title: Integrating a novel SN38 prodrug into the PEGylated liposomal system as a robust platform for efficient cancer therapy in solid tumors.
abstract: Liposomal nanoassemblies have been used extensively as carriers for the delivery of both lipophilic and hydrophilic drugs. They represent a mature, versatile technology with considerable potential for improving the pharmacokinetics of drugs. However, the formulation of many chemotherapeutics into liposome systems has posed a significant challenge due to their incompatible physicochemical properties, as was the case with camptothecin-based chemotherapeutics. Here, we present a rational paradigm of potent chemotherapeutics that were reconstructed and subsequently integrated into liposomal nanoassemblies. Using SN38 (7-ethyl-10-hydroxy camptothecin) as a model drug, a lipophilic prodrug 1 (designated as LA-SN38) was constructed by tethering the linoleic acid (LA) moiety via esterification, which was further facilitated to form liposomal nanoparticles (LipoNP) through supramolecular nanoassembly. The resulting 1-loaded LipoNP exhibited sustained drug release kinetics and decreased cellular uptake by macrophage cells. Uptake by tumor cells was enhanced relative to our previous supramolecular nanoparticles (SNP 1), which were derived from the self-assembling prodrug 1. Notably, LipoNP outperformed SNP 1 in terms of pharmacokinetics and in vivo therapeutic efficacy in both human BEL-7402 hepatocellular carcinoma (HCC) and HCT-116 colorectal cancer-derived xenograft mouse models. These results were likely due to the improved systemic circulation and preferential accumulation of nanodrugs in tumors. Hence, our results suggest that the combination of liposomal delivery platforms with rational prodrug engineering may emerge as a promising approach for the effective and safe delivery of anticancer chemotherapeutics.
authors.affiliation: Jinhua People's Hospital, Jinhua, Zhejiang Province, 321000, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Fang
authors.affiliation: Department of Applied Engineering, Zhejiang Economic and Trade Polytechnic, Hangzhou, 310018, PR China.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xie
authors.affiliation: Jinhua People's Hospital, Jinhua, Zhejiang Province, 321000, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Jinhua People's Hospital, Jinhua, Zhejiang Province, 321000, PR China; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, PR China. Electronic address: wanghx@zju.edu.cn.
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin
keywords: Cancer therapy; Drug delivery; Liposome; Prodrug; Supramolecular nanoassembly