Abstract
Nitric oxide (NO) is a short-lived, endogenously produced, signaling molecule which plays multiple roles in mammalian physiology. Underproduction of NO is associated with several pathological processes; hence a broad range of NO donors have emerged as potential therapeutics for cardiovascular and respiratory disorders, wound healing, the immune response to infection, and cancer. However, short half-lives, chemical reactivity, rapid systemic clearance, and cytotoxicity have hindered the clinical development of most low molecular weight NO donors. Hence, for controlled NO delivery, there has been extensive effort to design novel NO-releasing biomaterials for tumor targeting. This review covers the effects of NO in cancer biology, NO releasing moieties which can be used for NO delivery, and current advances in the design of NO releasing biomaterials focusing on their applications for tumor therapy.
Highlights
The therapeutic applications of glyceryl trinitrate (GTN) have been established for over 165 years, until the 1980s little was known about GTN’s physiological mechanism of action [1, 2]
This review covers the effects of Nitric oxide (NO) in cancer biology, NO releasing moieties which can be used for NO delivery, and current advances in the design of NO releasing biomaterials focusing on their applications for tumor therapy
At low and intermediate concentrations, NO normally stimulates cancer cell progression, prevents apoptosis and enhances angiogenesis and metastasis via various signaling pathways which are crucial for tumor cell survival, such as the extracellular signal-regulated kinase (ERK), Akt, mammalian target of rapamycin, Ras and epidermal growth factor receptor (EGFR) pathways [23]
Summary
The therapeutic applications of glyceryl trinitrate (GTN) have been established for over 165 years, until the 1980s little was known about GTN’s physiological mechanism of action [1, 2]. 2211-7393/19 $58.00+.00 diatomic free radical, NO is a short-lived molecule with a half-life (t1/2) between 0.1 to 5s in aqueous solutions, and in vivo its levels are continuously modulated by the nitric oxide synthases (NOS) [5]. Inhaled NO is recognized as an invaluable tool for decreasing pulmonary inflammation, neonatal pulmonary hypertension, and for heart and lung surgery Beyond these applications it has limited, if any, other clinical value due to its low water solubility, instability and inconvenient handling of authentic aqueous solutions of NO [13,14,15]. For cancer therapy the utility of authentic aqueous solutions of NO, and most currently available NO donor agents (consisting of low molecular weight molecules), is highly limited due to their low half-lives, instability under physiological conditions, rapid systemic clearance, unspecific NO release and NO-independent toxicities. We review current advances in the design of NO releasing biomaterials and their applications for tumor therapy
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