Carboxymethylcellulose-based and docetaxel-loaded nanoparticles circumvent P-glycoprotein-mediated multidrug resistance.

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.

• 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)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Polymers
• RNA, Messenger
• Taxoids
• Docetaxel
• Carboxymethylcellulose Sodium

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)