title: Nanoassemblies from amphiphilic cytarabine prodrug for leukemia targeted therapy.
abstract: The anti-leukemia effect of cytarabine (Ara-C) is severely restricted by its high hydrophilic properties and rapid plasma degradation. Herein, a novel amphiphilic small molecular prodrug of Ara-C was developed by coupling a short aliphatic chain, hexanoic acid (HA) to 4-NH2of the parent drug. Based on the amphiphilic nature, the resulting bioconjugate (HA-Ara) could spontaneously self-assemble into stable spherical nanoassemblies (NAs) with an extremely high drug loading (∼71wt%). Moreover, folate receptor (FR)-targeting NAs with high grafting efficient folic acid - bovine serum albumin (FA-BSA) conjugate immobilized on the surface (NAs/FA-BSA) was prepared. The results of MTT assays on FR-positive K562 cells and FR-negative A549 cells demonstrated higher cytotoxicity of HA-Ara NAs than the native drug. Especially, the IC50values revealed that NAs/FA-BSA was 3 and 2-fold effective than non-targeted NAs after 24 and 48h treatment with K562 cells, respectively indicating FR-mediated enhanced anti-tumor efficacy. In vitro cellular uptake, larger accumulation of HA-Ara NAs were observed in comparative with the free FITC and the results further confirmed the selective uptake of NAs/FA-BSA in folate receptor enriched cancer cells. Above all, self-assembled HA-Ara NAs exhibited potential superiority for Ara-C delivery and FA-modified NAs would be an excellent candidate for targeting leukemia therapy.
authors: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors: Jing
authors: J
authors: Liu
authors: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors: Dujuan
authors: D
authors: Zhao
authors: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors: Wenxiu
authors: W
authors: He
authors: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
authors: Huiyuan
authors: H
authors: Zhang
authors: Key Lab of Colloid & Interface Chemistry, Shandong University, Ministry of Education, 250100, PR China.
authors: Zhonghao
authors: Z
authors: Li
authors: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China. Electronic address: yuxialuan@sdu.edu.cn.
authors: Yuxia
authors: Y
authors: Luan
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002208:Caproates / Q000737:chemistry*; D002417:Cattle; D003561:Cytarabine / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D004339:Drug Compounding; D058975:Folate Receptor 1 / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D058990:Molecular Targeted Therapy; D058726:Nanoconjugates / Q000737:chemistry* / Q000648:ultrastructure; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000737:chemistry
chemical_list: D000964:Antimetabolites, Antineoplastic; D002208:Caproates; D004337:Drug Carriers; D058975:Folate Receptor 1; D058726:Nanoconjugates; D011355:Prodrugs; D003561:Cytarabine; C037652:hexanoic acid; D012710:Serum Albumin, Bovine; D005492:Folic Acid
keywords: Amphiphilic small molecular prodrug; Cytarabine; Folic acid; Leukemia therapy; Nanoassembly