Project 3: Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules Non-small cell lung cancer (NSCLC) kills more patients than the next three highest cancers combined. Approximately 70% of the patients are not diagnosed until stage IV metastatic disease where the prognosis is very poor. The standard-of-care with a platinum drug and Taxol only extends life minimally due to many factors including formulation limitations, resistance, poor treatment of metastases, and drug related toxicities. Project 3 takes a translational pipeline approach, using an excellent orthotopic mouse model of metastatic NSCLC to, for the first time, directiy compare three distinct nanoparticle (NP) approaches to deliver otherwise effective small molecule chemotherapies. The unique chemistry, composition, drug release characteristics, formulation and surfaces of the three NPs will optimized and then tested in sensitive and resistant NSCLC cells. Developed drug NPs containing either cisplatin or paditaxel, meeting defined performance and safety criteria, will be screened in an established orthotopic NSCLC model that is metastatic and either sensitive or resistant. In parallel, NPs will be targeted to tumor cells using unique epidermal growth factor receptor (EGFR) recognition ligands developed in the Targeting Ligand Core. Sophisticated pharmacokinetics and direct measurement of in-vivo drug delivery will be performed In collaboration with the PK/PD Core. In-vivo efficacy of drug NPs will be followed with luminescence detection of the luciferase containing lung cancer cells in the orthotopic model in partnership with the Animal Studies Core and the Small Animal Imaging Core. Positive results will be confirmed by CT/PET scanning. The strength of the project is its project management approach and the comparison of three core nanotechnology platforms developed and tested In our current CCNE;1) BTM - a highly scalable oil-core nanocapsule approach with unique activity in multidrug resistant expressing cells and mouse models, 2) PRINT - a 'top-down'fabrication technique to engineer a shape and size specific delivery system with high packaging efficiency and fiexible surface chemistry, and 3) PSQ - a unique inorganic/organic hybrid technology that packages platinum agents in nanoparticles that are targetable and have very favorable drug release capabilities. Successful results in the orthotopic models will be followed by development ofthe drug NP product for eariy phase human trials using UNC-Chapel Hill, NCI NCL/RAID and/or start-up company support. The University Cancer Research Fund (UCRF) has committed $1 million to accelerate selected drug NP product testing in IND enabling studies

Public Health Relevance

In most developed countries, non-small cell lung cancer (NSCLC) is the leading cause of death from malignant disease. Nanoparticles targeted to primary and metastatic NSCLC may improve the standard of care and quality of life for cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
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
Tian, Xi; Nguyen, Minh; Foote, Henry P et al. (2017) CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1?. Cancer Res 77:112-122
Miao, Lei; Li, Jingjing; Liu, Qi et al. (2017) Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer. ACS Nano 11:8690-8706
Shi, Kai; Zhao, Yi; Miao, Lei et al. (2017) Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition. Mol Ther 25:1567-1579

Showing the most recent 10 out of 190 publications