Cancer-selective targeting and cytotoxicity by liposomal-coupled lysosomal saposin C protein

Clin Cancer Res. 2009 Sep 15;15(18):5840-51. doi: 10.1158/1078-0432.CCR-08-3285. Epub 2009 Sep 8.


Purpose: Saposin C is a multifunctional protein known to activate lysosomal enzymes and induce membrane fusion in an acidic environment. Excessive accumulation of lipid-coupled saposin C in lysosomes is cytotoxic. Because neoplasms generate an acidic microenvironment, caused by leakage of lysosomal enzymes and hypoxia, we hypothesized that saposin C may be an effective anticancer agent. We investigated the antitumor efficacy and systemic biodistribution of nanovesicles comprised of saposin C coupled with dioleoylphosphatidylserine in preclinical cancer models.

Experimental design: Neuroblastoma, malignant peripheral nerve sheath tumor and, breast cancer cells were treated with saposin C-dioleoylphosphatidylserine nanovesicles and assessed for cell viability, ceramide elevation, caspase activation, and apoptosis. Fluorescently labeled saposin C-dioleoylphosphatidylserine was i.v. injected to determine in vivo tumor-targeting specificity. Antitumor activity and toxicity profile of saposin C-dioleoylphosphatidylserine were evaluated in xenograft models.

Results: Saposin C-dioleoylphosphatidylserine nanovesicles, with a mean diameter of approximately 190 nm, showed specific tumor-targeting activity shown through in vivo imaging. Following i.v. administration, saposin C-dioleoylphosphatidylserine nanovesicles preferentially accumulated in tumor vessels and cells in tumor-bearing mice. Saposin C-dioleoylphosphatidylserine induced apoptosis in multiple cancer cell types while sparing normal cells and tissues. The mechanism of saposin C-dioleoylphosphatidylserine induction of apoptosis was determined to be in part through elevation of intracellular ceramides, followed by caspase activation. In in vivo models, saposin C-dioleoylphosphatidylserine nanovesicles significantly inhibited growth of preclinical xenografts of neuroblastoma and malignant peripheral nerve sheath tumor. I.v. dosing of saposin C-dioleoylphosphatidylserine showed no toxic effects in nontumor tissues.

Conclusions: Saposin C-dioleoylphosphatidylserine nanovesicles offer promise as a novel, nontoxic, cancer-targeted, antitumor agent for treating a broad range of cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Screening Assays, Antitumor
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Humans
  • Liposomes
  • Lysosomes / chemistry*
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Nerve Sheath Neoplasms / drug therapy
  • Nerve Sheath Neoplasms / pathology
  • Neuroblastoma / drug therapy
  • Neuroblastoma / pathology
  • Phosphatidylserines / chemistry*
  • Saposins / chemistry
  • Saposins / metabolism
  • Saposins / pharmacology*
  • Saposins / therapeutic use*
  • Substrate Specificity
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Liposomes
  • Phosphatidylserines
  • Saposins
  • 1,2-dioleoylphosphatidylserine