Improved Therapeutic Efficacy of Doxorubicin through Conjugation with a Novel Peptide Drug Delivery Technology (Vectocell)

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 th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-11, Vol.49 (23), p.6908-6916
Main Authors: Meyer-Losic, Florence, Quinonero, Jérôme, Dubois, Vincent, Alluis, Bertrand, Dechambre, Mireille, Michel, Matthieu, Cailler, Françoise, Fernandez, Anne-Marie, Trouet, André, Kearsey, Jonathan
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Doxorubicin - chemistry
Doxorubicin - pharmacology
Drug Delivery Systems
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Female
General aspects
Humans
Medical sciences
Mice
Neoplasm Transplantation
Peptides - chemistry
Pharmacology. Drug treatments
Structure-Activity Relationship
Transplantation, Heterologous
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0606591