Improved methods to simultaneously deliver drugs and genes are needed to fully realize the potential of drug-gene combination therapies. Our long-term goal is to establish a new class of biodegradable gene delivery vectors capable of functioning dually as (i) gene delivery vectors and (ii) active pharmacologic agents after intracellular degradation. The objective of this proposal is to design innovative biodegradable dendritic BENSpm polycations (BDBP) capable of functioning dually as a gene delivery vector and an active anticancer agent targeting dysregulated polyamine metabolism in cancer. We will develop biodegradable dendrimer prodrugs based on a cationic drug N1,N11-bis(ethyl)norspermine (BENSpm) that will efficiently deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene to triple negative breast cancer cells and then decompose into the original drug BENSpm, thus augmenting the therapeutic effect of TRAIL. We hypothesize that the combined drug-gene delivery will improve TRAIL anticancer activity due to synergistic enhancement by BENSpm released from BDBP, as suggested by our preliminary data. Our overall objective will be achieved by pursuing two specific aims: 1) synthesize biodegradable dendritic BENSpm polycations;2) determine whether BDBP combined with TRAIL enhances antiproliferative activity in human breast cancer.
In aim 1, a synthetic methodology, which has been established as feasible by the applicant will be used to prepare BDBP that are degradable in a reducing intracellular environment and capable of releasing intact BENSpm.
In aim 2, the BDBP will be used to deliver TRAIL-GFP plasmid in triple-negative breast cancer cells, MDA-MB-231, and to evaluate the effect of intracellular BDBP degradation and BENSpm release on the antiproliferative activity of expressed TRAIL-GFP in 3-D culture. The approach is innovative because of the novel design of delivery vectors that not only deliver therapeutic genes but also augment the activity of the therapeutic gene by exerting its own pharmacologic effect. The proposed research is significant because it will establish a widely applicable design paradigm for non-viral gene delivery systems for simultaneous drug-gene delivery and thus it will improve outcome of gene therapy strategies.

Public Health Relevance

Therapies based on combinations of therapeutic genes with traditional small-molecule drugs promise to improve treatment of many diseases that are refractory to treatment. There is a critical need to develop new technologies to deliver gene-drug combinations. The proposed research is relevant to public health because it will develop such a new delivery system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21EB014570-02
Application #
8614186
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Tucker, Jessica
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$219,685
Indirect Cost
$63,840
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
Wang, Y; Li, J; Chen, Y et al. (2015) Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes. Biomater Sci 3:1114-23
Li, Jing; Yu, Fei; Chen, Yi et al. (2015) Polymeric drugs: Advances in the development of pharmacologically active polymers. J Control Release 219:369-82
Zhu, Yu; Li, Jing; Kanvinde, Shrey et al. (2015) Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer. Mol Pharm 12:332-41
Li, Jing; Lepadatu, Ana-Maria; Zhu, Yu et al. (2014) Examination of structure-activity relationship of viologen-based dendrimers as CXCR4 antagonists and gene carriers. Bioconjug Chem 25:907-17
Li, Jing; Oupický, David (2014) Effect of biodegradability on CXCR4 antagonism, transfection efficacy and antimetastatic activity of polymeric Plerixafor. Biomaterials 35:5572-9
Oupický, David; Li, Jing (2014) Bioreducible polycations in nucleic acid delivery: past, present, and future trends. Macromol Biosci 14:908-22
Wang, Yan; Li, Jing; Oupický, David (2014) Polymeric Plerixafor: effect of PEGylation on CXCR4 antagonism, cancer cell invasion, and DNA transfection. Pharm Res 31:3538-48
Wu, Chao; Li, Jing; Zhu, Yu et al. (2013) Opposing influence of intracellular and membrane thiols on the toxicity of reducible polycations. Biomaterials 34:8843-50
Li, Jing; Wang, Yan; Zhu, Yu et al. (2013) Recent advances in delivery of drug-nucleic acid combinations for cancer treatment. J Control Release 172:589-600
Dong, Yanmei; Zhu, Yu; Li, Jing et al. (2012) Synthesis of bisethylnorspermine lipid prodrug as gene delivery vector targeting polyamine metabolism in breast cancer. Mol Pharm 9:1654-64

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