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: Ji-young Kim, Gayong Shim, Hyun-woo Choi, Jooho Park, Seung Woo Chung, Sunil Kim, Kwangmeyung Kim, Ick Chan Kwon, Chan-Wha Kim, Sang Yoon Kim, Victor C Yang, Yu-Kyoung Oh, Youngro Byun
• Journal: Biomaterials (Biomaterials) Vol. 33 Issue 17 Pg. 4424-30 (Jun 2012) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 22425551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cations
• Hydroxamic Acids
• Liposomes
• Vorinostat
• Taurocholic Acid
• Heparin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cations
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Delivery Systems (methods)
• Electrophoretic Mobility Shift Assay
• Heparin (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Hydroxamic Acids (administration & dosage, pharmacology, therapeutic use)
• Injections, Intravenous
• Liposomes (chemistry)
• Mice
• Nanoparticles (chemistry)
• Neoplasms (blood supply, drug therapy, pathology)
• Neovascularization, Pathologic (drug therapy)
• Rats
• Rats, Sprague-Dawley
• Serum (metabolism)
• Taurocholic Acid (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Time Factors
• Tissue Distribution (drug effects)
• Vorinostat