SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice.
METHODS
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, Kras(G12D);p53(flox/-);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.
Cancer Research UK Cambridge Institute, The University of Cambridge, , Cambridge, UK.
Albrecht
A
Neesse
Kristopher K
KK
Frese
Derek S
DS
Chan
Tashinga E
TE
Bapiro
William J
WJ
Howat
Frances M
FM
Richards
Volker
V
Ellenrieder
Duncan I
DI
Jodrell
David A
DA
Tuveson
D000230:Adenocarcinoma / Q000188:drug therapy*; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D030801:Animals, Genetically Modified; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D014677:Pharmaceutical Vehicles / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D015676:Osteonectin; D014677:Pharmaceutical Vehicles; C578250:SPARC protein, mouse; C022131:cremophor; D011092:Polyethylene Glycols; D003094:Collagen; D017239:Paclitaxel
Pancreatic Cancer