Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract with no available permanent cure. Conventional IBD treatment relies on systemically acting anti-inflammatory and immunosuppressive agents. The current treatments face a range of problems related to their cost, systemic immune suppression and increased cancer risk. There is a great need and potential for novel treatments, especially if those treatments can be delivered locally to the site of intestinal inflammation by oral route. One of the hallmarks of IBD is the activation of immune cells and the production of proinflammatory cytokines such as TNF?. Furthermore, the chemokine receptor CXCR4 is ubiquitously overexpressed in inflamed intestinal mucosa. Both TNF? and CXCR4 levels are increased in IBD and represent an exciting putative combination target for local combination therapy. The objective of this proposal is to develop and test novel dual-function particles for combination oral treatment designed to safely reduce colonic inflammation. The central hypothesis is that the proposed combined approach will result in improved treatment of IBD as a result of decreased inflammation due to anti-TNF? siRNA and inhibition of CXCR4 by polymeric CXCR4 antagonists (PCXA). The hypothesis is based on (i) available evidence that blockade of TNF? reduces local inflammation in IBD and (ii) our current studies, which demonstrate that PCXA alone enhances healing of experimental IBD in mice. The overall objective of this application will be achieved by pursuing two specific aims: 1) design PCXA capable of oral delivery of siRNA; and 2) evaluate effectiveness of the combined TNF? silencing and CXCR4 antagonism of PCXA/siRNA in a mouse model of IBD. Design of delivery vectors that exhibit their own pharmacologic activity independent of the delivered therapeutic agent represents innovative approach to combination therapies of IBD. The proposed research is significant because it will establish a novel platform for simultaneous targeted local delivery f CXCR4 antagonists and anti-inflammatory siRNA to improve delivery for better treatment and outcome of IBD.

Public Health Relevance

The proposed research is relevant to public health because it will establish a novel platform for simultaneous local delivery of CXCR4 antagonists and anti-inflammatory siRNA to improve delivery for better treatment and outcome of inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB020308-01
Application #
8873035
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Tucker, Jessica
Project Start
2015-04-15
Project End
2017-01-31
Budget Start
2015-04-15
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$201,313
Indirect Cost
$63,125
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Xie, Ying; Yu, Fei; Tang, Weimin et al. (2018) Synthesis and Evaluation of Chloroquine-Containing DMAEMA Copolymers as Efficient Anti-miRNA Delivery Vectors with Improved Endosomal Escape and Antimigratory Activity in Cancer Cells. Macromol Biosci 18:
Kanvinde, Shrey; Chhonker, Yashpal Singh; Ahmad, Rizwan et al. (2018) Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. Acta Biomater 82:158-170
Xie, Ying; Wang, Yazhe; Li, Jing et al. (2018) Promise of chemokine network-targeted nanoparticles in combination nucleic acid therapies of metastatic cancer. Wiley Interdiscip Rev Nanomed Nanobiotechnol :e1528
Wang, Yazhe; Xie, Ying; Li, Jing et al. (2017) Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy. ACS Nano 11:2227-2238
Peng, Zheng-Hong; Xie, Ying; Wang, Yan et al. (2017) Dual-Function Polymeric HPMA Prodrugs for the Delivery of miRNA. Mol Pharm 14:1395-1404
Sleightholm, Richard; Yang, Bin; Yu, Fei et al. (2017) Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy. Biomacromolecules 18:2247-2257
Yu, Fei; Xie, Ying; Wang, Yan et al. (2016) Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis. ACS Macro Lett 5:342-345
Yu, Fei; Li, Jing; Xie, Ying et al. (2016) Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis. J Control Release 244:347-356
Wang, Yan; Kumar, Sushil; Rachagani, Satyanarayana et al. (2016) Polyplex-mediated inhibition of chemokine receptor CXCR4 and chromatin-remodeling enzyme NCOA3 impedes pancreatic cancer progression and metastasis. Biomaterials 101:108-120
Xie, Ying; Wehrkamp, Cody J; Li, Jing et al. (2016) Delivery of miR-200c Mimic with Poly(amido amine) CXCR4 Antagonists for Combined Inhibition of Cholangiocarcinoma Cell Invasiveness. Mol Pharm 13:1073-80

Showing the most recent 10 out of 12 publications