Docetaxel–Carboxymethylcellulose Nanoparticles Display Enhanced Anti-Tumor Activity in Murine Models of Castration-Resistant Prostate Cancer


Authors: Hoang B, Ernsting MJ, Murakami M, Undzys E, Li SD

Journal: International Journal of Pharmaceutics

DOI: 10.1016/j.ijpharm.2014.05.021

Publication - Summary

August 25, 2014

Summary:

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with poor prognosis and very few treatment options. Fractures and bone pain due to loss of bone density caused by bone metastasis is highly prevalent, rendering mCRPC a highly debilitating condition. While hormone-based therapeutic interventions can improve survival of patients, mCRPC patients have very few options as they typically develop drug resistance linked to over-expression of P-glycoprotein (P-gp) and β-III tubulin. Taxanes are antineoplastic agents that remain the only approved and effective treatment against mCRPC. Treatment of mCRPC via Docetaxel (DTX) and prednisone can improve patients’ quality of life significantly. However, this treatment is only effective in half mCRPC patients and the side effects include neurotoxicity, myalgia and febrile neutropenia. Additionally, patients initially responding to DTX eventually exhibit DTX resistance. It is speculated that novel formulations of DTX can lead to better prognosis and quality of life by 1. Reducing side effects that are associated with the solubility agents required for injection of DTX and 2. Improving drug delivery to tumors and also bypassing the drug resistance mechanisms. Nanotechnology therefore, can be used to improve traditional chemotherapeutic interventions by adding features such as enhanced permeability and retention which leads to increased tumour localization of the drug. It can also inhibit the drug resistance phenomenon by providing new means of cellular drug uptake. In this article, the Shyh-Dar Li group from the University of Toronto (Now at the University of British Columbia) describe a new formulation for delivery of DTX to metastatic prostate cancer tumours. Cellax consists of DTX and PEG-conjugated to a carboxymethylcellulose polymer, which the Li group then formulates into nanoparticles using NanoAssemblrTM technology. The particles minimize DTX side affects and drug resistance while maximizing efficacy.

In their article featured in the International Journal of Pharmaceutics(2014), the authors demonstrate that the Cellax particles have significantly lower toxicity effects than native DTX. In contrast to the native-DTX treated mice, subjects injected with Cellax did not exhibit neutropenia (a common side effect of Taxane therapy) and serological analysis of liver enzymes indicated that liver function was not disturbed in these mice. In the tumor xenograft model, Cellax was compared to native DTX and a saline control. Control saline treated mice had aggressive tumour growth and were sacrificed at day 20. DTX treated mice exhibited tumour inhibition initially, but rebounded after the 20-day mark. Cellax in contrast, led to complete tumour regression in mice up to 120 days.

The bone metastatic model was developed by intra-femoral injection of prostate cancer cells to the bone marrow, where Cellax increased survival rate by 2-fold over the native DTX-treated mice and 3-fold over saline control mice. Additionally, the authors performed MicroCT imaging on bones to measure the bone density and bone loss in the metastatic model mice. Contrary to the saline and DTX-treated mice, Cellax-treated mice displayed no sign of bone loss at 4-weeks post treatment. In DTX treated mice P-gp and β-III tubulin expression was respectively 9- and 2.5-fold higher than normal, while Cellax treatment did not up-regulate drug resistance markers such as P-gp and β-III tubulin suggesting the lack of Taxane resistance phenomenon.

In conclusion, the Li group has developed a promising polymer formulation of DTX, Cellax, that can potentially be used as an effective mCRPC intervention. Currently, the only option for mCRPC patients is treatment with DTX, which is hindered with debilitating side effects and drug resistance. Combining a chemotherapeutic with nanotechnology can improve its toxicity and efficacy profile, which is the case for Cellax. Unlike native DTX, Cellax bypasses the previously shown drug resistance mechanisms and is well tolerated in the xenograft model, inhibiting bone loss and reducing tumour burden. This study indicates that traditional drugs can be reprogrammed and improved by packing into nanoparticles that can be easily modified and adjusted to different purposes.


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.

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