title: 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.affiliation: Drug Delivery and Formulation, Medicinal Chemistry Platform, Ontario Institute for Cancer Research , 101 College Street, Suite 800, Toronto, Ontario, Canada M5G 0A3.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Roy
authors.forename: Mami
authors.initials: M
authors.lastname: Murakami
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.forename: Bryan
authors.initials: B
authors.lastname: Hoang
authors.forename: Elijus
authors.initials: E
authors.lastname: Undzys
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents; D001943:Breast Neoplasms / Q000188:drug therapy; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053758:Nanoparticles / Q000737:chemistry*; D010641:Phenotype; D011108:Polymers / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011108:Polymers; D012333:RNA, Messenger; D043823:Taxoids; D000077143:Docetaxel; D002266:Carboxymethylcellulose Sodium