Elsevier

Journal of Controlled Release

Volume 132, Issue 3, 18 December 2008, Pages 260-266
Journal of Controlled Release

Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction

https://doi.org/10.1016/j.jconrel.2008.06.024Get rights and content

Abstract

The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [P. Poirier, et al., Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss, Arterioscler Thromb Vasc Biol. 26(5), (2006) 968–976.; K. Obunai, S. Jani, G.D. Dangas, Cardiovascular morbidity and mortality of the metabolic syndrome, Med.Clin. North Am., 91(6), (2007) 1169–1184]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453–462].

Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [C.F. McTiernan, et al., Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts, Gene Ther, 14(23), (2007) 1613–1622]. However, this high transduction does not necessarily translate into improved efficacy [X. Hao, et al., Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model, Cardiovasc Res., 73(3), (2007) 481–487]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regard to secondary end-points of reduced symptomatology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [P.B. Shah, D.W. Losordo, Non-viral vectors for gene therapy: clinical trials in cardiovascular disease, Adv Genet, 54, (2005) 339–361]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes.

Currently, polymeric non-viral gene delivery to cardiac myocardium remains underrepresented. In the past decade several advances in non-viral vector development has demonstrated increased transfection efficiency [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453–462]. Of these polymers, those that employ lipid modifications to improve transfection or target cardiovascular tissues have proven themselves to be extremely beneficial.

Water-soluble lipopolymer (WSLP) consists of a low molecular weight branched PEI (1800) and cholesterol. The cholesterol moiety adds extra condensation by forming stable micellular complexes and was later employed for myocardial gene therapy to exploit the high expression of lipoprotein lipase found within cardiac tissue. Use of WSLP to deliver hypoxia-responsive driven expression of hVEGF to ischemic rabbit myocardium has proven to provide for even better expression in cardiovascular cells than Terplex and has demonstrated a significant reduction in infarct size (13 ± 4%, p < 0.001) over constitutive VEGF expression (32 ± 7%, p = 0.007) and sham-injected controls (48 ± 7%). A significant reduction in apoptotic values and an increase in capillary growth were also seen in surrounding tissue.

Recently, investigations have begun using bioreducible polymers made of poly(amido polyethylenimines) (SS-PAEI). SS-PAEIs breakdown within the cytoplasm through inherent redox mechanisms and provide for high transfection efficiencies (upwards to 60% in cardiovascular cell types) with little to no demonstrable toxicity. In vivo transfections in normoxic and hypoxic rabbit myocardium have proven to exceed those results of WSLP transfections by 2–5 fold [L.V. Christensen, et al., Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery, J Control Release, 118(2), (2007) 254–261]. This new breed of polymer(s) may allow for decreased doses and use of new molecular mechanisms not previously available due to low transfection efficiencies.

Little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neo-genesis and provide a new means of investigation for treatment.

Section snippets

Clinical gene therapy for therapeutic myocardial angiogenesis

Ischemic heart disease is the leading cause of death in the United States today. Currently, the mainstay of therapy for ischemic heart disease (IHD) is revascularization. Nearly 2,000,000 cardiac catheterizations and 553,000 coronary artery bypass grafting procedures are performed annually [2]. Technological developments in these areas have led to an improved survival and quality of life for patients with IHD. However, increasing evidence suggests that revascularization alone is insufficient

Polyethylenimine conjugates

The molecular weight of PEI plays a significant role in transfection efficiency and toxicity [16]. Lower molecular weights of PEI exhibit poor transfection characteristics with virtually no toxicity. As the molecular weight of PEI increases, transfection efficiency increases along with cytotoxicity. The reduced transfection efficiency of PEI 1.8 kDa is attributed to its dissociative properties in physiological salt concentrations. The addition of amine groups provides the charge for

Biodegradable polymers

Key modifications to increase polymeric gene delivery efficiency will incorporate molecules that have the ability to discriminate between differences in biologic microenvironments, including pH, ionic or redox potentials [28]. One type of modification has taken advantage of changes in pH to assist in targeting through the incorporation of acid-labile linkages to facilitate polymer degradation within the local environment of a tumor [29], or to assist in endosomal release of stabilizing

Non-viral targeting vectors of myocardium

Targeting of these reducible polymers has not yet occurred but may be accomplished through the addition of shielding molecules such as polyethylene glycol (PEG) and targeting moieties. Unfortunately, antibodies specific to cardiac surface markers are scarce. However, it was first theorized by Khaw et al. that if intracellular myocardial proteins egress upon an ischemic event and can be measured in the serum, then there must also be an entry that may allow for a means of targeting [66].

This

Molecular targeting of myocardium

In lieu of specific targeting ligands, molecular targeting confers tissue or cellular specificity at the transcriptional level. These targeting methods are primarily used to bypass non-specific interactions of the gene vectors with other tissues [73], [74], [75], [76]. These issues are of primary concern with all gene therapy applications and so interest remains high. Cell or tissue-specific promoters are constitutively active and thus may not provide specific cues for environmental changes

Conclusion

The work described in this article demonstrates current advances in the field of non-viral polymers for therapeutic gene delivery to the myocardium. It is essential that continuing innovations in non-viral gene delivery, molecular and cellular biology be combined to increase acceptance of non-viral polymeric gene delivery as a viable option for the clinical treatment of ischemic myocardium.

Acknowledgments

This work was supported by NIH Grants HL071541 (DAB) and HL65477 (SWK).

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