SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice
- Albrecht Neesse1,2,
- Kristopher K Frese1,
- Derek S Chan1,
- Tashinga E Bapiro1,
- William J Howat1,
- Frances M Richards1,
- Volker Ellenrieder2,
- Duncan I Jodrell1,
- David A Tuveson1,3
- 1Cancer Research UK Cambridge Institute, The University of Cambridge, Cambridge, UK
- 2Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany
- 3Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
- Correspondence to Dr David A Tuveson, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA;
- Received 1 July 2013
- Revised 24 July 2013
- Accepted 28 July 2013
- Published Online First 25 September 2013
Design Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA).
Results nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, KrasG12D;p53flox/−;p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response.
Conclusions nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.
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