title: Mitoxantrone- and Folate-TPGS2k Conjugate Hybrid Micellar Aggregates To Circumvent Toxicity and Enhance Efficiency for Breast Cancer Therapy.
abstract: Mitoxantrone (MTO) is a potent drug used to treat breast cancer; however, efforts to expand its clinical applicability have been restricted because of its high risk for cardiotoxicity. In this study, we successfully conjugated MTO or folic acid (FA) to a synthesized D-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k), herein, shortened to MCT and FCT, respectively. The two produced conjugates could self-assemble to form MCT micelles or MCT/FCT mixed micelles (FMCT) aiming to lower systemic toxicity, enhance entrapment efficiency, and provide a platform for targeted delivery. Moreover, these micellar materials showed a significantly low CMC and could be used to load MTO. The diameters of MTO-loaded micelles (MTO-MCT and MTO-FMCT) were less than 100 nm with a negative zeta potential. We further characterized the pH-responsive drug release of MTO-MCT and MTO-FMCT and then assessed their cellular uptake and antitumor efficacy in human breast cancer cell lines (MCF-7) via confocal microscopy, flow cytometry, and cytotoxicity studies. All the results revealed that both MTO-MCT and MTO-FMCT increased drug loading and entrapment efficiency and possessed sufficient pH-sensitive release. Additionally, MTO-FMCT displayed an improved uptake through folate-mediated endocytosis, resulting in a higher cytotoxic effect on MCF-7 cells compared with that of MTO-MCT. Meanwhile, both MTO-MCT and MTO-FMCT exhibited a low toxicity on hCMEC/D3 normal cells. More importantly, pharmacokinetic study demonstrated that, in comparison with free MTO injection, MTO-MCT and MTO-FMCT, respectively, achieved half-lives 11.5 and 13 times longer and a 9.7- and 5.8-fold increase in AUC. In vivo, both MTO-MCT and MTO-FMCT formulations significantly prolonged the survival time of MCF-7 tumor-bearing mice and had a better efficacy/toxicity ratio. Promisingly, MTO-FMCT micelles remarkably increased MTO accumulation in tumors in vivo, induced higher tumor cell apoptosis, and showed lower toxicity toward major organs. These results imply that MTO-FMCT may be used as a potential drug delivery system for breast cancer targeted therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.|Department of Pharmacy, Faculty of Medicine, Ferhat Abbas University , Setif 19000, Algeria.
authors.forename: Nida El Islem
authors.identifier: 0000-0003-4425-7580
authors.initials: NE
authors.lastname: Guissi
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Huipeng
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Yurui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University , Nanjing, China.
authors.forename: Farouk
authors.initials: F
authors.lastname: Semcheddine
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Minglei
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Qineng
authors.initials: Q
authors.lastname: Ping
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D065546:Drug Liberation / Q000502:physiology; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D008942:Mitoxantrone / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D014810:Vitamin E; D005492:Folic Acid; D008942:Mitoxantrone; C014225:tocophersolan
keywords: TPGS2k; breast cancer therapy; folate targeting; mitoxantrone; self-assembled micelle