title: iRGD-Decorated Polymeric Nanoparticles for the Efficient Delivery of Vandetanib to Hepatocellular Carcinoma: Preparation and in Vitro and in Vivo Evaluation.
abstract: Molecularly targeted agents that are designed to target specific lesions have been proven effective as clinical cancer therapies; however, most currently available therapeutic agents are poorly water-soluble and require oral administration, thereby resulting in low bioavailability and a high risk of side effects due to dose intensification. The rational engineering of systemically injectable medicines that encapsulate such therapeutic payloads may revolutionize anticancer therapies and remains an under-explored area of drug development. Here, the injectable delivery of a nanomedicine complexed with an oral multitargeted kinase inhibitor, vandetanib (vanib), was explored using polymeric nanoparticles (NPs) to achieve the selective accumulation of drug payloads within tumor lesions. To demonstrate this concept, we used biodegradable amphiphilic block copolymer poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA) to nanoprecipitate this potent agent to form water-soluble NPs that are suitable for intravenous administration. NP-vanib induced cytotoxic activity by inhibiting the angiogenetic events mediated by VEGFR and EGFR kinases in tested cancer cells and inhibited the growth, tube formation and metastasis of HUVECs. The intravenously injection of NP-vanib into mice bearing HCC BEL-7402 xenografts more effectively inhibited the tumor than the oral administration of vanib. In addition, due to the modular design of these NPs, the drug-loaded particles can easily be decorated with iRGD, a tumor-homing and -penetrating peptide motif, which further improved the in vivo performance of these vanib-loaded NPs. Our results demonstrate that reformulating targeted therapeutic agents in NPs permits their systemic administration and thus significantly improves the potency of currently available, orally delivered agents.
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Hangxiang
authors.initials: H
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Zhikun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Xuyong
authors.initials: X
authors.lastname: Wei
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Runzhou
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
authors.affiliation: The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, 310003, PR China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D010880:Piperidines; D011108:Polymers; D011799:Quinazolines; C452423:vandetanib
keywords: cancer nanomedicine; hepatocellular carcinoma; molecularly targeted agents; self-assembly; targeted delivery