title: Liposomes for targeting hepatocellular carcinoma: use of conjugated arabinogalactan as targeting ligand.
abstract: Present study investigates the potential of chemically modified (Shah et al., 2013) palmitoylated arabinogalactan (PAG) in guiding liposomal delivery system and targeting asialoglycoprotein receptors (ASGPR) which are expressed in hepatocellular carcinoma (HCC). PAG was incorporated in liposomes during preparation and doxorubicin hydrochloride was actively loaded in preformed liposomes with and without PAG. The liposomal systems with or without PAG were evaluated for in vitro release, in vitro cytotoxicity, in vitro cell uptake on ASGPR(+) cells, in vivo pharmacokinetic study, in vivo biodistribution study, and in vivo efficacy study in immunocompromised mice. The particle size for all the liposomal systems was below 200 nm with a negative zeta potential. Doxorubicin loaded PAG liposomes released significantly higher amount of doxorubicin at pH 5.5 as compared to pH 7.4, providing advantage for targeted tumor therapy. Doxorubicin in PAG liposomes showed superior cytotoxicity on ASGPR(+) HepG2 cells as compared to ASGPR(-), MCF7, A549, and HT29 cells. Superior uptake of doxorubicin loaded PAG liposomes as compared to doxorubicin loaded conventional liposomes was evident in confocal microscopy studies. Higher AUC in pharmacokinetic study and higher deposition in liver was observed for PAG liposomes compared to conventional liposomes. Significantly higher tumor suppression was noted in immunocompromised mice for mice treated with PAG liposomes as compared to the conventional liposomes. Targeting ability and superior activity of PAG liposomes is established pre-clinically suggesting potential of targeted delivery system for improved treatment of HCC.
authors.affiliation: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400098, India.
authors.forename: Sanket M
authors.initials: SM
authors.lastname: Shah
authors.affiliation: Tata Memorial Centre, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India.
authors.forename: Peeyush N
authors.initials: PN
authors.lastname: Goel
authors.affiliation: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400098, India.
authors.forename: Ankitkumar S
authors.initials: AS
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400098, India.
authors.forename: Pankaj O
authors.initials: PO
authors.lastname: Pathak
authors.affiliation: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400098, India.
authors.forename: Sameer G
authors.initials: SG
authors.lastname: Padhye
authors.affiliation: Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007, India.
authors.forename: Srinath
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Small Animal Imaging Facility (SAIF), Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Mumbai 410210, India.
authors.forename: Sandipto S
authors.initials: SS
authors.lastname: Ghosh
authors.affiliation: Small Animal Imaging Facility (SAIF), Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Mumbai 410210, India.
authors.forename: Pradip R
authors.initials: PR
authors.lastname: Chaudhari
authors.affiliation: Tata Memorial Centre, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India.
authors.forename: Rajiv P
authors.initials: RP
authors.lastname: Gude
authors.affiliation: Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad 500007, India.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Gopal
authors.affiliation: Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400098, India. Electronic address: mangal.nagarsenker@gmail.com.
authors.forename: Mangal S
authors.initials: MS
authors.lastname: Nagarsenker
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D005685:Galactans / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D005685:Galactans; D008024:Ligands; D008081:Liposomes; D004317:Doxorubicin; C005653:arabinogalactan
keywords: Arabinogalactan; Asialoglycoprotein receptors; Doxorubicin liposome; Hepatocellular carcinoma; Targeted delivery; Targeted liposomes