Nanotechnology-based chemotherapy is efficient in cancer treatment due to the targeted delivery of small molecules via nano-carriers, which are usually regarded as "inert". However, nano-materials are more preferred as carriers since many cause synergistic anti-tumor effects along with the drug cargo. In this study, a "bioactive" tocopherol succinate (TOS) was grafted to hyaluronic acid (HA) via of disulfide bonds to obtain HA-ss-TOS conjugates which can assemble into nano-micelles but dissociate when exposed to reducing environments in vitro and in vivo. Moreover, paclitaxel-loaded HA-ss-TOS micelles (HA-ss-TOS-PTX) can be efficiently taken up by B16F10 cells overexpressing CD 44, thereafter exhibiting enhanced cytotoxicity. The in vivo imaging study here revealed much greater tumor accumulation of Dir-labeled HA-ss-TOS compared to the free Dir group. In vivo antitumor activities further ensured that the PTX-loaded HA-ss-TOS micelles provided superior antineoplastic responses versus PTX-loaded HA-TOS micelles and Taxol. Moreover, the subcellular dissociated TOS from HA-ss-TOS showed synergistic effects with PTX. These experimental results revealed that reduction-responsive PTX-loaded polymeric nano-micelles with multi-functional properties hold great potential for anti-tumor treatment and, thus, should be further studied.
Keywords: Active tumor targeting; Hyaluronic acid; Redox-response nanomicelles; Synergistic effect; Tocopherol succinate.
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