title: Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance.
abstract: Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Tangjian
authors.initials: T
authors.lastname: Cheng
authors.affiliation: 2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, P.R. China.
authors.forename: Jinjian
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: 2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Huang
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Hanlin
authors.initials: H
authors.lastname: Ou
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: 2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, P.R. China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Rujiang
authors.initials: R
authors.lastname: Ma
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: An
authors.affiliation: 2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, P.R. China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.; 3. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, P.R. China.
authors.forename: Linqi
authors.initials: L
authors.lastname: Shi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000517:prevention & control; D002392:Catechin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple; D006801:Humans; D008823:Micelles; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D013662:Tea / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D013662:Tea; D004317:Doxorubicin; D002392:Catechin; C045651:epigallocatechin gallate
keywords: cardiotoxicity; catechin; combination therapy; multidrug resistance.