Improved therapeutic efficacy of doxorubicin through conjugation with a novel peptide drug delivery technology (Vectocell)

摘要

Improvement in the therapeutic index of doxorubicin, a cytotoxic molecule, has been sought through its chemical conjugation to short ( 15-23 amino acid) peptide sequences called Vectocell peptides. Vectocell peptides are highly charged drug delivery peptides and display a number of characteristics that make them attractive candidates to minimize many of the limitations observed for a broad range of cytotoxic molecules. The studies reported here characterized the in vitro and in vivo efficacy of a range of Vectocell peptides conjugated to doxorubicin through different linkers. These studies show that the in vivo therapeutic index of doxorubicin can be improved by conjugation with a specific Vectocell peptide ( DPV1047) through an ester linker to C14 of doxorubicin, in both colon and breast tumor models. This conjugate was also shown to have significant in vivo antitumoral activity in a model resistant to doxorubicin, suggesting that this conjugate is able to circumvent the multidrug resistance ( MDR) phenotype. These experiments therefore provide support for the use of the Vectocell technology with other cytotoxic agents.