PT  - JOURNAL ARTICLE
AU  - Johnstone, Sharon A.
AU  - Ansell, Steven M.
AU  - Harasym, Troy O.
AU  - Xie, Sherwin
AU  - Mayer, Lawrence D.
AU  - Tardi, Paul
TI  - Abstract 3698: Development of a hydrophobic docetaxel prodrug nanoparticle with enhanced plasma circulation lifetime and improved efficacy
AID  - 10.1158/1538-7445.AM10-3698
DP  - 2010 Apr 15
TA  - Cancer Research
PG  - 3698--3698
VI  - 70
IP  - 8 Supplement
4099  - http://cancerres.aacrjournals.org/content/70/8_Supplement/3698.short
4100  - http://cancerres.aacrjournals.org/content/70/8_Supplement/3698.full
SO  - Cancer Res2010 Apr 15; 70
AB  - Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCAmphiphilic block co-polymers can form highly stable micellar-nanoparticles which can be used to trap hydrophobic chemotherapeutic agents. While block co-polymer formulations effectively retain drugs in vitro, nanoparticles frequently display burst release of trapped agents upon injection into animals. As a result, nanoparticles often show only limited improvements in drug circulation lifetime and likely provide little improvement in drug delivery to the tumor site. To address this issue, we previously generated hydrophobic prodrugs of paclitaxel to enhance retention within the nanoparticle and observed a correlation between drug circulation lifetime and the hydrophobicity of the anchor. When these formulations were evaluated for anti-tumor efficacy, the longest circulating paclitaxel prodrugs were the most efficacious. We have now extended our assessment to hydrophobic docetaxel prodrug formulations and have related plasma circulation characteristics of the docetaxel prodrug nanoparticles to suppression of tumor growth in mice bearing HT-29 human colorectal tumor xenographs. Docetaxel-docosanyl diglycolate (procet 7), and docetaxel-cholesteryl diglycolate (procet 8) were formulated in PS-PEG nanoparticles at a drug:polymer weight ratio of1:2 and injected i.v. into mice. The plasma half-life of the docetaxel prodrug was enhanced relative to the corresponding paclitaxel prodrug and significantly greater than docetaxel formulated in polysorbate 80. When dosed at their respective maximum tolerated dose (MTD), docetaxel, procet 7 and procet 8 nanoparticles resulted in a tumor growth delay (TGD) of 66%, 213% and 241% respectively. In addition docetaxel prodrugs administered at equimolar doses to docetaxel displayed greater antitumor activity than the free drug (77% and 105% TGD for procet 7 and procet 8 nanoparticles respectively). We attribute the increased potency of docetaxel prodrugs over paclitaxel prodrugs to the extended plasma circulation lifetimes of the former. These results confirm that hydrophobic docetaxel prodrugs can be formulated into block co-polymer nanoparticles to achieve prolonged circulation kinetics which result in enhanced therapeutic activity.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3698.