The natural product curcumin and the chemotherapeutic agent doxorubicin have been used in the treatment of many cancers, including breast cancer. However, fast clearance and unspecific distribution in the body after intravenous injection are still challenges to be overcome by an ideal nano-sized drug delivery system in cancer treatment. In this study we design transferrin (Tf) decorated nanoparticles (NPs) to co-deliver CUR and DOX for breast cancer treatment. A pH-sensitive prodrug, transferrin-poly(ethylene glycol)-curcumin (Tf-PEG-CUR), was synthesized and used for the self‑assembling of NPs (Tf-PEG-CUR NPs). DOX is incorporated into the Tf-PEG-CUR NPs to obtain Tf-PEG-CUR/DOX NPs. In vitro cytotoxicity studies and in vivo antitumor activity were carried out using MCF-7 cells and mice bearing MCF-7 cells, respectively. Tf-PEG-CUR/DOX NPs has a particle size of 89 nm and a zeta potential of -15.6 mV. This system displayed remarkably higher efficiency than other systems both in vitro and in vivo. DOX and CUR were successfully loaded into nanocarriers. The in vitro cell viability assays revealed the combination of Tf-PEG-CUR and DOX NPs exhibited higher cytotoxicity in vitro in MCF-7 cells compared with Tf-PEG-CUR NPs alone. Using the breast cancer xenograft mouse model, we demonstrate that this co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and exhibited stronger antitumor effect.
Abstract. Mel-P15 is a peptide derived from melittin, the main toxic component in the venom of the European honeybee Apis mellifera. In the present study, the antitumor effects of Mel-P15 and the underlying molecular mechanisms of these effects in vivo were investigated. Mel-P15 directly stimulated natural killer (NK) cell cytotoxicity in vitro, which was increased to 55.45% at a 4 µg/ml dose of Mel-P15. In the mouse liver cancer (H22) xenograft mice model, Mel-P15 suppressed tumor growth in vivo; the tumor inhibitory rate was 61.15% following treatment with 2 mg/kg Mel-P15. In addition, the immune response was activated following Mel-P15 treatment. Mel-P15 treatment increased the spleen and thymus indices, promoted splenocyte proliferation, stimulated NK cytotoxicity and upregulated the secretion of cytokines, including interleukin-2, interferon-γ and tumor necrosis factor-α. In addition, the tumor inhibitory effect of Mel-P15 on BEL-7402-bearing nude mice was abrogated by the selective depletion of NK cells via the intraperitoneal injection of an anti-asialo GM-1 antibody. The results suggest that Mel-P15 inhibits tumor growth in vivo by promoting NK cell cytotoxicity. Mel-P15 may therefore be a potential immunotherapy candidate for the treatment of hepatocellular carcinoma.
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