Open Access Nano Commentary

Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity

Po-Chang Chiang1*, Stephen Gould2, Michelle Nannini2, Ann Qin3, Yuzhong Deng3, Alfonso Arrazate2, Kimberly R Kam1, Yingqing Ran1 and Harvey Wong3*

Author Affiliations

1 Department of Pharmaceutics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

2 Department of In-Vivo Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

3 Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

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Nanoscale Research Letters 2014, 9:156  doi:10.1186/1556-276X-9-156

Published: 1 April 2014

Abstract

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

Keywords:
Paclitaxel; Nanosuspension; Cremophor EL; Pharmacokinetics; Tissue distribution; Xenograft