Cancer is one of the leading causes of death in the US. Chemotherapy remains an important cancer treatment modality. Traditionally, cytotoxic molecules that activate only a single tumor-killing mechanism are used. Combination chemotherapy is now a common practice, which involves treating patients with several medicines that differ in their killing mechanisms. Gemcitabine is approved for the treatment of various carcinomas: pancreatic, breast, lung, and bladder cancers. Although it is extremely potent in tumor cells in culture, the clinical outcomes of gemcitabine in patients is rather modest, and recent pre-clinical data indicated that a gemcitabine-in-liposome formulation helped improve the efficacy of gemcitabine. A recent new development is the use of synthetic double-stranded RNA (dsRNA) as a potential chemotherapy agent. Certain dsRNA molecules have multiple direct and indirect pro-apoptotic, anti-proliferative, and anti-angiogenic activities. Interestingly, our recent data showed that the anti-tumor activity of a locally injected synthetic dsRNA was significantly enhanced when the dsRNA was dosed in combination with systemically dosed gemcitabine, indicating that a combination therapy using gemcitabine and dsRNA represents a promising tumor therapy approach. However, local peritumoral injection is clinically impractical for the majority of tumors. We propose to develop epidermal growth factor (EGF)-conjugated, long-circulating, nanometer-scale liposomal dsRNA formulation and gemcitabine formulation to target them into EGF receptor-over-expressing tumor cells after intravenous injection and to validate the resultant anti-tumor activity in mouse models of mouse or human cancers. To accomplish our overall goal, we propose the following three specific aims: (i) to engineer EGF-coated, long-circulating liposomal carriers for a synthetic dsRNA and for gemcitabine and to validate their activities in vitro, (ii) to evaluate the extent to which the liposomal carriers will deliver the dsRNA and/or the gemcitabine into model tumors in mice after intravenous injection, and (iii) to evaluate the extent to which a combination therapy using tumor-targeting liposomal dsRNA and gemcitabine will inhibit the tumor growth in vivo. The completion of this application will lay a solid scientific foundation for us to devise strategies to improve the clinical outcome of cancers sensitive to dsRNA and gemcitabine in the future. A similar strategy can also be adopted to combine dsRNA with other chemotherapy agents to fight other tumors.

Public Health Relevance

Many tumor cells over-express the EGF receptor. The successful engineering of EGF-conjugated, long- circulating liposomal synthetic dsRNA and liposomal gemcitabine and the validation of their anti-tumor activities when given in combination will lay a sound scientific foundation for future improvement of the clinical outcomes of tumors sensitive to both gemcitabine and dsRNA. A similar strategy can also be utilized to fight other cancers by combining dsRNA with other chemotherapy agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA135274-05
Application #
8111826
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2008-09-26
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$293,365
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Li, Xu; Hufnagel, Stephanie; Xu, Haiyue et al. (2017) Aluminum (Oxy)Hydroxide Nanosticks Synthesized in Bicontinuous Reverse Microemulsion Have Potent Vaccine Adjuvant Activity. ACS Appl Mater Interfaces 9:22893-22901
O'Mary, Hannah L; Aldayel, Abdulaziz M; Valdes, Solange A et al. (2017) Acid-Sensitive Sheddable PEGylated, Mannose-Modified Nanoparticles Increase the Delivery of Betamethasone to Chronic Inflammation Sites in a Mouse Model. Mol Pharm 14:1929-1937
Li, Xu; Naguib, Youssef W; Valdes, Solange et al. (2017) Reverse Microemulsion-Based Synthesis of (Bis)phosphonate-Metal Materials with Controllable Physical Properties: An Example Using Zoledronic Acid-Calcium Complexes. ACS Appl Mater Interfaces 9:14478-14489
Valdes, Solange; Naguib, Youssef W; Finch, Rick A et al. (2017) Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2´, 2´- Difluorodeoxycytidine (DHA-dFdC). Pharm Res 34:1224-1232
Li, Xu; Naguib, Youssef W; Cui, Zhengrong (2017) In vivo distribution of zoledronic acid in a bisphosphonate-metal complex-based nanoparticle formulation synthesized by a reverse microemulsion method. Int J Pharm 526:69-76
Naguib, Youssef W; Lansakara-P, Dharmika; Lashinger, Laura M et al. (2016) Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity. Neoplasia 18:33-48
Niu, Mengmeng; Valdes, Solange; Naguib, Youssef W et al. (2016) Tumor-Associated Macrophage-Mediated Targeted Therapy of Triple-Negative Breast Cancer. Mol Pharm 13:1833-42
Aldayel, Abdulaziz M; Naguib, Youssef W; O'Mary, Hannah L et al. (2016) Acid-Sensitive Sheddable PEGylated PLGA Nanoparticles Increase the Delivery of TNF-? siRNA in Chronic Inflammation Sites. Mol Ther Nucleic Acids 5:e340
Zheng, Yuan-qiang; Naguib, Youssef W; Dong, Yixuan et al. (2015) Applications of bacillus Calmette-Guerin and recombinant bacillus Calmette-Guerin in vaccine development and tumor immunotherapy. Expert Rev Vaccines 14:1255-75
Prasad, Leena Kumari; O'Mary, Hannah; Cui, Zhengrong (2015) Nanomedicine delivers promising treatments for rheumatoid arthritis. Nanomedicine (Lond) 10:2063-74

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