Tumor vasculature targeting following co-delivery of heparin-taurocholate conjugate and suberoylanilide hydroxamic acid using cationic nanolipoplex
- Tumor vasculature targeting following co-delivery of heparin-taurocholate conjugate and suberoylanilide hydroxamic acid using cationic nanolipoplex
- 김지영; 심가영; 최현우; 박주호; 정성우; 김선일; 김광명; 권익찬; 김찬하; 김상윤; Victor C. Yang; 오유경; 변영로
- Heparin-taurocholate conjugate; Angiogenesis inhibitor; Histone deacetylase inhibitor; Tumor vasculature targeting; Cationic nanolipoplex
- Issue Date
- VOL 33, NO 17, 4424-4430
- 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.
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