PUBLICATION

A Novel PEGylated Liposome-Encapsulated SANT75 Suppresses Tumor Growth through Inhibiting Hedgehog Signaling Pathway

Authors
Yuan, Y., Zhao, Y., Xin, S., Wu, N., Wen, J., Li, S., Chen, L., Wei, Y., Yang, H., and Lin, S.
ID
ZDB-PUB-130416-23
Date
2013
Source
PLoS One   8(4): e60266 (Journal)
Registered Authors
Lin, Shuo
Keywords
none
MeSH Terms
  • Zebrafish
  • Signal Transduction/drug effects*
  • Trans-Activators/antagonists & inhibitors*
  • Trans-Activators/genetics
  • Trans-Activators/metabolism
  • Xenograft Model Antitumor Assays
  • Mice, Inbred C57BL
  • Cell Line, Tumor
  • Embryo, Nonmammalian
  • Genes, Reporter
  • Cell Proliferation/drug effects
  • Tumor Burden/drug effects
  • Humans
  • Gene Expression Regulation, Neoplastic/drug effects*
  • Liposomes/chemistry*
  • Animals
  • Polyethylene Glycols/chemistry
  • Oncogene Proteins/antagonists & inhibitors*
  • Oncogene Proteins/genetics
  • Oncogene Proteins/metabolism
  • Female
  • Receptors, G-Protein-Coupled/antagonists & inhibitors*
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism
  • Drug Compounding
  • Antineoplastic Agents/chemical synthesis
  • Antineoplastic Agents/pharmacology*
  • Mice
  • Apoptosis/drug effects
  • Green Fluorescent Proteins
(all 30)
PubMed
23560085 Full text @ PLoS One
Abstract

The Hedgehog (Hh) pathway inhibitors have shown great promise in cancer therapeutics. SANT75, a novel compound we previously designed to specially inhibit the Smoothened (SMO) protein in the Hh pathway, has greater inhibitory potency than many of commonly used Hh inhibitors. However, preclinical studies of SANT75 revealed water insolubility and acute toxicity. To overcome these limitations, we developed a liposomal formulation of SANT75 and investigated its antitumor efficacy in vitro and in vivo. We encapsulated SANT75 into PEGylated liposome and the mean particle size distribution and zeta-potential (ZP) of liposomes were optimized. Using the Shh-light2 cell and Gli-GFP or Flk-GFP transgenic reporter zebrafish, we confirmed that liposome-encapsulated SANT75 inhibited Hh activity with similar potency as the original SANT75. SANT75 encapsulated into liposome exerted strong tumor growth-inhibiting effects in vitro and in vivo. In addition, the liposomal SANT75 therapy efficiently improved the survival time of tumor-bearing mice without obvious systemic toxicity. The pathological morphology and immunohistochemistry staining revealed that liposomal SANT75 induced tumor cell apoptosis, inhibited tumor angiogenesis as assessed by CD31 and down-regulated the expression of Hh target protein Gli-1 in tumor tissues. Our findings suggest that liposomal formulated SANT75 has improved solubility and bioavailability and should be further developed as a drug candidate for treating tumors with abnormally high Hh activity.

Genes / Markers
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Expression
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Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
la116TgTransgenic Insertion
    zf412TgTransgenic Insertion
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
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      Fish
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      Antibodies
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      Orthology
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      Engineered Foreign Genes
      Marker Marker Type Name
      GFPEFGGFP
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      Mapping
      No data available