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

Abstract

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.

• Authors: Xiaoyang Qi, Zhengtao Chu, Yonatan Y Mahller, Keith F Stringer, David P Witte, Timothy P Cripe
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 18 Pg. 5840-51 (Sep 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19737950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, 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, pathology)
• Nerve Sheath Neoplasms (drug therapy, pathology)
• Neuroblastoma (drug therapy, pathology)
• Phosphatidylserines (chemistry)
• Saposins (chemistry, metabolism, pharmacology, therapeutic use)
• Substrate Specificity
• Tumor Cells, Cultured