Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction
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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2015, Journal of Controlled ReleaseReducible Poly(Oligo- d -Arginine) as an Efficient Carrier of the Thymidine Kinase Gene in the Intracranial Glioblastoma Animal Model
2015, Journal of Pharmaceutical SciencesCitation Excerpt :One of the solutions to increase transfection efficiency and reduce the cytotoxicity of non-viral gene carriers is to use reducible polymers.11–13 Recent studies showed that cationic peptides with reducible bonds induced stable condensing, high transfection efficiency and low toxicity.12,14–17 One of the examples is 9-arginine-based reducible poly (oligo-d-arginine) (rPOA).18–20
Bioreducible polymers for therapeutic gene delivery
2014, Journal of Controlled ReleaseCitation Excerpt :And this in vivo improved gene delivery effect provided a two-fold higher expression of VEGF, suggesting the triblock copolymer, PEG13-PLGA10-PEG13, is applicable as a carrier for skeletal muscle gene delivery applications [44]. Cardiovascular disease is the leading cause of death in the world [17,19]. After a decade of pre-clinical and early phase 1 clinical investigations, gene therapy has emerged as a genuine possible therapeutic alternative to conventional therapies, especially in coronary artery disease and heart failure [1,8,45,46].