Vitamin E-based redox-sensitive salinomycin prodrug-nanosystem with paclitaxel loaded for cancer targeted and combined chemotherapy

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2018-12, Vol.172, p.506-516
• Main Authors: Liang, De-Sheng, Liu, Jian, Peng, Tao-Xing, Peng, Hui, Guo, Feng, Zhong, Hai-Jun
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Cycle Checkpoints - drug effects; Cell Death - drug effects; Cell Survival - drug effects; Combined chemotherapy; D-α-tocopheryl succinate; Drug Liberation; Female; Humans; MCF-7 Cells; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Neoplastic Stem Cells - pathology; Oxidation-Reduction; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Particle Size; Prodrug nanoparticles; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Pyrans - therapeutic use; Salinomycin; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Tumor targeting; Vitamin E - pharmacology; X-Ray Diffraction
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2018.08.063

[Display omitted] •The TS prodrug conjugates were designed by covalently coupling the lipophilic TOS moiety to SAL via disulfide linkages.•The TS prodrug conjugates were readily self-aggregated into stable nanoparticles.•The TS prodrug nanoparticles were tumor-targeting and glutathione-sensitive.•The TS prodrug nanoparticles were designed for synergistic salinomycin-paclitaxel combination chemotherapy. Cancer stem cells (CSCs) can resist conventional chemotherapy to lead to cancer recurrence. For complete eradication of cancers, an effective CSCs therapeutic strategy should be developed to combine with conventional chemotherapy. In this work, a novel vitamin E-based redox-sensitive salinomycin (SAL, an inhibitor for CSCs) prodrug nanoparticles (TS NPs) and hyaluronic acid (HA)-coated TS NPs (HTS NPs) were fabricated to deliver paclitaxel (PTX) for cancer-targeted and combined chemotherapy. Both TS and HTS prodrug NPs had mean diameter of about 200 nm with uniform size distribution, excellent drug loading capacity for PTX, and glutathione-triggered SAL and PTX release profiles. The HTS prodrug NPs had enhanced cellular uptake efficiency over TS NPs due to CD44 receptor-mediated endocytosis, hence exerting stronger potency of SAL upon CSCs-enriched mammospheres formation and G0/G1 cell phase arresting. Cytotoxicity and 3D tumor spheroids assays demonstrated that both TS and HTS prodrug NPs themself can synergize with loaded PTX to maximize the chemotherapeutic effect. Obviously, the latter demonstrated a more potent anticancer efficacy due to improved intracellular drug delivery efficiency. These results suggested that the designed TS prodrug NPs, especially the coated HTS NPs can serve as an effective anti-CSCs strategy for cancer targeted and combination treatments.