Storage and Release of Nitric Oxide from Molecular Sieve

Chapter 9

Downloaded by DUKE UNIV on June 23, 2012 | http://pubs.acs.org Publication Date (Web): November 17, 2010 | doi: 10.1021/bk-2010-1053.ch009

Storage and Release of Nitric Oxide from Molecular Sieve Nanoparticles Harvey A. Liu, Angelo Lubag, and Kenneth J. Balkus, Jr.* Department of Chemistry, 800 West Campbell Rd., Richardson, TX 75080-3021 *[email protected]

The role of nitric oxide (NO) as a vasodilator has long been established. Due to the high reactivity and a lack of a practical delivery system for gaseous NO, its applicability has been limited. In this study, we examine the adsorption of the NO within molecular sieves and demonstrate the ability to fabricate composite materials in the form of electrospun fibrous bandage that can release NO with a controlled rate and in physiological relevant doses. The use of the NO releasing fibers for the preservation of transplant organs was demonstrated on rat hearts.

Introduction Since the discovery of the diatomic free radical nitric oxide (NO) as the endothelium-derived relaxing factor (EDRF) in the 1980s, there have been many studies aimed at understanding the nitric oxide pathways (1–3). The increased interest in NO led to its implication in many physiological processes in the body including vasodilation (2–4), the immune response (5, 6), social dysfunction (7), wound healing (8, 9), as well as many others. The involvement of the signaling molecule, NO, in many mechanisms suggests that storage and delivery systems capable of generating NO may find utility for many applications. An ability to deliver NO in a controlled manner can be exploited for the anti-aggregation of platelets in implants (10, 11), cancer treatment (12), antifungal and/or antibacterial coatings (6, 13, 14), smart textiles for increased circulation in diabetic patients (15–18), as well as organ preservation (19, 20). © 2010 American Chemical Society In Polymeric Delivery of Therapeutics; Morgan, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


While NO has been shown to be involved in many processes, the delivery of NO in its natural gaseous state is impractical for therapeutic applications. This problem has led to the development of many materials that can store NO. These materials can be broadly categorized into two classes of materials. A type of NO storage and delivery system includes the covalent attachment of NO with a secondary amine to form a class of molecules deemed diazeniumdiolates (4, 11, 21–24). Diazeniumdiolates have been synthesized in many forms such as free powders, ligands to nanoparticles, as well as in electrospun fibers functionalized with secondary amines (25–32). While these are the most well studied materials, their application still poses problems including the leaching of the parent amine upon NO release, which may contribute to an increased toxicity (22, 23). Additionally, the mechanism of NO release from diazeniumdiolates require careful regulation of the surrounding conditions. It has been demonstrated that the rate and efficiency of NO release from diazeniumdiolates are not only dictated by the parent secondary amine, but by the relative humidity as well as the pH of the surrounding environment (22, 23, 25, 33). Recently, we have addressed these concerns by electrospinning composite fibers within the degradable PLA fibers and controlled the release of NO through changing the fiber morphology. While this has addressed the problems posed by diazeniumdiolates, a slow rate of NO release and the low capacity of NO storage prevents its application for organ tranplant applications (34). The stringent requirements for the optimal conditions in NO delivery from diazeniumdiolates, as well as the requirements for organ preservation applications have led to the development of a more simplified strategy in NO storage and delivery. In this effort, zeolites have been utilized because of their low toxicity as well as high storage capacity (35–38). Recently, Wheatley et al. demonstrated the ability to store and release NO from the pores of zeolite A for anti-thrombotic applications (38). The mechanism of storage in zeolites involves the coordination of the nitric oxide with the metal ions that reside in the pores of the crystalline structure. It has also been shown by Wheatley et al. that the storage capacity as well as the rate can be tailored by varying the exchangeable metal ion that occupies the pores of the zeolite (38). The method of NO release in this system is initiated by its exposure to moisture; because of the higher affinity of the metal ion to water, the nitric oxide is released almost immediately upon the presence of atmospheric moisture (38). While the greater storage capacity of NO in zeolites is an integral step in NO delivery for therapeutics, its rapid rate of release as well as its physical state as a powder is not ideal for many physiological applications (38). Recently, we have exploited the high NO storage capacity of zeolite A and embedded them within hydrolysable polylactic acid (PLA) polymer fibers by electrospinning (39). In this effort we have demonstrated the ability to well disperse the zeolites within the polymer matrix and show a slightly slower rate of release from the fibers than from the pure powder. By integrating the free powder in a free-standing bandage, we have introduced a facile method of NO administration. Additionally, we have also demonstrated that the integration into a fibrous polymer matrix slows the rate of NO release, which can be further dampened through heat-treatment of the polymer fibers (39). 182 In Polymeric Delivery of Therapeutics; Morgan, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.

Research in zeolites as vehicles for NO storage has naturally progressed and developed into the study of NO storage in other porous materials, particularly metal-organic frameworks (MOFs) (35, 40). As part of this effort, we found that Cu(4,4′-OOC-Ph-Ph-COO)•1/2 TED (Cu-MOF) exhibited a high NO storage capacity, as high as 5 mmol/g, much higher than that seen in zeolitic materials (1mmol/g). In this study we also demonstrate the application of the NO releasing PLA/Zeolite A bandages for the preservation of procured rat hearts, which showed physiological efficacy through the increase in coronary flow rate after its application.


Experimental Section Materials Biphenyl-4,4′-dicarboxylic acid (BPDA, 97%), triethylenediamine (TED, 98%), and copper acetate monohydrate (Cu(OAc)2·H2O, >99%) were obtained from Aldrich and used without further treatment. Formic acid (98%, 2% H2O) was purchased from Fluka and used as received. HPLC grade water was obtained from Fisher and used as received. Molecular sieves 4A 4-8 mesh (Sigma-Aldrich) were washed with HPLC grade water, activated at 400 °C for 1 d, cooled to room temperature in a vacuum oven at low pressure, and stored in capped bottles filled with nitrogen for later use. Chloroform (99.9%, H2O

Storage and Release of Nitric Oxide from Molecular Sieve

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