title: Precise Engineering of Prodrug Cocktails into Single Polymeric Nanoparticles for Combination Cancer Therapy: Extended and Sequentially Controllable Drug Release.
abstract: The synergistic combination of two or more chemotherapeutics frequently requires packaging in single delivery vehicles for the sequential release of each substance in a predictable manner. Here, we demonstrate for the first time that the rational engineering of a prodrug cocktail into single polymeric nanoparticles (NPs) can enable the sequential release of chemotherapeutics in a controllable manner. Exploiting combretastatin-A4 (CA4, 1) as a model antiangiogenesis agent, two ester derivatives, 2 and 3, tethered with saturated fatty acids (butanoic and heptanoic acid for 2 and 3, respectively) were synthesized. 7-Ethyl-10-hydroxycamptothecin (SN38) derivative 4, esterified with α-linolenic acid, was used as a cytotoxic drug. Because of their augmented lipophilicity and miscibility, all constructed prodrugs readily assembled with clinically approved polymeric matrices. Results showed that altering the aliphatic chains of modifiers for CA4 chemical derivatization enabled the drug retention capacity within particle systems to be adjusted, leading to the identification of the prodrug cocktail of 2 and 4 as an optimal combination for subsequent preclinical studies. Furthermore, in vivo assessements indicated that the resulting NPs simultaneously formulating 2 and 4 exhibited synergistic activities and outperformed NPs loaded with individual prodrugs 2 or 4 in terms of therapeutic efficacy. These findings highlight a novel and versatile strategy for tailoring chemically disparate prodrug cocktails for adaptation within a single nanoplatform as a potential modality for synergistic cancer therapy.
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Hangxiang
authors.identifier: http://orcid.org/0000-0001-6370-9728
authors.initials: H
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Jiaping
authors.initials: J
authors.lastname: Wu
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xie
authors.affiliation: Jinhua People's Hospital , Jinhua, Zhejiang Province 321000, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Fang
authors.affiliation: College of Life Sciences, Huzhou University , Huzhou, Zhejiang Province 313000, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health and Key Laboratory of Organ Transplantation of Zhejiang Province, School of Medicine, Zhejiang University , Hangzhou 310003, P.R. China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D053758:Nanoparticles; D009369:Neoplasms; D011108:Polymers; D011355:Prodrugs
chemical_list: D011108:Polymers; D011355:Prodrugs
keywords: antiangiogenesis; cancer nanomedicine; combination therapy; prodrug cocktail; self-assembly