title: Doxorubicin and curcumin co-delivery by lipid nanoparticles for enhanced treatment of diethylnitrosamine-induced hepatocellular carcinoma in mice.
abstract: At present, the treatment of hepatocellular carcinoma (HCC) is an international problem. The delivery of a chemotherapeutic agent and chemosensitizer using nanocarriers has been suggested as a novel and promising strategy in cancer treatment. However, such studies in HCC remain very limited. In this study, we developed doxorubicin (DOX) and curcumin (Cur) co-delivery lipid nanoparticles (DOX/Cur-NPs) and examined its inhibitory effect on diethylnitrosamine (DEN)-induced HCC in mice. DOX/Cur-NPs displayed the physicochemical characterizations with uniform particle size, high encapsulation efficacy and sustained release profile. In DNE-induced HCC mice treated with DOX/Cur-NPs, we observed decreased liver damage assessed by serum ALT and AST levels, liver/body weight ratio, and histopathological analysis. Compared with DOX-loaded nanoparticles (DOX-NPs), DOX/Cur-NPs induced increased Caspase-3 and Bax/Bcl-2 ratio, and decreased C-myc, PCNA and VEGF. The results revealed the synergistic effect of DOX/Cur-NPs on the apoptosis, proliferation and angiogenesis of HCC. The mRNA levels of MDR1, bcl-2 and HIF-1α, and protein levels of P-gp, Bcl-2 and HIF-1α were decreased in DOX/Cur-NPs than those in DOX-NPs, indicating that Cur might reverse multidrug resistance (MDR) through these pathways. In HCC cells, enhanced cytotoxicity and decreased IC50 and resistant index further confirmed the synergistic effects of DOX/Cur-NPs than DOX-NPs. Our studies suggest that simultaneous delivery of DOX and Cur by DOX/Cur-NPs may be a promising treatment for HCC.
authors.affiliation: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, Wuhan, Hubei, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, Wuhan, Hubei, China. Electronic address: liys2006@mail.scuec.edu.cn.
authors.forename: Yusang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Pharmacy, South-Central University for Nationalities, Wuhan, Hubei, China.
authors.forename: Hebin
authors.initials: H
authors.lastname: Tang
authors.affiliation: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: wliu@hust.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiangliang
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D003692:Delayed-Action Preparations; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050997:Nanomedicine; D053758:Nanoparticles; D009389:Neovascularization, Pathologic; D010316:Particle Size; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D008055:Lipids; D004052:Diethylnitrosamine; D004317:Doxorubicin; D003474:Curcumin
keywords: Co-delivery lipid nanoparticles; Curcumin; Curcumin (PubChem CID: 969516); Diethylnitrosamine (PubChem CID: 5921); Doxorubicin; Doxorubicin (PubChem CID: 31703); Doxorubicin hydrochloride (PubChem CID: 443939); Hepatocellular carcinoma; Multidrug resistance; Synergistic effect; Tumor growth inhibition