Abstract 4578: A novel polymer-anticancer drug micelle formulation showing enhanced efficacy over Abraxane
Authors: Ying Wenbin , Liu Jihua , Tsang Kwok Yin , Wang Li , Yin Haiqing , Bai Hao , Wang Yuwei , Wang Liping , Niitsu Yoshiro 
Published: May 2015

Abstract
Advances in the development of novel nanocarriers and their applications in the area of drug delivery have inspired and created new opportunities for anticancer formulation development. About 10 anticancer nanomedicines in various dosage forms of liposomes and polymeric micelles have been approved since 1995, with albumin-bound paclitaxel (Abraxane) being a milestone in the treatment of a variety of aggressive cancers. These nanomedicines outperform the low molecular weight anticancer chemotherapeutic agents by their favorable pharmacokinetics and tissue distribution, resulting in improved efficacy and concomitantly decreased systematic side effect.
We have developed a novel linear water soluble polymeric nano-carrier, poly-(L-γ-glutamylglutamine) (PGGA) by addition of a hydrophilic glutamic acid layer onto a poly-(L-glutamic acid) backbone. PGGA is proved to be versatile as nanocarrier for making both polymer drug conjugates as well as polymeric micelle formulations. By incorporating an appropriate hydrophobic moiety to PGGA backbone, a novel series of PGGA-based polymer hydrotrope is created and utilized in producing stable paclitaxel-encapsulated polymeric micelles (PMs). A lead candidate, designated as NittoX, has been identified from a matrix of such PMs varying in encapsulated paclitaxel and conjugated hydrophobic moiety contents. For NittoX bioperformance, an outstanding anticancer efficacy is observed in NCI-H460 lung cancer xenograft. Dose response is evident and NittoX is able to completely suppress tumor growth at the dosage of 80 mg/kg. More importantly, NittoX is statistically significantly more efficacious than Abraxane at the same dose levels. Dosages are well tolerated by animals in terms of body weight loss and survival. In addition to NCI-H460, NittoX is also found efficacious in a variety of tumor models, including pancreatic cancer. The improved performance is even more evident when administrated with multiple-dose regimens. The improved efficacy is presumably attributed to its superior plasma and tumor pharmacokinetic profile. NittoX not only enhances circulation stability over Abraxane, but also demonstrates preferential tumor PK profile with three-fold elevation of Cmax and AUC(0-168h) as compared to Abraxane. Meanwhile, the results from pharmacodynamic analysis of tubulin polymerization alteration and consequent tumor cell proliferation inhibition are in accordance with in vivo tumor efficacy data. Strong correlation between tumor PK and PD is observed.
These preclinical data undoubtedly suggest that NittoX has potential to become a more potent taxane nanomedicine superior to Abraxane.
Citation Format: Wenbin Ying, Jihua Liu, Kwok Yin Tsang, Li Wang, Haiqing Yin, Hao Bai, Yuwei Wang, Liping Wang, Yoshiro Niitsu. A novel polymer-anticancer drug micelle formulation showing enhanced efficacy over Abraxane. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2014-4578