Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer.
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.
Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Bryan
B
Hoang
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.
Mark J
MJ
Ernsting
Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Mami
M
Murakami
Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Elijus
E
Undzys
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.
Shyh-Dar
SD
Li
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D013499:Surface Properties; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004337:Drug Carriers; D043823:Taxoids; D000077143:Docetaxel; D002266:Carboxymethylcellulose Sodium
Castration-resistant prostate cancer; Cellax; Docetaxel; Nanoparticles