Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts

Frontiers in Cardiovascular Medicine

article

Nenad Bursac¹  Andrew M. Vekstein²  David C. Wendell³  Sophia DeLuca¹  Ruorong Yan⁴  Yifan Chen¹  Muath Bishawi²  Garth W. Devlin¹  Aravind Asokan¹  Kenneth D. Poss⁴  Dawn E. Bowles⁷  Adam R. Williams² 

[1] Department of Biomedical Engineering, Duke University;Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center;Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center;Department of Cell Biology, Duke Regeneration Center, Duke University;Department of Surgery, Duke University Medical Center;Department of Molecular Genetics and Microbiology, Duke University Medical Center;Department of Surgery, Surgical Sciences, Duke University Medical Center

关键词: heart;    gene therapy;    iron oxide;    regeneration;    magnetic resonance imaging;   

DOI  :  10.3389/fcvm.2022.833335

学科分类：地球科学(综合)

来源: Frontiers

【 摘 要 】

Background The optimal delivery route to enhance effectiveness of regenerative therapeutics to the human heart is poorly understood. Direct intra-myocardial (IM) injection is the gold standard, however, it is relatively invasive. We thus compared targeted IM against less invasive, catheter-based intra-coronary (IC) delivery to porcine myocardium for the acute retention of nanoparticles using cardiac magnetic resonance (CMR) imaging and viral vector transduction using qPCR. Methods Ferumoxytol iron oxide (IO) nanoparticles (5 ml) were administered to Yorkshire swine ( n = 13) by: (1) IM via thoracotomy, (2) catheter-based IC balloon-occlusion (BO) with infusion into the distal left anterior descending (LAD) coronary artery, (3) IC perforated side-wall (SW) infusion into the LAD, or (4) non-selective IC via left main (LM) coronary artery infusion. Hearts were harvested and imaged using at 3T whole-body MRI scanner. In separate Yorkshire swine ( n = 13), an adeno-associated virus (AAV) vector was similarly delivered, tissue harvested 4–6 weeks later, and viral DNA quantified from predefined areas at risk (apical LV/RV) vs. not at risk in a potential mid-LAD infarct model. Results were analyzed using pairwise Student's t -test. Results IM delivery yielded the highest IO retention (16.0 ± 4.6% of left ventricular volume). Of the IC approaches, BO showed the highest IO retention (8.7 ± 2.2% vs. SW = 5.5 ± 4.9% and LM = 0%) and yielded consistent uptake in the porcine distal LAD territory, including the apical septum, LV, and RV. IM delivery was limited to the apex and anterior wall, without septal retention. For the AAV delivery, the BO was most efficient in the at risk territory (Risk: BO = 6.0 × 10 −9 , IM = 1.4 × 10 −9 , LM = 3.2 × 10 −10 viral copies per μg genomic DNA) while all delivery routes were comparable in the non-risk territory (BO = 1.7 × 10 −9 , IM = 8.9 × 10 −10 , LM = 1.2 × 10 −9 ). Conclusions Direct IM injection has the highest local retention, while IC delivery with balloon occlusion and distal infusion is the most effective IC delivery technique to target therapeutics to a heart territory most in risk from an infarct.

【 授权许可】

CC BY