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Title
  • Vascular-targeted nanotherapy for obesity: Unexpected passive targeting mechanism to obese fat for the enhancement of active drug delivery
Creator

Hossen, Md. Nazir

Kajimoto, Kazuaki

Akita, Hidetaka

Hyodo, Mamoru

Harashima, Hideyoshi

Subject
  • Other Active targeting
  • Other Passive targeting
  • Other Vascular-targeted nanoparticle
  • Other Anti-angiogenesis
  • Other Obesity
  • NDC 499
Description
Other
  • We previously reported that nanoparticles (NPs) modified with a prohibitin- homing peptide ligand via a short PEG_[2kDa]-spacer could deliver its pay-load into the cytoplasm of endothelial cells in murine adipose tissue and escape from endosomes/lysosomes in vitro. We herein report, for the first time, on a dual-targeting strategy for mediating the enhanced targeting activity of NPs to adipose endothelial cells in diet-induced obesity (DIO). The targeted accumulation of prohibitin-targeted nanoparticles (PTNP), modified with a peptide ligand via a long PEG-linker, was significantly increased in white fat vessels of normal healthy mice compared to the other non-PEGylated targeted NPs, whereas the undesired accumulation of PTNP in the liver was considerably reduced. These results demonstrate that the PEGylation of targeted NPs is a critical factor in maximizing the in vivo targeted delivery of NPs and can be attributed to a significant decrease in recognition by the reticuloendothelial system. After systemic administration to DIO mice, PTNP exclusively accumulated in both adipose vessels and angiogenic clusters of obese fat cells. Surprisingly, PEGylated NPs with no active targeting moieties also accumulated in these clusters, demonstrating that the nanoscaled carriers passively accumulate in clusters via a mechanism similar to that for the enhanced permeability and retention effect, as has been well established in tumor targeting. Therefore, the enhanced delivery of PTNP appears to be mediated by both passive accumulation to angiogenic regions and active recognition by endothelial cells. Thus, the systemic administration of a proapoptotic peptide with the delivery via PTNP significantly reduced the body weight of DIO mice, as evidenced by the targeted ablation of adipose endothelial cells. These findings are potentially useful in terms of the design and development of vascular-targeted nanotherapy in the effective control of obesity.
PublisherElsevier B.V.
Date Issued 2012-10-28
Languageeng
NIItypejournal article
VersiontypeAM
Identifier URI http://hdl.handle.net/2115/50996
Relation
  • isIdenticalTo PMID 22982237
  • isIdenticalTo DOI https://doi.org/10.1016/j.jconrel.2012.09.002
Journal
    • ISSN 0168-3659
    • Journal of Controlled Release
    163(2), 101-110
File
Oaidate2019-03-15T05:20:37Z