We read with great interest your recently published article of Maslov and colleagues [Citation1]. The review summarized local myocardial delivery of drugs, genes, and cells delivered via different routes for sustained targeted heart therapy. This is an important area of research and often the most underappreciated limitation to a broader application of the drug therapy in cardiology, especially translating previous success from preclinical to clinical stages. There is a substantial literature in this area, making this key manuscript timely and relevant. We would like to add several issues that we believe will promote a better understanding of review’s contribution to delivery science applied to the heart.
Much of the focus of the review was direct intramyocardial delivery. There are several novel alternatives to direct myocardial injection that should be noted. For example, an alternative to standard syringe-driven needle injection through epicardial or endocardial surface is the use of pressurized ballistic delivery via ‘needleless’ liquid jet methodology [Citation2,Citation3]. The needleless jet offered a robust, yet homogenous distribution pattern with nearly equal levels in the different heart sections validated in the rodent model of ischemic myocardial infarction. Pressure and jet settings are optimized for varying levels of myocardial thickness and safety considerations. Preliminary studies argued that the advantage of this route’s approach over needle intramuscular injection is that it facilitates better transfer via greater percentage of myocardium due to its dispersive and higher retention profile [Citation2].
In the review’s section, ‘IMC drug delivery’ the authors described in detail different methods of intramyocardial delivery with various vehicles. We assert that in this regard, it would be appropriate to cite study in the porcine model, whereby Grossman et al. compared two approaches of intramyocardial delivery through the endocardium and epicardium surfaces. They found that endomyocardial injection was associated with a 43% microsphere retention compared with only 15% after epicardial injection. Moreover, a reduction of injectate volume resulted in significantly improved retention [Citation4].
In the article, the authors rightly argued that angiogenic therapy, viral vectors, and stem cells utilize large molecules that have very limited capacity to diffuse within myocardium. However, recent advances were reported on the development of nanoparticle gene and cell technology [Citation5,Citation6]. Moreover, it was demonstrated that nano-formulated anti-inflammatory drugs in combination with gene product may offer a clinical solution to maximize cardiac delivery efficiency in diseased myocardium [Citation7].
Unfortunately, we cannot agree with the author’s claim that intracoronary delivery does not provide sustained release or significant drug retention in heart muscle. Generally accepted percutaneous intervention with coronary administration of drug-eluting stents is currently an effective treatment for patients with ischemic heart disease. A meta-analysis of more than 30 randomized trials with sirolimus–paclitaxel and second stent generation like everolimus and zotarolimus demonstrated excellent clinical results regarding local drug delivery and sustained release [Citation8].
We also note that the article could have included a stand-alone section describing physical methods enhancing the cell membrane permeabilization and altering the biological barriers to drug or gene uptake [Citation9]. For example, sonoporation has been developed for numerous applications in the heart. Its mode of action involves the attachment of plasmid DNA to gas-filled microbubbles which are then mechanically destroyed within target tissue by ultrasound pulses. Another less common approach due to translational limitations is electroporation. This approach has been applied successfully in preclinical cardiac delivery studies and successful in physically altering the biological barriers to drug, cell, or gene uptake by application of short-duration high-intensity electric pulses to facilitate uptake. Another interesting method is a magnetofection, a process that employs the principle of transferring paramagnetic nanoparticles containing different protein into tissues infer the influence of strong magnetic fields is also in development.
In summary, we find this review very helpful to all researchers and clinicians that study local myocardial drug, cell, and gene delivery.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
- Maslov M, Foianini S, Lovich M. Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. Expert Opin Drug Deliv. 2017;1–13.
- Fargnoli AS, Katz MG, Williams RD, et al. A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression. J Cardiovasc Transl Res. 2014;7(8):756–767.
- Nishizaki K, Mazda O, Dohi Y, et al. In vivo gene gun-mediated transduction into rat heart with Epstein-Barr virus-based episomal vectors. Ann Thorac Surg. 2000;70(4):1332–1337.
- Grossman PM, Han Z, Palasis M, et al. Incomplete retention after direct myocardial injection. Catheter Cardiovasc Interv. 2002;55(3):392–397.
- Dobson J. Gene therapy progress and prospects: magnetic nanoparticle-based gene delivery. Gene Ther. 2000;13(4):238–287.
- Stephan MT, Moon JJ, Um SH, et al. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med. 2010;16(9):1035–1041.
- Fargnoli AS, Mu A, Katz MG, et al. Anti-inflammatory loaded poly-lactic glycolic acid nanoparticle formulations to enhance myocardial gene transfer: an in-vitro assessment of a drug/gene combination therapeutic approach for direct injection. J Transl Med. 2014;12:171.
- Von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet. 2014;383(9915):413–423.
- Katz MG, Fargnoli AS, Bridges CR. Myocardial gene transfer: routes and devices for regulation of transgene expression by modulation of cellular permeability. Hum Gene Ther. 2013;24(4):375–392.