vascular compatibility of polymers and drugs in drug ... › › resource... · vascular...
TRANSCRIPT
![Page 1: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/1.jpg)
Jai Pal Singh Ph. D. Jai Pal Singh Ph. D. Chief Scientific Officer Chief Scientific Officer Vice President of ResearchVice President of Research
SJTRI Atlanta, GA, USASJTRI Atlanta, GA, USA
Vascular compatibility of polymers and Vascular compatibility of polymers and drugs in drug eluting stents drugs in drug eluting stents
![Page 2: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/2.jpg)
• SJTRI is a research arm of the St. Joseph Hospital, Atlanta, GA
• Founded in 1999
• Non-profit, private institute
• Saint Joseph’s is one ofthe 32 hospitals in CHS• $4 billion in annualrevenue
Saint Joseph’s Translational ResearchInstitute ( SJTRI)
![Page 3: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/3.jpg)
SJTRI Near Georgia Tech in theTechnology Enterprise Park
![Page 4: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/4.jpg)
State-of-the-art preclinical facility• 32,000 sq feet, 12 flex labs
– Houses rodents, rabbits, swine,dogs, sheep, and goats
– Preclinical models• Cath labs, OR, imaging, cell and
molecular biology, histology,biomaterial, bio analytical labs andtraining center
• Full AAALAC accreditation, GLP
SJTRI: Open Access Translational Lab
![Page 5: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/5.jpg)
SJTRI MissionTranslate scientific discoveriesinto modern therapeutics for
patient care
Achieve mission through collaboration withindustry, academic, governmental and
philanthropic organizations
![Page 6: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/6.jpg)
Innovation Death Valley
>500,000 IP 2009
BasicResearch
Patients, Society
![Page 7: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/7.jpg)
Basic Research
Clinical Applications
S J T R I
![Page 8: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/8.jpg)
Translational Research at SJTRI
• Scientificknowledge
• Cell free• Cellular systems• MOA
• Preclinical Efficacy• PK/PD• Safety vs. standard of care• Differentiation
• FDAsubmission• Clinical plan• Enable
• GLP Efficacy • Safety
VCPharma
GovBiotechVIC
• Commercialization • IP creation • Patient care
Biotech
Alliances
CHE clinical resource, tissues for genomics, proteomics -----
PharmaAcademia
Biotech
Inventions:
• Device, drug
• Gene, cells
• Antibody
• siRNA
Phase1 unitPhase1 unit
![Page 9: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/9.jpg)
• Wireless sensing device thatis implanted usingminimally invasivetechniques and transmitscardiac output, bloodpressure and heart rate datathat are critical to themanagement of patients
• 5 million patients with heartfailure, $68 billion cost tosociety
Sensors have proven to save lives and hospitalization
Technology Translated at SJTRI
![Page 10: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/10.jpg)
Heart patch implanted after bypass surgery
Products Developed at SJTRI
![Page 11: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/11.jpg)
Drug delivery patch to prevent arrhythmia
SEM
Heart Patch Drug Coated Heart Patch
SJTRI - New Drug-Patch
![Page 12: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/12.jpg)
Pre-clinical Research
•Interventional Cardiology -Development of interventional medical devices -Endothelial function and vascular disease
•Structural heart disease-Congestive heart failure-Heart valves-Ischemic heart disease
•Regenerative Medicine; Tissue Engineering-Adult stem cell therapy and enabling technologies-Cardiac and peripheral vascular disease-Islet cell transplantation-Vascular graft and heart patch engineering-Biopolymer based cells and drug delivery
•Orthopedic -Fracture healing drug- device research -Orthopedic device development
•Other areas: Neurology, genomics
![Page 13: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/13.jpg)
Jai Pal Singh Ph. D. Jai Pal Singh Ph. D. Chief Scientific Officer Chief Scientific Officer Vice President of ResearchVice President of Research
SJTRI Atlanta, GA, USASJTRI Atlanta, GA, USA
Vascular compatibility of polymers and Vascular compatibility of polymers and drugs in drug eluting stents drugs in drug eluting stents
![Page 14: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/14.jpg)
Metallic strutMetallic strut Cobalt-ChromiumCobalt-Chromium
Polymer Polymer coatingcoating
Drug DrugRapamycinRapamycin,,
Drug Eluting Stent (DES)Drug Eluting Stent (DES)
An interventional device used in more that 1 million patients An interventional device used in more that 1 million patients each year to restore blood flow in a blocked coronary arteryeach year to restore blood flow in a blocked coronary artery
stent
Coronary arteryAngiogram
![Page 15: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/15.jpg)
BMS
Baseline After 1 month
DES
DES Reduces Restenosis
![Page 16: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/16.jpg)
Vascular Pathophysiology of DES
• Late restenosis• Stent thrombosis• Malapposition• Aneurysm• Long term antiplatelet therapy• Poor efficacy in diabetics
Finn et al Eur Heart J 2009
![Page 17: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/17.jpg)
SES ZESBMS
Stent Biocompatibility is Determinedby Vascular Histology
The molecular bases of DES pathopysiology is not well defined
![Page 18: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/18.jpg)
• Determine gene expression changes in vessel wall in response to DES implantation
• Determine linkage of gene expression with pathways relevant to vascular pathophysiology
• To discern the changes attributed to the polymer or the drug
Objectives of the studies
![Page 19: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/19.jpg)
• Juvenile Yorkshire swine received overlapping BMS,SES and ZES with S:A 1.1:1 and 4-6mm of overlap.
• All animals were terminated after one month• Histopathology and gene expression studies were
conducted
Experimental Strategy Experimental Strategy
• Use swine as a preclinical model for DES study
• Develop biomarkers to establish connectivity with human
![Page 20: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/20.jpg)
Stent Groups For Micro-Array
Bare metal Zotarolimus Sirolimus
4746 RCA 4751 RCA 4745 LCX
4746 LAD 4751 LAD 4745 RCA
4747 LAD 4757 RCA 4750 LAD
4747 RCA 4757 LAD 4750 RCA
![Page 21: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/21.jpg)
ZES BMS
Genes
SES
Gene Expression Analysis: Micro-ArrayGene Expression Analysis: Micro-Array
![Page 22: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/22.jpg)
Gene Changes Relevant to Vascular Gene Changes Relevant to Vascular Physiological ResponsesPhysiological Responses
![Page 23: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/23.jpg)
Genes Relevant to Vascular Pathophysiology
GS activator 2ACaviolinPRMT5ArginaseVEGFHIF1a, HiF2aEndothelin -1SODThioredoxinPON2HSP70
NFkB1AIL-1bIL-8CXCL2CCL5CCR2CCL3CCR9CXCL2CCL2CCR1ICAM-1
Tissue FactortPA DPP4L-selectinP-selectinvWF
Nitric Oxide NDNitric Oxide NDOxidative stressOxidative stress
InflammationInflammation ThrombosisThrombosisPathwayPathway
![Page 24: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/24.jpg)
L-ArginineL-ArginineeNOS
cGMP
DES Induces NO Pathway Deficiencyand Endothelial Dysfunction
NO
Low Arginine
• Vasodilation• Anti-platelet• Anti-inflammation• Endothelial progenitor cell •AngiogenesisADMAADMA
O2
O ˙ 2-
![Page 25: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/25.jpg)
Impaired Vasodilation in DES
![Page 26: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/26.jpg)
Superoxide (O ˙ 2- ) Production
P=0.044 P=0.032
n=5
n=9
n=7
n=4
n=7
n=60
5
10
15
20
25
30
35
40
proximal distal
Chemiluminiscence(RLU/s/mgoftissue)
BMS
SES
ZES
![Page 27: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/27.jpg)
Both the Polymer and the Drug Contribute to Vascular Pathology
• Genes changes observed with both stents may represent a response to drug
• Differential gene changes in response may be related to differences in the polymer
![Page 28: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/28.jpg)
• Gene expression profiling reveals unique pathological vascular responses to DES
• Changes in gene expression were associated with vascular pathophysiological responses
• Polymer biocompatibility and the drug contribute to vascular gene expression
• The molecular profiling can serve as a guide to differentiate/develop improved biocompatible DES.
Summary
![Page 29: Vascular compatibility of polymers and drugs in drug ... › › resource... · Vascular compatibility of polymers and drugs in drug eluting stents ... Bare metal Zotarolimus Sirolimus](https://reader036.vdocuments.net/reader036/viewer/2022070715/5ed95dacf59b0f56f45f5b6d/html5/thumbnails/29.jpg)
AcknowledgementAcknowledgementDongming HouDongming HouJohn McDonald GTJohn McDonald GTAndrew Huang GTAndrew Huang GTNatarajan SelvamuthuNatarajan SelvamuthuJimmy LiJimmy LiNicolas ChronosNicolas ChronosSJTRI staffSJTRI staff