Introduction
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.
Cellax Does Not Upregulate P-gp Expression
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 P-gp expression was measured with native docetaxel (DTX) treatment.
Fig 1. In vivo expression of P-gp protein in an orthotopic breast tumor model of MDA-MB-231. Cellax does not up-regulate P-glycoprotein, whereas DTX caused an overexpression of P-glycoprotein (P-gp). Both were given at the maximum tolerated dose (10mg DTX/kg for DTX, 170mg DTX/kg for Cellax). Image from Roy et al. Mol Pharm 2014;11(8):2592-2599. doi:10.1021/mp400643p.
Cellax Displays Efficacy Against MDR Tumors with P-gp Upregulation
Here we demonstrated that Cellax therapy displayed efficacy against MDR tumor models where there was increased P-gp expression, specifically EMT6/AR1.
Fig 2. Cellax exhibits enhanced efficacy against MDR tumor. Both DTX and Cellax at 10 mg DTX/kg displayed little antitumor activity against this aggressive MDR tumor, while Cellax at an increased dose (30 mg DTX/kg) exhibited significant antitumor efficacy, and on day 9, the tumor growth inhibition was 90%. Image from Roy et al. Mol Pharm 2014;11(8):2592-2599. doi:10.1021/mp400643p.