Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle.

Abstract

Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in an aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focusing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10-fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which are associated with significant changes in tumor progression and metastasis.

• Authors: Mark J Ernsting, Bryan Hoang, Ines Lohse, Elijus Undzys, Pinjiang Cao, Trevor Do, Bethany Gill, Melania Pintilie, David Hedley, Shyh-Dar Li
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 206 Pg. 122-30 (May 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25804872 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Taxoids
• Docetaxel
• Polyethylene Glycols
• Carboxymethylcellulose Sodium

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, therapeutic use)
• Carboxymethylcellulose Sodium (chemistry)
• Cell Line, Tumor
• Docetaxel
• Drug Delivery Systems
• Female
• Fibroblasts (drug effects, pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Nanoparticles (economics)
• Neoplasm Metastasis (pathology, prevention & control)
• Pancreas (drug effects, pathology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Polyethylene Glycols (chemistry)
• Taxoids (administration & dosage, chemistry, therapeutic use)
• Xenograft Model Antitumor Assays