The development of siRNA cancer therapeutics has been impeded by its inadequate delivery and transfection in solid tumors in vivo. This is due to their unfavorable physicochemical properties, instability and rapid elimination or entrapment in the reticuloendothelial system (RES), lysosomal degradation, and toxicity. Some of these problems can be overcome by structural modifications of RNA and by using "stealth" nano carriers that improve the stability and reduce the RES-entrapment and toxicity. The two remaining problems are the inability to reach tumor cells located distal to blood vessels and the inability to achieve sufficient transfection. We have obtained preliminary results indicating that certain combinations of chemotherapy and siRNA loaded in a pegylated cationic lipid carrier yielded significant target protein knockdown and therapeutic synergy in animals bearing several types of solid tumors. The goals of this project are to determine the mechanisms of in vivo synergy and to translate these findings into potentially useful chemo-siRNA therapy. The proposed studies are expected to improve the understanding of the barriers to siRNA delivery and transfection in solid tumors in vivo and indicate paths to overcome these major impediments, while translational studies will build on this information to develop optimal chemo-siRNA therapy regimens for clinical evaluation. If successful, the studies will lead to the development of effective chemo-siRNA therapies with broad applications.

Public Health Relevance

The current proposal is to evaluate novel combinations of chemotherapy and siRNA therapeutics for treating solid tumors. Successful completion of the proposed studies can potentially lead to useful treatments of major cancer types such as lung, breast, ovarian and pancreatic cancers.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA158300-04
Application #
8703038
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Optimum Therapeutics, LLC
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
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Wong, Ho Lun; Shen, Zancong; Lu, Ze et al. (2011) Paclitaxel tumor-priming enhances siRNA delivery and transfection in 3-dimensional tumor cultures. Mol Pharm 8:833-40
Li, Yinghuan; Wang, Jie; Gao, Yue et al. (2011) Relationships between liposome properties, cell membrane binding, intracellular processing, and intracellular bioavailability. AAPS J 13:585-97
Wang, Jie; Lu, Ze; Gao, Yue et al. (2011) Improving delivery and efficacy of nanomedicines in solid tumors: role of tumor priming. Nanomedicine (Lond) 6:1605-20