title: Tumor vasculature targeting following co-delivery of heparin-taurocholate conjugate and suberoylanilide hydroxamic acid using cationic nanolipoplex.
abstract: The chemical conjugate of low molecular weight heparin with taurocholate (LHT7) was previously designed to offer anticancer activity while minimizing the anticoagulant activity. In the present study, we found that the systemic administration of LHT7 in nanolipoplex could substantially enhance tumor vasculature targeting and anticancer effects. Moreover, we found that co-delivery of LHT7 with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, in nanolipoplex could provide synergistic antitumor effect. LHT7/SAHA nanolipoplex was formulated by encapsulating SAHA inside cationic liposomes, followed by complexation of negatively charged LHT7 onto the cationic surfaces of SAHA-loaded liposomes (SAHA-L). LHT7/SAHA nanolipoplex was positively charged with a mean diameter of 117.6 nm, and stable in serum. The nanolipoplex form of LHT7 could alter its pharmacokinetics and biodistribution. Compared to the free form of LHT7, LHT7 in the nanolipoplex showed 1.9-fold higher mean residence time, and higher tumor vasculature accumulation after its intravenous administration. LHT7/SAHA nanolipoplex showed highest antitumor efficacy in SCC-bearing mice, compared to LHT7, SAHA-L and sequential co-administration of LHT7 and SAHA-L. Consistent with the enhanced antitumor effect, the reduction of abnormal vessels in the tumor site was also the highest in the LHT7/SAHA nanolipoplex-treated group. These results suggested the potential of LHT7/SAHA nanolipoplex for enhanced tumor vasculature targeting, and the importance of nanolipoplex-mediated co-delivery with a histone deacetylase inhibitor for maximal anticancer effect.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Ji-young
authors.initials: JY
authors.lastname: Kim
authors.forename: Gayong
authors.initials: G
authors.lastname: Shim
authors.forename: Hyun-woo
authors.initials: HW
authors.lastname: Choi
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.forename: Sunil
authors.initials: S
authors.lastname: Kim
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.forename: Chan-Wha
authors.initials: CW
authors.lastname: Kim
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002412:Cations; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D024202:Electrophoretic Mobility Shift Assay; D006493:Heparin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044967:Serum / Q000378:metabolism; D013656:Taurocholic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D006877:Hydroxamic Acids; D008081:Liposomes; D000077337:Vorinostat; D013656:Taurocholic Acid; D006493:Heparin