Nitric oxide-modified linear poly(ethylenimine) fibers and uses therefor

#This invention relates to the production of fibers of linear poly(ethylenimine) modified with nitric oxide (NO). More particularly, the present invention relates to the use of these NO-modified linear poly(ethylenimine) fibers that can be applied to medical devices such as catheters, stents, vascular grafts, wound dressings, and the like, to release therapeutic levels of NO for wound healing or other medical purposes. Specifically, the present invention relates to the production of electrospun nanofibers of linear poly(ethylenimine) diazeniumdiolate for use in the delivery of NO to a patient.

#The importance of nitric oxide (NO) in biological repair mechanisms is well known even though the precise mechanism of its action has not been completely elucidated. NO is known to inhibit the aggregation of platelets and to reduce smooth muscle proliferation, which is known to reduce restenosis. When delivered directly to a particular site, it has been shown to prevent or reduce inflammation at the site where medical personnel have introduced foreign objects or devices into the patient.

#Researchers have sought various ways to deliver NO to damaged tissue and to tissues and organs at risk of injury. NO can be delivered systemically, but such delivery can bring undesired side effects with it. Ideally, NO should be delivered in a controlled manner specifically to those tissues and organs that have been injured or are at risk of injury. Various compounds have been used to deliver NO therapeutically. Diazeniumdiolates (NONOates) exhibit the ability to release NO spontaneously. Other classes of NO donors either require activation to release therapeutic levels of nitric oxide, or they release both NO and undesired free radicals.

#As noted hereinabove, the present invention is directed toward the production of very small diameter fibers (on the order of nanometers) of linear poly(ethylenimine) modified with nitric oxide (NO). These fibers, when deposited on medical devices as a coating or the like, may release therapeutic levels of NO at the site where the medical device has been implanted or otherwise rests in the patient. The term medical device is intended to encompass all types of medical devices, including those used in connection with either external or internal treatment of a mammal. Medical devices used in the external treatment of a mammal include, but are not limited to, wound dressings, burn dressings or other skin coverings, and surgical thread. Medical devices used in the internal treatment of a mammal include, but are not limited to, vascular grafts, stents, catheters, valves, artificial joints, artificial organs, and surgical thread.

#In order to produce the fibers of the present invention, linear poly(ethylenimine) must first be obtained. Linear poly(ethylenimine) may be prepared by any method known in the art or may be obtained commercially, if available. One well known and published method of synthesizing linear poly(ethylenimine) is by hydrolysis of poly(2-ethyl-2-oxazoline). This method is well known to those skilled in the art and, therefore, details of the process are not provided herein. Typically, the poly(2-ethyl-2-oxazoline) should have a number average molecular weight of about 500,000, although smaller or larger molecular weights should not readily affect the formation of linear poly(ethylenimine). In a preferred embodiment, the linear poly(ethylenimine) synthesized should have a molecular weight ranging from about 100,000 to about 500,000, although higher or lower molecular weights are not seen as materially affecting the essential nature of the invention, provided of course, the compound can be effectively dissolved in the desired solvent for use in electrospinning fibers therefrom. Preferably, linear poly(ethylenimine) having a molecular weight of about 200,000 is employed.

#Linear poly(ethylenimine) is known to be water insoluble, but soluble in alcohols or other organic solvents. In one embodiment of the present invention, the polymer is exposed to nitric oxide in chloroform/acetonitrile or in methanol/sodium methoxide as set forth in Scheme I hereinbelow. Upon exposure, the polymer is converted to a diazeniumdiolate derivative of linear poly(ethylenimine).