Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with S-Nitroso-N-acetyl-d-penicillamine

Abstract

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-d-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC–MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer–crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4–4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.

Biodegradable poly(lactic-co-glycolic acid) microspheres loaded with S-nitroso-N-acetyl-D-penicillamine for controlled nitric oxide delivery

“…The encapsulated microcrystalline SNAP showed excellent stability also at elevated temperature, which is in agreement with our previous findings for SNAP in certain polymeric materials [39]. Indeed, the SNAP loading did not decrease below 90% after a one-month storage period in the dark (Figure 8) at room temperature, and even when stored at an elevated temperature of 37 °C, there was still ca.…”

The preparation and characterization of nitric oxide releasing silicone rubber materials impregnated with S-nitroso-tert-dodecyl mercaptan

“…11 This phenomenon doesn’t pose a toxicity concern for intravascular catheters since excess NO is rapidly consumed by the surrounding oxyhemoglobin in blood. Therefore, an intravascular catheter’s therapeutic window is maximized, accounting for the entire duration of NO release (at least 26 days).…”

“…Recently, our group reported ~87% of the SNAP impregnated in SR to still be present after 8 months of storage in the dark. 11 While SNAP impregnated SR provides superior storage stability, one must also keep in mind that the higher levels of RSNO may not be beneficial since a larger portion of them will leach from the polymer. For clinical applications, SNTDM impregnated SR devices could be stored in foil packages containing desiccant at reduced temperatures to extend their lifetime.…”

“…8–10 Staphylococcus aureus is the most common cause of nosocomial bloodstream infections, specifically those associated with biofilm formation on indwelling biomedical devices. 11 It can cause a range of illnesses, from skin infections to life-threatening diseases like bacteremia or sepsis. Given this and the ever-growing concern of antibiotic-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), developing effective ways to combat infections by this organism is crucial.…”

“…Given this and the ever-growing concern of antibiotic-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), developing effective ways to combat infections by this organism is crucial. 6–11 …”