The utility of these changes on protein surface adsorption in serum (important to scaffold clearance from the bloodstream) is also investigated, with attention to NO-release properties as a function of solution media. As such, the focus of this research is developing strategies for altering the properties of NO release (e.g., half-life and total storage) by modifying the N-diazeniumdiolate and phospholipid structures. 25 However, the kinetic tunability of this system was rather limited (i.e., controlled only by pH) with the relationship between liposomal characteristics (e.g., composition and size) and NO-release properties remaining unclear. The liposomes exhibited enhanced NO donor stability (>3 mo shelf-life) along with greater in vitro cytotoxicity toward pancreatic cancer cells compared to the free, unencapsulated NO donor. 21– 24 In contrast to these studies that used gaseous NO and NO photodonors, our lab has utilized encapsulated N-diazeniumdiolates to deliver NO.
Others have previously demonstrated that liposomes can encapsulate NO donors in order to enhance delivery and prolong NO release. In contrast to healthy tissue where pH homeostasis is maintained near pH 7.4, these diseased tissues should promote more rapid NO release at the site of interest, thereby mitigating off-target cytotoxicity. 17 This breakdown of N-diazeniumdiolates to NO can be used therapeutically by exploiting the microenvironment of certain disease sites (e.g., cancer, dental caries, and ulcerative colitis) that exhibit a lowered pH due to altered cellular metabolisms. For example, spermine/NO (SPER/NO) exhibits a much longer half-life than proline/NO (PROLI/NO) at pH 7.4 ( t 1/2 = 37 min and 2 s, respectively). 16 Structures bearing cationic primary amines can electrostatically stabilize their anionic diazeniumdiolate group, thus yielding longer NO-release half-lives. Furthermore, the breakdown and release of NO is a direct function of the molecular structure of the donor, enabling exquisite control over the rate of release. 12– 16 N-diazeniumdiolates are a particularly attractive vehicle for NO storage and delivery because they undergo pH-dependent decomposition (faster release as the pH is lowered) to liberate NO ( Scheme S1). Based on NO’s promise as a potential therapeutic, a significant body of research has focused on strategies to exogenously deliver NO using synthetic NO donors, such as metal-NO complexes, S-nitrosothiols (RSNOs), and N-diazeniumdiolates.
8– 11 Unlike current chemotherapeutics, NO is rapidly converted to a harmless metabolite (i.e., nitrite) and cleared in biological media, mitigating the toxic accumulation common to most drugs.
#Sigma fp l used free#
Nitric oxide (NO) is an endogenously produced free radical involved in multiple physiological processes, including blood pressure regulation, the immune response to pathogens, neurotransmission, and cellular proliferation. 6– 7 The need to develop therapeutics with limited off-target cytotoxicity remains highly desirable. 5 Although liposomes passively localize themselves at the site of interest, 5 post-delivery accumulation of the encapsulated therapeutic (e.g., cisplatin and doxorubicin) has been shown to negatively impact surrounding healthy tissue. 1– 4 Using liposomes as drug delivery vehicles affords many benefits, including reduced immune response, increased cellular uptake, and protection of drug payload from premature action or breakdown. The drug delivery field has demonstrated that the encapsulation of therapeutics (e.g., antifungals, biocides, chemotherapeutics, and virucides) within liposomes is an effective strategy for controlled delivery to select targets of interest.
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