A Comparative Study of Folate Receptor-Targeted Doxorubicin Delivery Systems: Dosing Regimens and Therapeutic Index

In this study, we compared the selectivity, safety and activity of doxorubicin (Dox) entrapped in PEGylated liposomes versus Dox conjugated to pullulan (Pull) based nanocarriers and their Folate Receptor (FR)-targeted version, bearing Folic Acid (FA). Both FR-targeted drug delivery systems (DDS) were shown to interact in vitro specifically with cells via the FA ligand. When the DDS were administered intravenously every other day to FR-overexpressing human cervical carcinoma KB tumor-bearing mice, the Pull conjugates displayed similar and low antitumor activity as free Dox. At this dosing regimen, both liposome-based formulations displayed enhanced antitumor activity although they suffered from reversible toxicity. Using a daily dosing schedule, with higher cumulative dose, the folated-Pull conjugate strongly inhibited tumor growth while free Dox was toxic. For polymeric constructs, increasing dose intensity and cumulative dose strongly affects the therapeutic index and reveals a major therapeutic advantage for the FR-targeted formulation. All DDS were able to abrogate doxorubicin-induced cardiotoxicity.