title: Combination therapy with doxorubicin-loaded galactosylated poly(ethyleneglycol)-lithocholic acid to suppress the tumor growth in an orthotopic mouse model of liver cancer.
abstract: Despite advances in technology, neither conventional anti-cancer drugs nor current nanoparticle (NP) drugs have gained substantial success in cancer treatment. While conventional chemotherapy drugs have several limitations such as low potency, poor in vivo stability and limited bioavailability, non-specific targeting of NP drugs diminishes their potency at actual target sites. In addition, the development of drug resistance to anti-cancer drugs is another challenging problem. To overcome these limitations, we aimed to develop a polymer-drug conjugate, which functions as an active NP drug and drug carrier both, to deliver a chemotherapeutic drug for combination therapy. Accordingly, we made targeting NP carrier of lithocholic acid-poly(ethylene glycol)-lactobionic acid (LPL) loading doxorubicin (Dox) to produce Dox/LPL NPs. The cellular uptake of Dox/LPL NPs was relatively higher in human liver cancer cell line (SK-HEP-1) due to galactose ligand-asialoglycoprotein receptor interaction. Consequently, the cellular uptake of Dox/LPL NPs led to massive cell death of SK-HEP-1 cells by two different mechanisms, particularly apoptotic activity by LPL and mitotic catastrophe by Dox. Most importantly, Dox/LPL NPs, when administered to orthotopic xenograft model of liver cancer, greatly reduced proliferation, invasion, migration, and angiogenesis of liver tumor in vivo. Thus, this study exemplifies the superiority of combination therapy over individual NP drug or conventional small molecule drug for cancer therapy. Overall, we present a promising approach of combinatorial therapy to inhibit the hepatic tumor growth and metastasis in the orthotopic xenograft model mice, thus representing an effective weapon for cancer treatment.
authors.affiliation: Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, South Korea; Research Institute for Bioscience and Biotechnology, Kathmandu, Nepal.
authors.forename: Bijay
authors.initials: B
authors.lastname: Singh
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Yoonjeong
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Sushila
authors.initials: S
authors.lastname: Maharjan
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Hyeon-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Sanghwa
authors.initials: S
authors.lastname: Kim
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Nomundelger
authors.initials: N
authors.lastname: Gankhuyag
authors.affiliation: Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonbuk National University, Jeonju, 54896, South Korea.
authors.forename: Myeon-Sik
authors.initials: MS
authors.lastname: Yang
authors.affiliation: Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, South Korea.
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea. Electronic address: mchotox@snu.ac.kr.
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 08826, South Korea. Electronic address: chocs@snu.ac.kr.
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage; D005690:Galactose / Q000737:chemistry*; D008095:Lithocholic Acid / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D053769:Nanocapsules; D011092:Polyethylene Glycols; D008095:Lithocholic Acid; D004317:Doxorubicin; D005690:Galactose
keywords: Cancer; Combination therapy; Doxorubicin; Nanoparticles; Orthotopic mouse model; Targeted drug delivery