Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant MCF-7 cells.

Abstract

PURPOSE:

The purpose of this work was to demonstrate the advantage of using pH-sensitive polymeric mixed micelles (PHSM) composed of poly(L: -histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(L: -lactic acid) (pLLA)/PEG block copolymers with folate conjugation to increase drug retention in wild-type and MDR tumor cells.

MATERIALS AND METHODS:

Both wild-type and multidrug resistant (MDR) human breast adenocarcinoma (MCF-7) cell lines were used to investigate the accumulation and elimination of doxorubicin (DOX), PHSM with folate (PHSM/f), and pH-insensitive micelles composed of pLLA/PEG block copolymer with folate (PHIM/f).

RESULTS:

Cells treated with PHSM/f showed decelerated elimination kinetics compared to cells treated with PHIM/f. MDR cells treated with drug-containing PHSM/f for 30 min retained 80% of doxorubicin (DOX) even after incubation for 24 h in the absence of drug. On the other hand, cells treated with drug-containing PHIM/f retained only 40% of DOX within the same period of time. Flow cytometry and confocal microscopy confirmed these results.

CONCLUSIONS:

Cellular entry of the micelles occurred via receptor-mediated endocytosis using folate receptors. The pH-induced destabilization of PHSM/f led to rapid distribution of drug and polymer throughout the cells, most likely due to polyHis-mediated endosomal disruption. This reduced the likelihood of drug efflux via exocytosis from resistant tumor cells.

• Authors: Ghazal Mohajer, Eun Seong Lee, You Han Bae
• Journal: Pharmaceutical research (Pharm Res) Vol. 24 Issue 9 Pg. 1618-27 (Sep 2007) ISSN: 0724-8741 [Print] United States
• PMID: 17385015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Micelles
• Polymers
• Doxorubicin
• Fluorescein-5-isothiocyanate

Topics

• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacokinetics)
• Drug Delivery Systems
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Fluorescein-5-isothiocyanate
• Humans
• Hydrogen-Ion Concentration
• Micelles
• Polymers (pharmacokinetics)