Pathological enzyme activity describes overexpression of enzymes or deficient numbers of enzymes, which may prevent normal body function. Matrix metalloproteinase (MMP) overexpression is one example of such enzyme activity which can result in serious medical conditions including cardiovascular disease, chronic inflammation and tumor progression [1]. For example, myocardial infarction (MI) due to MMP overexpression may lead to excessive extracellular matrix (ECM) proteolysis, ventricle wall thinning, ventricle dilation and thus impaired blood pumping function. To treat pathologies due to enzyme overexpression, enzyme inhibitors have been extensively studied over the past 25 years; however, they have not translated into clinical applications due to the dose-limiting side effects following systemic drug administration [2]. Instead of systemic drug administration, local drug delivery therapy has been developed using injectable biomaterials such as hydrogels to deliver therapeutics in situ through diffusion and degradation mechanism [3]. Nevertheless, these approaches can only achieve a release profile within a certain therapeutic window and cannot self-regulate the release profile with the spatial and temporal variation during the disease progression, that is, they cannot provide responsive drug release. Targeted delivery of drugs using stimuli (e.g., pH, temperature) responsive polymers thus have further been actively explored [6] and [7], yet, these approaches have not been based on the specific features of the disease (enzyme dysregulation). These therapies are therefore not able to respond immediately to disease progression and heterogeneity in enzyme levels, making instant and uniform therapeutic dosing extremely difficult.
As recently published in Nature Materials, Burdick and colleagues designed a new generation of dynamic hydrogel systems that is able to respond to pathological triggers with temporal and spatial precision. Burdick's hydrogel system is injectable and enzyme-sensitive, and is able to release encapsulated enzyme inhibitors in a local enzyme activity controlled manner to regulate disease progression [8]. Such an approach is particularly exciting because it implies a breakthrough in the concept of ‘disease-triggered therapy’. This method provides an on-demand release of drugs based on local pathological activity, therefore providing temporal and spatial control of treatment while limiting the off-target effects of the drugs.
Burdick's hydrogel system provides a model of the ‘disease-triggered therapy’ concept targeting MI due to MMP overexpression. The hydrogel was composed of biocompatible natural polysaccharide backbones (hyaluronic acid (HA) and dextran sulfate (DS)), to which peptide cleavable by MMP and tissue inhibitor of MMP-3 (TIMP-3) were incorporated [9]. The liquid macromers (i.e., HA and DS) could be crosslinked to form solid hydrogel rapidly under physiological conditions. The team found that when this hydrogel was injected into an MI site, the local active MMPs would cleave the peptide, degrade the hydrogel and release the polysaccharide-bound TIMP-3, thereby inhibiting local MMP activity and attenuating adverse tissue remodeling.
To demonstrate the ‘disease-triggered drug release’ concept with this hydrogel system, the authors first confirmed the hydrogel MMP sensitivity by observing that the hydrogel degradation rate was dependent on the concentrations of active MMPs. Subsequently, the authors showed that the release of a model protein encapsulated in the hydrogel was proportional to the hydrogel degradation in vitro. From these observations, the authors demonstrated such hydrogel system's applicability for MMP-triggered release of encapsulated molecules in vitro. Further, the authors assessed the effectiveness of the drug delivery system using a porcine model of MI due to pathological MMP overexpression. The results revealed that delivery of TIMP-3 with hydrogel degradation brought TIMP-3 levels within the MI region to normal levels without raising systemic TIMP-3 levels. Moreover, attenuated adverse left ventricular (LV) remodeling in the animal model was evident by the substantial improvements in LV wall thinning and chamber dilation. These findings thus provided a solid explanation of the ‘disease-triggered therapy’ concept - where local presence of pathological MMPs can initiate the release of the matrix-bound TIMP-3, inhibit local MMP activity, and attenuate post tissue remodeling.
However, there are still some limitations of the developed hydrogel drug delivery system. For example, the hydrogel must be injected directly from a syringe and has not been translated to other delivery techniques, such as through a catheter. Additionally, the crosslinked hydrogel may be too weak (less than 1 MPa) for some applications resulting from MMP overexpression where mechanical properties are important. Moreover, this method of therapy may not be applicable to diseases caused by other factors (e.g., enzyme deficiency) other than enzyme overexpression.
This strategy takes advantage of the disease itself (i.e. presence of pathological enzymes) to initiate and regulate the therapy (release of therapeutic reagents). Such a technique is potentially powerful as enzyme expression varies both temporally and spatially from patient to patient [4] and [5], and therefore local, on-demand enzyme inhibition using this hydrogel therapy may replace the dose-limited systemic administration of the drugs. Ultimately, this approach may be used in clinic for treatment of numerous diseases with imbalanced enzyme activity, for example, treatment of Alzheimer's disease due to excessive glutaminyl cyclase activity [10]. In addition, the ‘disease-triggered hydrogel therapy’ boasts tremendous potential in prevention therapy as the dynamic hydrogel system functions instantly with pathological triggers, providing immediate and local prevention of disease progression.
Further reading
1. B. Fingleton, Curr. Pharm. Des., 13 (2007), pp. 333–346
2. B. Turk, Nat. Rev. Drug Discov., 5 (2006), pp. 785–799
3. E. Ruvinov, et al., Biomaterials, 32 (2011), pp. 565–578
4. F.G. Spinale, et al., Circulation, 118 (2008), pp. S16–S23
5. C.S. Webb, et al., Circulation, 114 (2006), pp. 1020–1027
6. H.S. Kim, H.S. Yoo, J. Control. Release, 145 (2010), pp. 264–271
7. J.R. Tauro, R.A. Gemeinhart, Bioconjugate Chem., 16 (2005), pp. 1133–1139
8. B.P. Purcell, et al., Nat. Mater., 13 (2014), pp. 653–661
9. L. Troeberg, et al., Biochem. J., 443 (2012), pp. 307–315
10. S. Schilling, et al., Nat. Med., 14 (2008), pp. 1106–1111