Cancer therapies that utilize the combination of small interfering RNA (siRNA) with traditional small-molecule drugs have the great potential to enhance the treatment repertoire to combat many types of cancers and are particularly important in the treatment of metastatic cancer. In order to allow clinicians to select optimal drug-siRNA combinations, an ideal delivery vector will be versatile enough to deliver siRNA and drugs ranging broadly in physicochemical properties. Importantly, mesoporous silica nanoparticles (MSN) can encapsulate a broad range of drugs in their internal porous structure and thus are well suited as the basic delivery platform onto which systems of drug-siRNA combinations can be constructed. The objective of this proposal is to design MSN capable of targeted, simultaneous, combined delivery of established chemotherapeutics and therapeutic siRNAs into metastatic cancer. The central hypothesis is that using multilayered MSN containing a redox-responsive, siRNA-binding layer and a colloidally stabilizing and targeting layer of hyaluronic acid (HA) to deliver the drug-siRNA combination into CD44-overexpressing lung metastases of breast cancer (BrCa) will improve anticancer activity as compared to either agent alone. The overall rationale for the project is that the combined drug-siRNA delivery will sensitize the cancer cells by simultaneously silencing genes involved in cancer progression while delivering effective therapeutics. The overall objective of this application will be achieved by pursuing three specific aims: 1) design, synthesize, and characterize redox-responsive multilayered MSN (RRM-MSN) for simultaneous delivery of drugs and siRNA into CD44-overexpressing cancer cells; 2) determine in vitro if combined drug-siRNA delivery using RRM-MSN improves anticancer activity in BrCa cells; and 3) determine in vivo if simultaneous drug-siRNA delivery using RRM-MSN improves antitumor activity in a lung metastasis model of CD44-overexpressing BrCa. The approach is innovative because of the versatile and modular multilayered design of nanoparticles with redox-triggered drug and siRNA release, which is suitable for the delivery of a broad range of drug-siRNA combinations. The proposed research is significant because it will establish a widely applicable and versatile method for simultaneous, targeted delivery of chemotherapeutics and therapeutic siRNAs to improve delivery and therapeutic outcome in metastatic cancer.

Public Health Relevance

The majority of cancer deaths are caused by metastases rather than primary tumors. To prevent these fatalities, there is a critical need to develop new technologies for specific delivery of chemotherapeutic and siRNA-based agents to disseminated metastatic cancer. The proposed research is relevant to public health because it will develop systems for simultaneous delivery of anticancer drugs and therapeutic siRNAs to metastatic breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB015216-04
Application #
9314566
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Rampulla, David
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
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:
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
Sun, Minjie; Wang, Kaikai; Oupický, David (2018) Advances in Stimulus-Responsive Polymeric Materials for Systemic Delivery of Nucleic Acids. Adv Healthc Mater 7:
Chen, Yi; Li, Jing; Oupický, David (2018) Conjugate Polyplexes with Anti-Invasive Properties and Improved siRNA Delivery In Vivo. Bioconjug Chem 29:296-305
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
Xie, Ying; Murray-Stewart, Tracy; Wang, Yazhe et al. (2017) Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy. J Control Release 246:110-119
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
Wani, Amit; Savithra, Galbokka H Layan; Abyad, Ayat et al. (2017) Surface PEGylation of Mesoporous Silica Nanorods (MSNR): Effect on loading, release, and delivery of mitoxantrone in hypoxic cancer cells. Sci Rep 7:2274
Wang, Yan; Xie, Ying; Oupický, David (2016) Potential of CXCR4/CXCL12 Chemokine Axis in Cancer Drug Delivery. Curr Pharmacol Rep 2:1-10

Showing the most recent 10 out of 17 publications