Atherosclerosis remains the leading cause of death and disability in the United States. Current therapeutic modalities for the treatment of severe coronary and peripheral artery disease include balloon angioplasty and stenting, endarterectomy, or bypass grafting. Unfortunately, a large number of these procedures fail due to the development of arterial restenosis secondary to neointimal hyperplasia. The overall goal of this Bioengineering Research Partnership (BRP) is to develop highly innovative targeted therapeutics delivered by bio-inspired tailorable constructs to prevent restenosis following vascular interventions. We expect to develop biocompatible nano- and microscale therapies that will be delivered systemically at the time of arterial intervention, target the manipulated arteria segment, and deliver molecular therapies and drugs to that site to inhibit restenosis. Each of the three platforms proposed are bio-inspired and share common physicochemical properties such that unique aspects of each one may be leveraged by the others to achieve maximal therapeutic efficacy. Preliminary data demonstrate the successful synthesis and in vivo targeting of a novel injectable peptide amphiphile (PA) to the site of vascular injury following intra-arterial injectio. We have also designed a biomimetic high density lipoprotein (HDL) using a gold nanoparticle (AuNP) as a template to control the size, shape, and surface chemical properties of the formed HDL AuNPs. Lastly, micron scale cell- like structures has been synthesized to mimic elements in the blood stream. Overall, we hypothesize that novel;targeted bioengineered therapeutic agents will prevent the development of restenosis following arterial interventions. To investigate this hypothesis, the specific aims are as follows: 1) synthesize and characterize novel bio-inspired delivery vehicles that are targeted to the site of vascular injury and deliver effective therapeutic agents;2) evaluate the effect of the targeted engineered therapeutic delivery vehicles on cells from the vascular wall in vitro;3) determine the specificity, safety, biocompatibility, and efficacy of the targeted engineered therapeutic delivery vehicles at inhibiting neointimal hyperplasia in vivo. Through our multidisciplinary team of investigators, we have already accrued preliminary data that supports the feasibility of our approach. With the support of this BRP, we will provide targeted therapies to prevent restenosis for patients undergoing any vascular intervention. These therapies could revolutionize how atherosclerotic arteries are treated and thus represent a paradigm-shifting technology. Finally, the bioengineered therapies developed in this proposal will be targeted to multiple cell types. Thus, project success will profoundly impact the fields of interventional cardiology, interventional radiology, cardiothoracic surgery, and vascular surgery, but will have more broad ranging impact in the fields of preventive cardiology, cancer, inflammation, and rheumatology.

Public Health Relevance

The overall goal of this Bioengineering Research Partnership is to develop highly innovative targeted therapeutics to prevent restenosis following vascular interventions. Given that atherosclerosis is a leading cause of death and disability in the USA, and the high incidence of restenosis following cardiovascular interventions, this novel translational research has the potential to impact millions of people, and thus has tremendous relevance to public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL116577-01A1
Application #
8579683
Study Section
Special Emphasis Panel (ZRG1-SBIB-N (55))
Program Officer
Danthi, Narasimhan
Project Start
2013-09-04
Project End
2017-05-31
Budget Start
2013-09-04
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$999,212
Indirect Cost
$341,407
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Rubert PĂ©rez, Charles M; Stephanopoulos, Nicholas; Sur, Shantanu et al. (2015) The powerful functions of peptide-based bioactive matrices for regenerative medicine. Ann Biomed Eng 43:501-14