Project 2: Therapeutic Targeting of the Ras Pathway by Nanoparticle Delivery of siRNA Three types of nanoparticles, i.e. LPD, LCP and PRINT, will be used to deliver siRNA to lung cancer cells in a genetically engineered mouse (GEM) model (Kim, co-PI). LPD is a self-assembled, core/membrane nanoparticle, the unique feature of which is the high density ofthe surface grafted PEG chains. Previous work by Huang (co-PI) has shown that LPD accumulates in xenografted human lung tumors at the level of 60-80 % injected dose per g of tissue with minimal uptake by liver and spleen. Three daily i.v. injections of LPD containing siRNA effectively silenced the tumor target gene expression. LCP is similar in structure to LPD, but the core is replaced with calcium phosphate amorphous nanoprecipltate that dissolves in the endosomal acidic pH to release its cargo and swells and bursts the endosomes. The PRINT (DeSimone, co-1) are topdown manufactured nanoparticles In which any carrier and cargo materials can be readily loaded. Dr. DeSimone has shown that siRNA can be successfully loaded in PRINT and delivered to tumor cells for gene silencing. A salient feature of the project is the KRas driven lung cancer GEM. sIRNAs designed against Ras and Ras effector pathways will be tested and delivered as therapeutics. This is particularly significant, because Ras is considered an undruggable target by conventional medicinal chemistry approaches. Furthermore, gemcitabine mono (or di-) phosphate (GMP or GDP), metabolites of gemcitabine will be formulated in LCP nanoparticles and delivered to the tumor cells by itself or together with siRNA. This is a novel approach that takes advantage of the large cargo capacity of these nanoparticles. The project is milestone driven in that by the end of the year 3, at least one nanoparticle formulation will be identified for therapy, pharmacokinetics and toxicity studies In GEM. The formulation should be ready for detailed characterization and toxicity studies in collaboration with Nanotechnology Characterization Lab at NCI for further translational development.

Public Health Relevance

Lung cancer Is a major cancer threat In human. The project will develop nanoparticle formulations for delivering siRNA and/or gemcitabine to a genetically engineered mouse model that is driven by KRas oncogene. This is a realistic approach to treat human lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-GRB-S)
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University of North Carolina Chapel Hill
Chapel Hill
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Sun, Junjiang; Shao, Wenwei; Chen, Xiaojing et al. (2018) An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs. Mol Ther Methods Clin Dev 10:257-267
Liu, Lina; Wang, Yuhua; Miao, Lei et al. (2018) Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. Mol Ther 26:45-55
Starling, Brittney R; Kumar, Parag; Lucas, Andrew T et al. (2018) Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients. Cancer Chemother Pharmacol :
Chai, Zheng; Zhang, Xintao; Rigsbee, Kelly Michelle et al. (2018) Cryoprecipitate augments the global transduction of the adeno-associated virus serotype 9 after a systemic administration. J Control Release 286:415-424
Wang, Yuhua; Zhang, Lu; Xu, Zhenghong et al. (2018) mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma. Mol Ther 26:420-434
Pei, Xiaolei; He, Ting; Hall, Nikita E et al. (2018) AAV8 virions hijack serum proteins to increase hepatocyte binding for transduction enhancement. Virology 518:95-102
Zhang, Xintao; He, Ting; Chai, Zheng et al. (2018) Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration. Biomaterials 176:71-83
Lucas, Andrew T; White, Taylor F; Deal, Allison M et al. (2017) Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models. Nanomedicine 13:471-482
Kim, Junghyun; Luo, Zhi-Xiang; Wu, Yue et al. (2017) In-Situ Formation of Holmium Oxide in Pores of Mesoporous Carbon Nanoparticles as Substrates for Neutron-Activatable Radiotherapeutics. Carbon N Y 117:92-99
Huo, Meirong; Zhao, Yan; Satterlee, Andrew Benson et al. (2017) Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment. J Control Release 245:81-94

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