Recently, we have developed nanocrystals capable of delivering anticancer drugs. These nanocrystals with possess low toxicity, high drug loading ratio, and overcome multidrug resistance (MDR) in cancer cells in vitro and in vivo. The overall goal of this research proposal is to further develop and investigate multifunctional nanocrystals for MDR cancer therapy. The scientific basis for this proposal originated from our three-phase nanoparticle engineering (3PNE) method recently developed, which includes phase 1, amorphous precipitate;phase 2, hydrated amorphous aggregate;and phase 3, stabilized nanocrystals (NCs). The 3PNE has been applied to the development of rod-shaped NCs for effective anticancer drug delivery. To achieve this goal, we propose three aims:
specific aim 1, to examine the mechanisms of the NCs for their ability to enhance physical stability, overcome MDR, and their in vivo behavior;
specific aim 2, to develop NCs that carry target ligands to deliver PTX to tumor;
and specific aim 3, to establish the NCs for co-delivering a hydrophobic drug (i.e., Paclitaxel) and a hydrophilic anti-cancer drug (i.e., 5-fluorouracil) to synergistically kill tumor cells through different cellular mechanisms. Accomplishing these specific aims will further develop efficient nano-drug carriers for the treatment of cancer, particularly MDR cancer.

Public Health Relevance

This project is relevant to cancer therapy in public health in two ways. First, it has the potential to develop novel nanocrystals (NCs) as an anticancer drug carrier for the efficient treatment of multidrug resistance (MDR) in cancer. Moreover, if successful, the development of new NCs in this proposal has the potential to deliver hydrophobic drugs for the treatment other diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149387-04
Application #
8680176
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Fu, Yali
Project Start
2011-08-17
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Liu, Qi; Zhu, Hongda; Liu, Yun et al. (2017) BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma. Cancer Immunol Immunother :
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
Ma, Yan; Wang, Yuhua; Xu, Zhenghong et al. (2017) Extreme low dose of 5-fluorouracil reverses MDR in cancer by sensitizing cancer associated fibroblasts and down-regulating P-gp. PLoS One 12:e0180023
Goodwin, Tyler J; Huang, Leaf (2017) Investigation of phosphorylated adjuvants co-encapsulated with a model cancer peptide antigen for the treatment of colorectal cancer and liver metastasis. Vaccine 35:2550-2557
Satterlee, Andrew B; Attayek, Peter; Midkiff, Bentley et al. (2017) A dosimetric model for the heterogeneous delivery of radioactive nanoparticles In vivo: a feasibility study. Radiat Oncol 12:54
Goodwin, Tyler J; Shen, Limei; Hu, Mengying et al. (2017) Liver specific gene immunotherapies resolve immune suppressive ectopic lymphoid structures of liver metastases and prolong survival. Biomaterials 141:260-271
Miao, Lei; Liu, Qi; Lin, C Michael et al. (2017) Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors. Cancer Res 77:719-731
Haynes, Matthew T; Huang, Leaf (2016) Multistage Delivery Technologies: Multifunctional, Interdisciplinary Approaches to Nanomedicine. Mol Ther 24:849-51
Luo, Cong; Sun, Jin; Sun, Bingjun et al. (2016) Facile Fabrication of Tumor Redox-Sensitive Nanoassemblies of Small-Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine. Small 12:6353-6362
Satterlee, Andrew B; Huang, Leaf (2016) Current and Future Theranostic Applications of the Lipid-Calcium-Phosphate Nanoparticle Platform. Theranostics 6:918-29

Showing the most recent 10 out of 41 publications