SS-PTX NPs accumulate more in the tumor compared with the extent of Taxol, as shown in an in vivo imaging study. Under reductive conditions, the HES-SS-PTX NPs could disassemble quickly as evidenced by their triggered collapse, burst drug release, and enhanced cytotoxicity against 4T1 tumor cells in the presence of a reducing agent. Collectively, the HES-SS-PTX NPs show improved in vivo antitumor efficacy (63.6 vs 52.4%) and reduced toxicity in 4T1 tumor-bearing mice compared with those of Taxol. These results highlight the advantages of HES-based α-amylase- and redox-responsive NPs, showing their great clinical translation potential for cancer chemotherapy.