title: Doxorubicin and paclitaxel co-bound lactosylated albumin nanoparticles having targetability to hepatocellular carcinoma.
abstract: Anticancer drug targeting to liver asialoglycoprotein receptors (ASGPR) is viewed as a good approach for hepatocellular carcinoma (HCC) treatment. Lactose residue is a promising ASGPR ligand due to its high receptor affinity. Herein, we introduce doxorubicin and paclitaxel co-bound lactosylated albumin (Lac-BSA) nanoparticles (Dox/Pac Lac-BSA NPs) with good liver targetability. Lac-BSA was synthesized by conjugating lactobionic acid to naïve BSA then characterized by mass spectrometry. Dox/Pac Lac-BSA NPs were fabricated utilizing high-pressure homogenization and evaporation with Nab®(nanoparticle albumin bound) technology. Dox/Pac Lac-BSA NPs were spherical and well-dispersed, with a 148.7±13.8nm particle size and -54.1±0.7mV zeta potential at a 100% Lac-BSA feed ratio. Combined Dox and Pac synergistic cytotoxicity was confirmed in Hep G2 cells. Specifically, the inhibitory concentration (IC50; 0.21±0.02μg/ml) for Dox/Pac Lac-BSA NPs was 3.2 time lower than plain Dox/Pac BSA NPs (IC50; 0.68±0.04μg/ml). Also, Dox/Pac Lac-BSA NPs exhibited better internalizing in Hep G2 cells (61.8% vs. 14.4% for Dox) and spheroids compared to Dox/Pac BSA NPs. Finally, Dox/Pac Lac-BSA NPs displayed much greater localization into ICR mice livers compared to Dox/Pac BSA NPs. This was indicated by the presence of NP lactose residues revealed by a galactose inhibition study. Based on these results, we suggest that lactose-modified albumin-based nanoparticles fabricated with the Nab®technique can be a potential therapeutic vector for treating HCC via hepatocyte targeting.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Le Quang
authors.initials: LQ
authors.lastname: Thao
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Changkyu
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Bomi
authors.initials: B
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Sungin
authors.initials: S
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 38541, Republic of Korea.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: Division of Biotechnology, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 06974, Republic of Korea.
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Sun Dong
authors.initials: SD
authors.lastname: Yoo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea. Electronic address: ysyoun@skku.edu.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D007785:Lactose / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry* / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D012709:Serum Albumin; C049720:lactosylated serum albumin; D004317:Doxorubicin; D007785:Lactose; D017239:Paclitaxel
keywords: Albumin nanoparticles; Asialoglycoprotein receptor; Hepatocellular carcinoma; Lactose; Liver targetability; Nab(®) Technology