Abstract |
Taxanes are a class of anticancer agents with a broad spectrum and have been widely used to treat a variety of cancer. However, its long-term use has been hampered by accumulating toxicity and development of drug resistance. The most extensively reported mechanism of resistance is the overexpression of P-glycoprotein (Pgp). We have developed a PEGylated carboxymethylcellulose conjugate of docetaxel (Cellax), which condenses into ∼120 nm nanoparticles. Here we demonstrated that Cellax therapy did not upregulate Pgp expression in MDA-MB-231 and EMT-6 breast tumor cells, whereas a significant increase in Pgp expression was measured with native docetaxel (DTX) treatment. Treatment with DTX led to 4-7-fold higher Pgp mRNA expression and 2-fold higher Pgp protein expression compared with Cellax treatment in the in vitro and in vivo system, respectively. Cellax also exhibited significantly increased efficacy compared with that of DTX in a taxane-resistant breast tumor model. Against the highly Pgp expressing EMT6/AR1 cells, Cellax exhibited a 6.5 times lower IC50 compared with that of native DTX, and in the in vivo model, Cellax exhibited 90% tumor growth inhibition, while native DTX had no significant antitumor activity.
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Authors | Aniruddha Roy, Mami Murakami, Mark J Ernsting, Bryan Hoang, Elijus Undzys, Shyh-Dar Li |
Journal | Molecular pharmaceutics
(Mol Pharm)
Vol. 11
Issue 8
Pg. 2592-9
(Aug 04 2014)
ISSN: 1543-8392 [Electronic] United States |
PMID | 24564177
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Polymers
- RNA, Messenger
- Taxoids
- Docetaxel
- Carboxymethylcellulose Sodium
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(chemistry)
- Animals
- Antineoplastic Agents
- Breast Neoplasms
(drug therapy)
- Carboxymethylcellulose Sodium
(chemistry)
- Cell Line, Tumor
- Docetaxel
- Drug Delivery Systems
- Drug Resistance, Multiple
(drug effects)
- Drug Resistance, Neoplasm
(drug effects)
- Female
- Humans
- Inhibitory Concentration 50
- Mammary Neoplasms, Experimental
(drug therapy)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, SCID
- Nanoparticles
(chemistry)
- Phenotype
- Polymers
(chemistry)
- RNA, Messenger
(metabolism)
- Taxoids
(administration & dosage, chemistry)
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