Innovative drug delivery platform based on biocompatible poly(2-oxazoline)s block copolymers is proposed to improve chemotherapy of cancer. The technology will overcome major therapeutic challenges in breast cancer. This will be realized by tailoring poly(2-oxazoline)s structure to incorporate very large amounts (>40 wt. %) of insoluble drugs in polymer micelles of narrow size distribution (20-50 nm). These high-capacity micelles can be lyophilized and re-dispersed without loss of the particle size, drug loading or drug activity. The micelles will carry paclitaxel and docetaxel using drastically less amount of excipients relative to current formulations. Hence, excipient-associated toxicities will be decreased. The micelles will be targeted using monoclonal antibodies to Her2-receptors. This strategy is expected to address Herceptin resistance in cancers overexpressing Her2. The proposed aims will 1) optimize poly(2-oxazoline)s structures for solubilization of water-insoluble drugs;2) determine pharmacokinetics and maximum tolerated doses in vivo;3) validate anti-tumor activity in mouse models of breast cancer, and 4) develop targeted micelles effective against Herceptin sensitive and resistant tumors. This CNPP joins together pharmaceutical scientists at [deleted], cancer researchers at [deleted], and polymer chemists at [deleted] who will contribute to the Alliance through challenge projects and other trans-alliance activities.

Public Health Relevance

Overcoming the historical limitations of dose-limiting toxicities, life-threatening side effects, and low water solubility of potentially highly-active drug candidates could result in the development of effective drug delivery systems that provide safety, bioavailability, and ease of use.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151806-02
Application #
8137210
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Farrell, Dorothy F
Project Start
2010-09-02
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$410,562
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
He, Zhijian; Wan, Xiaomeng; Schulz, Anita et al. (2016) A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 101:296-309
Lück, Steffen; Schubel, René; Rüb, Jannick et al. (2016) Tailored and biodegradable poly(2-oxazoline) microbeads as 3D matrices for stem cell culture in regenerative therapies. Biomaterials 79:1-14
Lang, Patrick Y; Nanjangud, Gouri J; Sokolsky-Papkov, Marina et al. (2016) ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation. Development 143:4038-4052
He, Zhijian; Schulz, Anita; Wan, Xiaomeng et al. (2015) Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation. J Control Release 208:67-75
He, Zhijian; Miao, Lei; Jordan, Rainer et al. (2015) A Low Protein Binding Cationic Poly(2-oxazoline) as Non-Viral Vector. Macromol Biosci 15:1004-20
Malhotra, Gautam K; Zhao, Xiangshan; Edwards, Emily et al. (2014) The role of Sox9 in mouse mammary gland development and maintenance of mammary stem and luminal progenitor cells. BMC Dev Biol 14:47
Alakhova, Daria Y; Kabanov, Alexander V (2014) Pluronics and MDR reversal: an update. Mol Pharm 11:2566-78
Zhao, Yi; Alakhova, Daria Y; Kabanov, Alexander V (2013) Can nanomedicines kill cancer stem cells? Adv Drug Deliv Rev 65:1763-83
Alakhova, Daria Y; Zhao, Yi; Li, Shu et al. (2013) Effect of doxorubicin/pluronic SP1049C on tumorigenicity, aggressiveness, DNA methylation and stem cell markers in murine leukemia. PLoS One 8:e72238
Helikar, Tomáš; Kochi, Naomi; Kowal, Bryan et al. (2013) A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. PLoS One 8:e61757

Showing the most recent 10 out of 27 publications