Abstract |
An optimized, pH-sensitive mixed- micelle system conjugated with folic acid is prepared in order to challenge multidrug resistance (MDR) in cancers. The micelles are composed of poly(histidine (His)-co- phenylalanine (Phe))-b-poly( ethylene glycol) (PEG) and poly(L-lactic acid) ( PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition are synthesized. The pH sensitivity of the micelles is controlled by the copolymer composition and is fine tuned to early endosomal pH by blending PLLA(3K)-b-PEG(2K)-folate in the presence of a basic anticancer drug, doxorubicin (DOX). In vitro tests are conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines. A mixed- micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) is selected to target early endosomal pH. DOX-loaded micelles effectively kill both wild-type sensitive (A2780) and DOX-resistant ovarian MDR cancer-cell lines (A2780/DOX(R)) through an instantaneous high dose of DOX in the cytosol, which results from active internalization, accelerated DOX release triggered by endosomal pH, and an endosomal membrance disruption.
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Authors | Dongin Kim, Eun Seong Lee, Kyung Taek Oh, Zhong Gao Gao, You Han Bae |
Journal | Small (Weinheim an der Bergstrasse, Germany)
(Small)
Vol. 4
Issue 11
Pg. 2043-50
(Nov 2008)
ISSN: 1613-6829 [Electronic] Germany |
PMID | 18949788
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Carrier Proteins
- Drug Carriers
- Folate Receptors, GPI-Anchored
- Micelles
- Polyesters
- Proteins
- Receptors, Cell Surface
- poly(histidine-co-phenylalanine)-block-poly(ethylene glycol)
- poly(lactic acid)-block-polyethylene glycol-folate
- Polyethylene Glycols
- Doxorubicin
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Topics |
- Carrier Proteins
(metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Doxorubicin
(administration & dosage, pharmacology)
- Drug Carriers
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Endosomes
(metabolism)
- Folate Receptors, GPI-Anchored
- Humans
- Hydrogen-Ion Concentration
- Micelles
- Polyesters
- Polyethylene Glycols
- Proteins
- Receptors, Cell Surface
(metabolism)
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