Although salinomycin sodium (SS) has shown in-vitro potential to inhibit cancer stem cell growth and development, its low water solubility makes it a poor candidate as an oral chemotherapeutic agent. To improve the bioavailability of SS, SS was encapsulated here using D-α-tocopherol polyethylene glycol succinate (TPGS)-emulsified poly(lactic-co-glycolic acid) (PLGA) nanoparticles and compared with its parent SS in terms of absorption, pharmacokinetics, and efficacy in suppressing nasopharyngeal carcinomas stem cells. The pharmacokinetics of SS and salinomycin sodium-loaded D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles (SLN) prepared by nanoprecipitation were analyzed in-vivo by timed-interval blood sampling and oral administration of SS and SLN to rats. Sensitive liquid chromatography-mass spectrometry (LC-MS) was developed to quantify plasma drug concentrations. SS and SLN transport in Caco-2 cells was also investigated. The therapeutic efficacy of SS and SLN against cancer stem cells was determined by orally administering the drugs to mice bearing CNE1 and CNE2 nasopharyngeal carcinoma xenografts and then evaluating CD133+ cell proportions and tumorsphere formation. The in-vivo trial with rats showed that the Cmax, AUC(0−t), and Tmax for orally administered SLN were all significantly higher than those for SS (P<0.05). These findings were corroborated by a Caco-2 cell Transwell assay showing that relative SLN absorption was greater than that of SS on the basis of their apparent permeability coefficients (Papp). Significantly, therapeutic SLN efficacy against nasopharyngeal carcinoma stem cells was superior to that of SS. TPGS-emulsified PLGA nanoparticles effectively increase SS solubility and bioavailability. SLN is, therefore, promising as an oral chemotherapeutic agent against cancer stem cells.
aDepartment of Anesthesiology, The Eye, Ear, Nose and Throat Hospital, Fudan University
bDepartment of Otolaryngology, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health Science
cDepartment of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine
dDepartment of Pharmaceutial Science, School of Pharmacy, Second Military Medical University, Shanghai
eDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
* Jie Li, Liang Zhai and Jiyang Xue contributed equally to the writing of this article.
Correspondence to Jie Gao, MD, Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China Tel/fax: +86 057 788 816 381; e-mail: email@example.com
Received May 16, 2018
Accepted August 25, 2018