|Category||Life Sciences and Bio Technology|
|Keywords||Chemotherapy, Drug resistance|
* The project is conducted in collaboration with Memorial Sloan-Kettering Cancer Center.
Cells with multidrug resistance (MDR) due to aberrant expression of the lipid transporter P-glycoprotein (P-gp) display a wide range of biochemical changes that affect membrane lipid composition. Despite significant clinical effort, no effective therapy currently exists to reverse P-gp mediated MDR in human cancers.
The inclusion of C16:0 ceramide, but no other natural ceramide species, in a nano-liposomal preparation enables rapid translocation of daunorubicin from cytoplasmic vesicles to the nucleus of ADX MDR cells.
Prof. Barenholz, has previously engineered Doxil which is the first successful liposomal drug that delivers doxorubicin systemically to tumors. This project sets the groundwork for the development of C16-ceramide Doxil-like liposomes for cancer therapy through three specific in vitro and in vivo aims. Successful completion of these studies will result in a direct path of drug development.
We posit that MDR chemoresistance results in part from failure to generate the fusogenic lipid ceramide in a vesicular trafficking system that normally transports daunorubicin into the nucleus, reversible by exogenous ceramide. Natural ceramides are categorized into long chain (C16:0-C20:0) and very long chain (C22:0-C24:1) species relative to the length of the N-acylated fatty acid at the second position of the sphingosine backbone.
We recently showed that different ceramide species possess distinct biologic attributes with long chain C16:0 ceramide being pro-apoptotic, while very long chain C24:0, C24:1 ceramides are anti-apoptotic. We now show that inclusion of C16:0 ceramide, but no other natural ceramide species, in a nano-liposomal preparation permits rapid translocation of daunorubicin from cytoplasmic vesicles to the nucleus of ADX MDR cells.
The study identifies a new facet of the P-gp multidrug resistance phenotype involving disordered sphingolipid metabolism resulting in defective vesicular trafficking of chemotherapeutic drugs to the nucleus, a prerequisite for drug-induced cell killing. Altered sphingolipid metabolism can be corrected by provision of specific ceramide species resulting in correction of the trafficking defect and markedly enhanced tumor cell death. The study serves as the basis for development of a nano-liposomal ceramide chemotherapeutic delivery system for specific correction of P-gp-driven multidrug resistance in cancer.
Granted US 10,052,387; Europe 2968143