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Erufosine (ErPC3) Cationic Prodrugs as Dual Gene Delivery Reagents for Combined Antitumor Therapy
Boris Gaillard1, Cendrine Seguin1, Jean-Serge Remy1
1Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin-BP 60024, 67401, Illkirch, France.
Abstract:
Sixteen cationic prodrugs of the antitumor alkylphospholipid (APL) erufosine were rationally synthesized to provide original gene delivery reagents with improved cytotoxicity profile. The DNA complexation properties of these cationic lipids were determined and associated transfection rates were measured. Furthermore, the self-assembly properties of the pro-erufosine compounds were investigated and their critical aggregation concentration was determined. Their hydrolytic stability under pH conditions mimicking the extracellular environment and the late endosome milieu was measured. Hemolytic activity and cytotoxicity of the compounds were investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosine display antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity, which is a dose-limiting side effect of APLs and a major obstacle to their use in anticancer therapeutic regimen. Furthermore, by using lipoplexes prepared from a prodrug of erufosine and a plasmid DNA encoding a pro-apoptotic protein (TRAIL), evidence was provided for selective cytotoxicity towards tumor cells while nontumor cells were resistant. This study demonstrates that the combination approach involving well tolerated erufosine cationic prodrugs and cancer gene therapy holds significant promise in tumor therapy.
Insights
New cationic prodrugs of erufosine, an antitumor alkylphospholipid (APL), show promise for cancer gene therapy. These compounds exhibit antineoplastic activity without hemolytic toxicity, offering a safer alternative for tumor treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Alkylphospholipids (APLs) like erufosine are effective antitumor agents but face limitations due to dose-limiting hemolytic toxicity.
- Developing novel drug delivery systems is crucial for enhancing cancer therapeutic efficacy and reducing side effects.
Purpose of the Study:
- To synthesize and characterize novel cationic prodrugs of erufosine for improved gene delivery and cytotoxicity.
- To evaluate the DNA complexation, self-assembly, hydrolytic stability, and hemolytic activity of these novel compounds.
- To assess the antineoplastic activity and selective cytotoxicity of erufosine prodrugs in cancer gene therapy.
Main Methods:
- Rational synthesis of sixteen cationic prodrugs of erufosine.
- Determination of DNA complexation and transfection efficiency.
- Investigation of self-assembly properties and critical aggregation concentration.
- Measurement of hydrolytic stability, hemolytic activity, and cytotoxicity in various cell lines.
- Evaluation of lipoplexes with TRAIL-encoding plasmid DNA for selective tumor cell targeting.
Main Results:
- Synthesized prodrugs demonstrated DNA complexation and transfection capabilities.
- Compounds exhibited self-assembly properties and varying hydrolytic stability.
- Erufosine prodrugs displayed antineoplastic activity comparable to the parent drug without hemolytic toxicity.
- Lipoplexes showed selective cytotoxicity towards tumor cells, sparing normal cells.
Conclusions:
- Cationic prodrugs of erufosine offer a promising platform for cancer gene therapy with an improved safety profile.
- The combination of well-tolerated erufosine prodrugs and gene therapy presents a significant advancement in tumor treatment strategies.
- These findings support the potential of erufosine prodrugs as effective and safer agents in anticancer therapeutics.
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