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Use of Gasotransmitters for the Controlled Release of Polymer Journal of Controlled Release 279 (2018) 157–170 Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel Review article Use of gasotransmitters for the controlled release of polymer-based nitric T oxide carriers in medical applications ⁎ ⁎⁎ Chungmo Yanga,1, Soohyun Jeonga,1, Seul Kub, Kangwon Leea,c, , Min Hee Parka, a Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea b School of Medicine, Stanford University, 291 Campus Drive, Stanford, CA 94305, USA c Advanced Institutes of Convergence Technology, Gyeonggi-do 16229, Republic of Korea ARTICLE INFO ABSTRACT Keywords: Nitric Oxide (NO) is a small molecule gasotransmitter synthesized by nitric oxide synthase in almost all types of Nitric oxide mammalian cells. NO is synthesized by NO synthase by conversion of L-arginine to L-citrulline in the human Polymeric carrier body. NO then stimulates soluble guanylate cyclase, from which various physiological functions are mediated in fi Hydrogen sul de a concentration-dependent manner. High concentrations of NO induce apoptosis or antibacterial responses Carbon monoxide whereas low NO circulation leads to angiogenesis. The bidirectional effect of NO has attracted considerable Crosstalk of gasotransmitters attention, and efforts to deliver NO in a controlled manner, especially through polymeric carriers, has been the Stimuli-responsive topic of much research. This naturally produced signaling molecule has stood out as a potentially more potent therapeutic agent compared to exogenously synthesized drugs. In this review, we will focus on past efforts of using the controlled release of NO via polymer-based materials to derive specific therapeutic results. We have also added studies and our future suggestions on co-delivery methods with other gasotransmitters as a step towards developing multifunctional carriers. 1. Introduction and CO have gained new potential as prospective therapeutic tools. NO is biologically synthesized by nitric oxide synthase (NOS), which Nitric oxide (NO) is a chemical compound, one of the several oxides exists as three isoforms: endothelial (eNOS), neuronal (nNOS) and in- of nitrogen, regarded as an industrial air pollutant until the 1987 dis- ducible (iNOS) nitric oxide synthase [11–14]. The family of NOS pro- covery by Louis J. Ignarro shed new light on its function as a bio-active duces NO catalyzed from the conversion of L-arginine to L-citrulline, and signaling molecule and physiological modulator [1]. The study initially each NOS can be activated by different conditions. The resulting NO aimed to elucidate on the similar properties of NO and endothelium- stimulates soluble guanylate cyclase (sGC), subsequently increasing the derived relaxing factor (EDRF) [1]. However, studies suggested that conversion of guanosine triphosphate (GTP) to 3′,5′-cyclic guanosine both were identical, and it was from this report that NO began to be monophosphate (cGMP) [15]. This signal transduction activates various investigated as a physiological modulator, a signaling molecule that can protein kinases such as protein kinase G (PKG). (Fig. 1.) These cascade also be applied in clinics [2–5]. This gaseous signaling molecule or reactions (NO-cGMP-kinase activation) amplify NO signal and lead to gasotransmitter works along the events of vascular tones, immune re- various functional outcomes in human nervous, cardiovascular, im- sponses, angiogenesis, apoptosis, wound healing and tissue repair, mune, respiratory, endocrine, urogenital and even excretory systems neurotransmission, and sleep control [3,6,7]. Such findings of NO as a [16]. Additionally, NO mediates various physiological, biochemical and comprehensive physiological modulator were granted the honor of a pathological functions based on its concentration (Fig. 2.). High con- Nobel prize in 1998. Ever since the discovery of NO as signaling mo- centrations of NO can induce cell apoptosis, DNA base deamination, lecule, other gaseous signaling molecules have been reported: carbon nitrosylation of enzymes, and mitochondrial damage with nitrosative monoxide (CO) (1991) [8] and hydrogen sulfide (H2S) (1996) [9]. stress [17], whereas low concentrations of NO can promote angiogen- These two gasotransmitters regulate various functions through sig- esis, cell proliferation, growth, and nutrient delivery [18–20]. Addi- naling pathways either with or without NO [10]. Altogether, NO, H2S tional reports describe the induction of anti-thrombus activity at NO ⁎ Correspondence to: K. Lee, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea. ⁎⁎ Corresponding author. E-mail addresses: [email protected] (K. Lee), [email protected] (M.H. Park). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.jconrel.2018.04.025 Received 30 January 2018; Received in revised form 11 April 2018; Accepted 13 April 2018 Available online 16 April 2018 0168-3659/ © 2018 Published by Elsevier B.V. C. Yang et al. Journal of Controlled Release 279 (2018) 157–170 has also been done in experimenting with various polymeric delivery systems as excellently reviewed elsewhere [42]. Polymeric carriers for NO delivery requires for the system to release NO in a controlled manner, as the physiological function in response to NO is concentra- tion-dependent. Although clinical trials on polymeric delivery of gaso- transmitters has been lacking, there are ample studies demonstrating their therapeutic potential, which we will discuss in our review. 2. NO-related therapeutic studies Use of gasotransmitters is a novel approach in the field of re- generative medicine and drug delivery studies. Among all, NO has been the most widely studied as its action includes but is not limited to ap- plications in wound healing, hypertension, cancer targeting and infec- tion. However, as mentioned earlier, NO’s reactive property makes it Fig. 1. Schematic illustration of endogenous nitric oxide synthesis by eNOS and prone to a short circulation time and an early burst release profile, the subsequent signaling cascade reactions (NO-cGMP-kinase activation) in making it cumbersome for disease-specific applications. Thus, many endothelial cells and smooth muscle cells. previous studies have focused on delivering NO in a more sustained manner through delivery systems ranging from low molecular weight – −1 −2 concentrations of 0.3 0.6 fmol s cm [21] and the inhibition of (LMW) NO donors [27,43] to polymer-encapsulation methods [44,45]. – −1 −2 bacterial adhesion at 1 20 pmol s cm [22]. The design of polymeric delivery systems of NO is especially important ff Di erent activities arising from NO delivery have been studied for in creating specific release profiles differing in time span and load ca- clinical use in the form of inhaled gas and injected medicines [2,23,24]. pacity, therefore, studying the various fabrication methods is vital. ® For example, BiDil is a FDA-approved drug used for treating heart However, we believe our review must let our readers, not only with failure in certain patients using isosorbide dinitrate, the precursor of those with backgrounds in nanoparticle research but also with back- ® NO [25,26]. However, given the limited clinical applications of BiDil grounds in other various scientific fields, grasp what physiological ef- ff and the side e ects that often follow, additional research took place, fect NO can bring before delving into the specific chemistry. This flow including the development of various NO donors that release NO upon of context would help people to better understand the concept of co- ff – di erent triggers like pH change, light, and heat [27 30]. Nitrate/ni- delivery of gasotransmitters, which we are stressing in the latter sec- trite/nitroso compounds [31,32], N-diazeniumdiolate (NONOate) tions of this review. Accordingly, we will first go through prior studies [33,34] and S-nitrosothiol (RSNO) [35,36] are the most widely studied that aimed for clinical benefits through the delivery of NO, focusing on donors and are considered for clinical applications (Fig. 3). NONOate their efforts to safeguard the delivery of NO. How they overcame the fi generates the stoichiometric product 2NO with rst-order release ki- challenges of burst release and a short half-life for specific disease netics, leading to the development of 1-(hydroxy-NNO-azoxy)-L-proline models is another focus discussed later in this chapter. (PROLI NONOate), 1-[(ethenyloxy)-NNO-azoxy]-pyrrolidine (PYRRO NONOate), 1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino]diazen- 2.1. Cardiovascular disease and wound healing 1-ium-1,2-diolate (DPTA NONOate), and 1-[N-(2-aminoethyl)-N-(2- ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate) [27]. Blood vessels are crucial in repairing and healing damaged tissues, RSNOs are adducts of R-SH and can generate NO upon various triggers, and it is not surprising to see studies that aimed to promote the for- such as the contact with metal ions, reducing agents and several en- mation of blood vessels in overcoming various diseases. Cardiovascular zymes [37]. There are also endogenous donors such as RSNO and S- disease is one of them [46], and applications include treating circula- nitrosoglutathione (GSNO) distributed in red blood cells, plasma, and tory dysfunction, ischemia-reperfusion injury, thrombosis, and rest- tissue [38]. However,
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