A Hydrogel Strategy to Augment Tissue Adenosine to Improve Hindlimb Perfusion

Abstract

Objective: Adenosine is an important vasodilatory, anti-inflammatory, and antithrombotic agent; however, its delivery for the treatment of cardiovascular diseases is challenging due to the drug’s short half-life and dose-limiting side effects. Peripheral artery disease, one of the most prevalent atherosclerotic diseases of the cardiovascular system, remains without adequate nonsurgical treatments, resulting in significant morbidity due to ischemia and inflammation. Here, we hypothesize that we can use an enzyme-loaded synthetic hydrogel for local adenosine production. Approach and Results: We engineer a protease-sensitive poly(ethylene glycol)-maleimide-based hydrogel and characterize its rheological parameters when modulating poly(ethylene glycol) density and tethering a peptide to the gel backbone, then test degradation in response to collagenase. We load the gel with an ecto-nucleotidase, CD73, which catalyzes adenosine production from phosphorylated substrates, and use the CD73-loaded gel to generate adenosine in vitro and inhibit neutrophils’ oxidative burst. When delivered in vivo, the CD73 hydrogel augments adenosine levels in hindlimb skeletal muscles 24 hours after induction of peripheral arterial ischemia and increases lower limb perfusion compared with control gel in healthy mice on laser Doppler imaging. Conclusions: This enzyme-delivering hydrogel provides a strategy for local and sustained adenosine generation to improve perfusion, and future work will optimize its use for disease modulation.

ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain

“…By potentiating adenosine's bioavailability, ticagrelor might have beneficial effects through an increase of coronary blood flow and the promotion of additional adenosine-induced physiologic responses in the vascular system. A novel poly(ethylene glycol) (PEG)-based hydrogel delivery system for CD73 has also been designed recently, which allows the improvement of blood flow via continuous generation of adenosine locally in the target tissue (Sayegh et al, 2021). Despite a high vascular density, tumor vessels are usually functionally and structurally perturbed by the creation of a hostile milieu that is deprived of oxygen and nutrients and from which cancer cells attempt to escape and metastasize to more favorable sites in the body (Peinado et al, 2017;Li et al, 2019b;Lugano et al, 2020;Huijbers et al, 2022).…”

Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease

“…51 CD73-mediated adenosine signaling is also known to regulate vascular homeostasis, act as a vasodilatory agent, and have anti-inflammatory and antithrombotic properties. 52,53 Because of these functions, Sayegh et al 54 created a CD73-delivering protease-sensitive poly(ethylene glycol)-maleimide-based hydrogel that when delivered in vivo, increased local adenosine levels and increased lower limb perfusion in mice after the induction of peripheral artery ischemia. This suggests that CD73-deficiency may contribute to PAD via multiple pathways.…”