Research ArticleCardiovascular Disease

Reloadable multidrug capturing delivery system for targeted ischemic disease treatment

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ra160
DOI: 10.1126/scitranslmed.aah6228

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Free refills on ischemia treatment

Restoring functional tissue after ischemia is thought to require neovascularization to replace the occluded blood vessels. Neovascularization can be induced by growth factor proteins, but they generally have short half-lives in circulation and are difficult to deliver to the site of injury. Wu et al. have designed a reloadable system that uses antibodies embedded in a hydrogel to capture tagged growth factor therapeutics and retain them at the site of ischemic injury. Moreover, it can be easily reloaded by intravenous injection of additional growth factors doses, which are then captured by the antibody-based system. The authors demonstrated the efficacy and safety of this system in mouse and pig models of limb ischemia, suggesting a potential for future clinical development.

Abstract

Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit “reloading” of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.

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