Phospho-ibuprofen (MDC-917) incorporated in nanocarriers: anti-cancer activity in vitro and in vivo.

Abstract

BACKGROUND AND PURPOSE:

Phospho-ibuprofen (P-I; MDC-917) inhibits the growth of colon cancer in mice. Here, we investigated the use of nanocarriers to improve its pharmacokinetics (PKs) and anti tumour efficacy.

EXPERIMENTAL APPROACH:

The cellular uptake and cytotoxicity of P-I encapsulated into liposomes and micelles, and its in vitro metabolic stability, were determined in cultures of human colon adenocarcinoma cells. The performance of liposomal P-I was further evaluated in PK studies in mice, and in a model of colon cancer xenografts in nude mice.

KEY RESULTS:

Liposomal P-I and micellar P-I showed significantly enhanced cellular uptake in the colon cancer cells. Liposomal P-I also demonstrated increased cytotoxicity in vitro. Free P-I was metabolized rapidly to ibuprofen in the presence of purified esterases. In contrast, liposomal P-I, and to a lesser extent micellar P-I, was resistant to esterase-mediated hydrolysis. In mice, liposomal P-I partially protected P-I from hydrolysis in the circulation, and improved the biodistribution of intact P-I and its metabolites compared to free P-I. Liposomal P-I was more effective at inhibiting the growth of human colon cancer xenografts in mice, which may be explained on the basis of its improved PK profile compared to free P-I.

CONCLUSIONS AND IMPLICATIONS:

Liposome encapsulation of P-I partially protected P-I from esterase-mediated hydrolysis in mice, enhanced the cytotoxicity and bioavailability of P-I and increased its efficacy at inhibiting the growth of human colon cancer xenografts. These results indicate that liposomes are suitable nanocarriers for the delivery of P-I, and that the anti-tumour potential of liposomal P-I merits further evaluation.

• Authors: T Nie, C C Wong, N Alston, P Aro, P P Constantinides, B Rigas
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 166 Issue 3 Pg. 991-1001 (Jun 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 22141583 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• 2-(4-isobutylphenyl)propionic acid 4-(diethoxyphosphoryloxy)butyl ester
• Antineoplastic Agents
• Drug Carriers
• Liposomes
• Micelles
• Organophosphates
• Ibuprofen

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Cell Culture Techniques
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Drug Carriers (chemistry)
• Drug Stability
• Female
• Humans
• Ibuprofen (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)
• Liposomes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Micelles
• Microscopy, Electron, Transmission
• Molecular Structure
• Nanostructures (chemistry)
• Organophosphates (administration & dosage, pharmacokinetics, therapeutic use)
• Particle Size
• Surface Properties
• Xenograft Model Antitumor Assays