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

Andrew M Vekstein; David C Wendell; Sophia DeLuca; Ruorong Yan; Yifan Chen; Muath Bishawi; Garth W Devlin; Aravind Asokan; Kenneth D Poss; Dawn E Bowles; Adam R Williams; Nenad Bursac

doi:10.3389/fcvm.2022.833335

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

Front Cardiovasc Med. 2022 Feb 10:9:833335. doi: 10.3389/fcvm.2022.833335. eCollection 2022.

Authors

Andrew M Vekstein¹, David C Wendell², Sophia DeLuca^{3

4}, Ruorong Yan⁴, Yifan Chen³, Muath Bishawi¹, Garth W Devlin^{3

5

6}, Aravind Asokan^{3

5

6}, Kenneth D Poss⁴, Dawn E Bowles⁷, Adam R Williams¹, Nenad Bursac³

Affiliations

¹ Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, United States.
² Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center, Durham, NC, United States.
³ Department of Biomedical Engineering, Duke University, Durham, NC, United States.
⁴ Department of Cell Biology, Duke Regeneration Center, Duke University, Durham, NC, United States.
⁵ Department of Surgery, Duke University Medical Center, Durham, NC, United States.
⁶ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States.
⁷ Department of Surgery, Surgical Sciences, Duke University Medical Center, Durham, NC, United States.

Abstract

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.

Keywords: gene therapy; heart; iron oxide; magnetic resonance imaging; regeneration.

Abstract

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