title: iTEP nanoparticle-delivered salinomycin displays an enhanced toxicity to cancer stem cells in orthotopic breast tumors.
abstract: Salinomycin (Sali) has selective toxicity to cancer stem cells (CSCs), a subpopulation of cancer cells that have been recently linked with tumor multidrug resistance (MDR). To utilize its selective toxicity for cancer therapy, we sought to devise a nanoparticle (NP) carrier to deliver Sali to solid tumors through the enhanced permeability and retention effect and, hence, to increase its exposure to CSCs. First, hydrophobic Sali was conjugated to a hydrophilic, immune-tolerant, elastin-like polypeptide (iTEP); the amphiphilic iTEP-Sali conjugates self-assemble into NPs. Next, free Sali was encapsulated into the NPs alone or with two additives, N,N-dimethylhexylamine (DMHA) and α-tocopherol. The coencapsulation significantly improved the loading efficiency and release profile of Sali. The resulting NPs of the coencapsulation, termed as iTEP-Sali NP3s, have an in vitro release half-life of 4.1 h, four times longer than iTEP-Sali NP2s, the NPs that have encapsulated Sali only. Further, the NP3 formulation increases the plasma area under curve and the tumor accumulation of Sali by 10 and 2.4 times, respectively. Lastly, these improved pharmacokinetic and tumor accumulation profiles are consistent with a boost of CSC-elimination effect of Sali in vivo. In NP3-treated 4T1 orthotopic tumors, the mean CSC frequency is 55.62%, a significant reduction from the mean frequencies of untreated tumors, 75.00%, or free Sali-treated tumors, 64.32%. The CSC-elimination effect of the NP3 can further translate to a delay of tumor growth. Given the role of CSCs in driving tumor MDR and recurrence, it could be a promising strategy to add the NP3 to conventional cancer chemotherapies to prevent or reverse the MDR.
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah , 30S 2000E, Salt Lake City, Utah 84112, United States.
authors: Peng
authors: P
authors: Zhao
authors: Shuyun
authors: S
authors: Dong
authors: Jayanta
authors: J
authors: Bhattacharyya
authors: Mingnan
authors: M
authors: Chen
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004549:Elastin / Q000737:chemistry; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011714:Pyrans / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution; D024502:alpha-Tocopherol / Q000737:chemistry; D000095662:Polyether Polyketides
chemical_list: D000588:Amines; D004337:Drug Carriers; D004549:Elastin; D011714:Pyrans; D024502:alpha-Tocopherol; C010327:salinomycin; D000095662:Polyether Polyketides