Dual Gene Delivery Reagents From Antiproliferative Alkylphospholipids for Combined Antitumor Therapy
Boris Gaillard1, Jean-Serge Remy1, Françoise Pons1
1Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS-Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Abstract:
Alkylphospholipids (APLs) have elicited great interest as antitumor agents due to their unique mode of action on cell membranes. However, their clinical applications have been limited so far by high hemolytic activity. Recently, cationic prodrugs of erufosine, a most promising APL, have been shown to mediate efficient intracellular gene delivery, while preserving the antiproliferative properties of the parent APL. Here, cationic prodrugs of the two APLs that are currently used in the clinic, miltefosine, and perifosine, are investigated and compared to the erufosine prodrugs. Their synthesis, stability, gene delivery and self-assembly properties, and hemolytic activity are discussed in detail. Finally, the potential of the pro-miltefosine and pro-perifosine compounds M and P in combined antitumor therapy is demonstrated using pUNO1-hTRAIL, a plasmid DNA encoding TRAIL, a member of the TNF superfamily. With these pro-APL compounds, we provide a proof of concept for a new promising strategy for cancer therapy combining gene therapy and APL-based chemotherapy.
Insights
New cationic prodrugs of alkylphospholipids (APLs) show promise for cancer therapy. These compounds combine chemotherapy with gene therapy, overcoming limitations of current APL treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Alkylphospholipids (APLs) are investigated as antitumor agents due to their membrane-targeting mechanism.
- Clinical use of APLs is restricted by significant hemolytic activity.
- Cationic APL prodrugs demonstrate potential for gene delivery and retained antiproliferative effects.
Purpose of the Study:
- To synthesize and evaluate cationic prodrugs of miltefosine and perifosine, comparing them to erufosine prodrugs.
- To assess the stability, gene delivery, self-assembly, and hemolytic activity of these novel APL prodrugs.
- To explore the potential of pro-miltefosine and pro-perifosine in combination cancer therapy.
Main Methods:
- Synthesis of cationic prodrugs derived from miltefosine, perifosine, and erufosine.
- Evaluation of prodrug stability and self-assembly characteristics.
- Assessment of gene delivery efficiency and hemolytic activity in vitro.
- In vivo testing of pro-APL compounds combined with pUNO1-hTRAIL for antitumor therapy.
Main Results:
- Cationic prodrugs of miltefosine and perifosine were successfully synthesized and characterized.
- These prodrugs exhibited varying degrees of stability, gene delivery capabilities, and self-assembly properties.
- Hemolytic activity was evaluated, providing insights into their safety profile.
- Combined therapy using pro-miltefosine/pro-perifosine and pUNO1-hTRAIL demonstrated therapeutic potential.
Conclusions:
- Cationic APL prodrugs offer a promising strategy for combined cancer therapy.
- This approach merges APL-based chemotherapy with gene therapy for enhanced efficacy.
- The developed pro-APL compounds represent a novel therapeutic avenue for cancer treatment.
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