Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer

Bryan Hoang; Mark J Ernsting; Mami Murakami; Elijus Undzys; Shyh-Dar Li

doi:10.1016/j.ijpharm.2014.05.021

Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer

Int J Pharm. 2014 Aug 25;471(1-2):224-33. doi: 10.1016/j.ijpharm.2014.05.021. Epub 2014 May 20.

Authors

Bryan Hoang¹, Mark J Ernsting², Mami Murakami¹, Elijus Undzys¹, Shyh-Dar Li³

Affiliations

¹ Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
² Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, ON, Canada.
³ Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; The Techna Institute, University Health Network, Toronto, ON, Canada. Electronic address: sli@oicr.on.ca.

Abstract

Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration resistant prostate cancer (mCRPC) patients. Despite some clinical successes with DTX-based therapies, advent of cumulative toxicity and development of drug resistance limit its long-term clinical application. The integration of nanotechnology for drug delivery can be exploited to overcome the major intrinsic limitations of DTX therapy for mCRPC. We evaluated whether reformulation of DTX by facile conjugation to carboxymethylcellulose nanoparticles (Cellax) can improve the efficacy and safety of the drug in s.c. and bone metastatic models of CRPC. A single dose of the nanoparticles completely regressed s.c. PC3 tumor xenografts in mice. In addition, Cellax elicited fewer side effects compared to native DTX. Importantly, Cellax did not increase the expression of drug resistance molecules in androgen-independent PC3 prostate cancer cells in comparison with DTX. Lastly, in a bone metastatic model of CRPC, Cellax treatment afforded a 2- to 3-fold improvement in survival and enhancements in quality-of-life of the animals over DTX and saline controls. These results demonstrate the potential of Cellax in improving the treatment of mCRPC.

Keywords: Castration-resistant prostate cancer; Cellax; Docetaxel; Nanoparticles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity
Bone Neoplasms / prevention & control
Bone Neoplasms / secondary
Carboxymethylcellulose Sodium / chemistry*
Cell Line, Tumor
Docetaxel
Drug Carriers / chemistry*
Gene Expression / drug effects
Humans
Male
Mice, Inbred BALB C
Nanoparticles / chemistry*
Particle Size
Prostatic Neoplasms, Castration-Resistant / drug therapy*
Prostatic Neoplasms, Castration-Resistant / pathology
Surface Properties
Survival Analysis
Taxoids / administration & dosage*
Taxoids / therapeutic use
Taxoids / toxicity
Xenograft Model Antitumor Assays

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Drug Carriers
Taxoids
Docetaxel
Carboxymethylcellulose Sodium

Abstract

Publication types

MeSH terms

Substances

Grants and funding