title: Doxorubicin-loaded nanoparticles consisted of cationic- and mannose-modified-albumins for dual-targeting in brain tumors.
abstract: Albumin nanoparticles have been increasingly viewed as an effective way of delivering chemotherapeutics to solid tumors. Here, we report the one-pot development of a unique prototype of doxorubicin-loaded nanoparticles (NPs) made of naïve albumin (HSA) plus cationic- (c-HSA) or mannose-modified-albumin (m-HSA), with the goal of traversing the blood-brain barrier and targeting brain tumors. c-HSA was synthesized by conjugating ethylenediamine to naïve HSA. Then, m-HSA was derivatized using mannopyranoside via a thiol-maleimide reaction. The c/m-HSA NPs were prepared using a mixture solution of c- and m-HSAs in deionized water and doxorubicin in ethanol/chloroform in the same pot using a high-pressure homogenizer. The c/m-HSA NPs were spherical and well-dispersed, with a particle size of 90.5±3.1nm and zeta-potential of -12.0±0.3mV at c- and m-HSA feed ratios of 5% and 10%, respectively. The c/m-HSA NPs displayed good stability over 3days based on particle size and a linear gradual doxorubicin release over 2days. Specifically, the inhibitory concentration (IC50; 0.5±0.02μg/ml) of c/m-HSA NPs was >2.2-15.6 fold lower than those of doxorubicin or the other HSA NPs. Moreover, among HSA NPs, c/m-HSA NPs exhibited the most prominent performances in transport across the bEnd.3 cell monolayer and uptake in bEnd.3 cells as well as U87MG glioblastoma cells and spheroids. Furthermore, c/m-HSA NPs were localized to a greater extent in brain glioma compared to naïve HSA NPs. Orthotopic glioma-bearing mice treated with c/m-HSA NPs displayed significantly smaller tumors than the mice treated with saline, doxorubicin or HSA NPs. This improved anti-glioma efficacy seemed to be due to the dual-enhanced system of dual cationic absorptive transcytosis and glucose-transport by the combined use of c- and m-HSAs. The c/m-HSA NPs have potential as a novel anti-brain cancer agent with good targetability.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Hyeong Jun
authors.initials: HJ
authors.lastname: Byeon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Le Quang
authors.initials: le Q
authors.lastname: Thao
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Min
authors.affiliation: Division of Biotechnology, Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Catholic University of Daegu, 330 Geumrak 1-ri, Hayang Eup, Gyeongsan si, Gyeongbuk 712-702, Republic of Korea.
authors.forename: Beom Soo
authors.initials: BS
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea. Electronic address: ysyoun@skku.edu.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008358:Mannose / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010316:Particle Size; D012709:Serum Albumin / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D012709:Serum Albumin; D004317:Doxorubicin; D008358:Mannose
keywords: Albumin nanoparticles; Blood–brain barrier; Brain tumor; Doxorubicin; Targeting