Targeted Doxycycline Release with a Therapeutic Hydrogel in the Infarct Area Modulates Matrix Metalloproteinase Activity Thereby Improving Left Ventricular Volume and Hemodynamics

Introduction: Myocardial infarction (MI) results in left ventricular (LV) remodeling leading to heart failure and subsequent high mortality rate. The induction of proteolytic enzymes in the myocardium, including the matrix metalloproteinases (MMPs) occurs early in following MI and modulate LV remodeling. Therapeutic interventions, including intramyocardial injections of hydrogels, show promise in prevention of adverse LV remodeling. We have used a ^99mTc-labeled MMP targeted SPECT radiotracer, ^99mTc-RP805, to evaluate therapeutic efficacy of an intramyocardial delivered hydrogel that incorporate MMP inhibitors in chronic porcine models of reperfused MI. Doxycycline (DOX), a synthetic tetracycline antibiotic, is known to inhibit MMP expression and activation. We hypothesize that intramyocardial injection of a DOX-loaded hydrogel in MI region 1-week post-MI will reduce remodeling and limit off-target systemic effects.

Methods: This study evaluates a previously engineered two-component system of adamantane-modified and β-cyclodextrine-modified hyaluronic acid hydrogel (HA) that incorporates a therapeutic dose of DOX (HA-Dox) (11.6 ± 5.7 mg per 900 ul) that previously demonstrated sustained release over 14 days. Reperfused MI was created in swine (n=16) by 90-min occlusion of left anterior descending coronary artery. 7 days post MI we performed nine 100 ul intramyocardial injections of HA-Dox (n=4) or HA-Only (n=5) into MI area or no injections in MI-Controls (n=7). At 3 days and 5 weeks following MI we performed hybrid ^99mTc-RP805 SPECT/CT imaging (GE Discovery 570 NM/CT). 5 weeks post-MI we also performed ECG-gated contrast CT to assess LV volume and function (AW Workstation, GE Healthcare) along with LV hemodynamics with a micromanometer to assess efficacy of targeted drug delivery followed by euthanasia and gamma well counting of regional myocardial ^99mTc-RP805 activity, which was compared with final LV geometry and hemodynamics.

Results: Therapeutic release of DOX resulted in a significant reduction in ^99mTc -RP805 uptake in the MI area compared to the referent control region in the HA-Dox vs MI-Controls (p=0.039, ANOVA), with no significant reduction in HA-Only group (p=0.174, ANOVA) (Figure 1C). While there was no significant difference in LV function (p>0.998, ANOVA) (Figure 1D), LV dilation was reduced in both hydrogel groups with a significant reduction in LV end-diastolic volumes (HA-Dox p<0.028; HA-Only p<0.045, ANOVA) when compared to MI-Controls (Figure 1E). LVEDP was reduced only in the HA-Dox group compared to MI-Controls (p=0.013, ANOVA) (Figure 1F).

Conclusions: Targeted intramyocardial delivery of DOX loaded hydrogel in the sub-acute phase following reperfused MI appears to provide sustained inhibition of MMPs in the MI region, reducing LV dilation and LVEDP 4 weeks following therapy.

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