title: 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: Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario M5B 1Z2, Canada.
authors: Mark J
authors: MJ
authors: Ernsting
authors: Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.
authors: Bryan
authors: B
authors: Hoang
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors: Ines
authors: I
authors: Lohse
authors: Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.
authors: Elijus
authors: E
authors: Undzys
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors: Pinjiang
authors: P
authors: Cao
authors: Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) Program, Princess Margaret Hospitals Radiation Medicine Program, Toronto, Ontario M5G 2M9, Canada.
authors: Trevor
authors: T
authors: Do
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors: Bethany
authors: B
authors: Gill
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors: Melania
authors: M
authors: Pintilie
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada; Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors: David
authors: D
authors: Hedley
authors: Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: shyh-dar.li@ubc.ca.
authors: Shyh-Dar
authors: SD
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D016503:Drug Delivery Systems; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000191:economics*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D011092:Polyethylene Glycols; D002266:Carboxymethylcellulose Sodium
keywords: Nanoparticles; Pancreatic cancer; Tumor-associated stroma