Enhanced anti-neuroblastoma activity of a fenretinide complexed form after intravenous administration.

Abstract

OBJECTIVES:

The major limitation to successful chemotherapy of neuroblastoma (NB) is the toxicity and the poor bioavailability of traditional drugs.

METHODS:

We synthesised an amphiphilic dextrin derivative (DX-OL) able to host fenretinide (4-HPR) by complexation. In this study, we have investigated the effects of 4-HPR-loaded amphipilic dextrin (DX-OL/4-HPR) in comparison with 4-HPR alone both in vitro on human NB cells and in vivo in pseudometastatic NB models. The haemolysis assay was used as a measure of the potential damage caused by the pharmaceutical formulation in vivo. Pharmacokinetic experiments were performed to assess drug plasma levels in mice treated with free or complexed 4-HPR.

KEY FINDINGS:

DX-OL/4-HPR exerted a more potent cytotoxic activity on NB cells. Complexed 4-HPR significantly increased the proportion of sub-G1 cells with respect to free 4-HPR. Dextrin derivatives showed no haemolytic activity, indicating their suitability for parenteral administration. DX-OL/4-HPR increased the lifespan and the long-term survival of treated mice over controls. The analysis of drug plasma levels indicates that the complexed drug has a higher AUC due to a reduced clearance from the blood.

CONCLUSIONS:

Our data suggest that DX-OL/4-HPR is an injectable formulation that is able to improve drug aqueous solubility and bioavailability.

• Authors: Roberta Carosio, Vito Pistoia, Isabella Orienti, Franca Formelli, Elena Cavadini, Salvatore Mangraviti, Paolo G Montaldo, Emanuela Ognio, Laura Emionite, Guendalina Zuccari
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 64 Issue 2 Pg. 228-36 (Feb 2012) ISSN: 2042-7158 [Electronic] England
• PMID: 22221098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Chemical References

• Antineoplastic Agents
• Fenretinide

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Apoptosis (drug effects)
• Biological Availability
• Cell Division (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Delivery Systems
• Female
• Fenretinide (administration & dosage, pharmacokinetics)
• Humans
• Infusions, Intravenous
• Mice
• Mice, Nude
• Neuroblastoma (drug therapy, metabolism, pathology)