Doxorubicin prodrug for cytoplasmic and nuclear delivery in breast cancer cells

Purpose: The objective of this study was to develop a novel peptide prodrug of doxorubicin which can evade over-expressed efflux pumps in breast cancer cells. This approach may lead to increased uptake and higher drug accumulation in nuclei of cancer cells. Materials and Methods: L-val-L-val doxorubicin prodrug was synthesized following standard f-moc chemistry. The prodrug was analyzed for stability, cellular and nuclear uptake and interaction with efflux and peptide transporters. Breast cancer cells (T47D) were grown on polystyrene 12-well plates. Result: The prodrug Val-Val-doxorubicin was found to be very stable in breast cancer cell homogenate. It was able to evade efflux pumps. The prodrug penetrated cytoplasm and nucleus of cancer cells by interacting with peptide transporters.These transporters (pepT1 and pepT2) are expressed both on plasma and nuclear membrane of breast cancer cells. Uptake of prodrug was found to be 10 times more than parent drug. Conclusion: Peptide prodrug derivatization of doxorubicin has potential to evade efflux pumps and increase availability and nuclear accumulation of doxorubcin in breast cancer cells.