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1 H NMR spectrum of mPEG-PLA-modified nitric oxidereleasing graft copolymer in DMSO-d 6. mPEG-PLA represents methoxy poly(ethylene glycol)-poly(lactic acid).
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A polymeric micelle is a versatile nanoscale platform for sustained release of short-lived nitric oxide (NO). The aim of this work was to better understand the correlation between polymer architecture and NO release kinetics. Stable nitrate was selected as the NO donor and co-conjugated to a multivalent polymer backbone together with amphiphilic me...
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... types of amphiphilic graing copolymers were successfully synthesized based on the 1 H NMR verication ( Fig. 2 and 3). Despite the non-degradability of PHEMA, it is an excellent model polymer for multivalent coupling with functional moie- ties. When necessary, PHEMA can be replaced with biodegrad- able polymers e.g. polypeptides. 22 The proton NMR peak area integration gave a molecular weight (M n ) of 3612 Da for mPEG- PLA, and 1630 Da for TPGS, ...
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Stereocomplexation of the complementary chiral blocks has been a feasible way to prepare the thermoresponsive physical gels (or thermogels). Understanding the thermoresponsive phase behavior of stereocomplexable amphiphilic copolymers in water is essential to prepare the thermogels with tunable physical properties. Herein, we use the enantiomeric m...
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... Incorporating polymers into a NO release platform allows delivering NO in a more continuous manner, including through micelles, dendrimers, star-shaped polymers, and polymeric nanoparticles [90]. Micelles use amphiphilic polymers to synthesize concentration-dependent structures through hydrophilic or hydrophobic interactions but have a low encapsulation efficiency [36,[90][91][92]. Dendrimers are three-dimensional hyperbranched globular nanopolymeric architectures with the advantages of a narrow polydispersity index, controllable structure, and the availability of multiple functional groups at the periphery [93][94][95]. ...
Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in the cardiovascular system, clinical applications centered on NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process, based on computational modeling and flow-mediated dilation, to assess endothelial function and vulnerability of atherosclerotic plaque. Then, emerging bioimaging technologies that have the potential to experimentally measure arterial NO concentration were discussed, including Raman spectroscopy and electrochemical sensors. In addition to diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the NO release platform to treat endothelial dysfunction and atherosclerosis and inhaled NO therapy to treat pulmonary hypertension and COVID-19. Two potential methods to improve the effectiveness of existing NO therapy were also discussed, including the combination of NO release platform and computational modeling, and stem cell therapy, which currently remains at the laboratory stage but has clinical potential for the treatment of CVD.
... Incorporating polymers into NO releasing platform allows transporting NO in a more continuous manner, including micelles, dendrimers, star-shaped polymers, and polymeric nanoparticles [128]. Micelles use amphiphilic polymers to synthesize concentration-dependent structures through hydrophilic or hydrophobic interactions, but have low encapsulation efficiency [128][129][130][131]. Dendrimers are three-dimensional hyperbranched globular nanopolymeric architectures with advantages of narrow polydispersity index, controllable structure and availability of multiple functional groups at the periphery [132][133][134]. ...
Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of Coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in cardiovascular system, the clinical applications centered on the NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process based on the clinical images and mathematical modeling to assess the endothelial function and vulnerability of atherosclerotic plaque. Then, the emerging bioimaging technologies that have the potential to directly measure the arterial NO concentration were discussed, including the Raman spectroscopy and electrochemical sensor. Aside from the diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the inhaled NO therapy to treat the pulmonary hypertension and COVID-19, stem cell therapy and NO-releasing platform to treat endothelial dysfunction and atherosclerosis.
... In detail, the sample solution (5 mg/mL, 20 μL) was placed onto copper grids with carbon support and air-dried prior to image acquisition. The critical micelle concentration (CMC) of conjugate micelles was determined using a published method wherein pyrene was the fluorescence probe [33]. Micellar aqueous solutions (0.4-400 μg/mL) were supplemented with fixed pyrene probe at a molar concentration of 0.5 μM. ...
Traditional antitumor nanomedicines have been suffering from the poor tumor targeting (ca. 1%) by the enhanced permeability and retention (EPR) effect, and the low drug loading (<5%). It was postulated that engineering all-active nanoplatform could increase the therapeutic efficacy to enable the nanocarrier function as both vehicle and active ingredient. To achieve this, a photosensitizer, Ce6 was encapsulated within polymeric micelles with unsaturated fatty acids as the building blocks. Upon light irradiation, the singlet oxygen produced by Ce6 induced lipid peroxidation, resulting in the generation of both active free radicals and aldehydes. These supplementary radicals could exert cytotoxic effect for direct killing tumor cells. The aldehyde end-products induced significant cell cycle arrest at G2 phase in 4T1 cells. The peroxidation process also facilitated the on-demand disassembly of micelles and rapid release of Ce6 to maximize the therapeutic effect of singlet oxygen. These all-active micelles showed a significantly enhanced cytotoxicity with the half maximal inhibitory concentration (IC50) of 0.6 ± 0.2 μg/mL in contrast to the control micelles at 3.4 ± 0.5 μg/mL. The improved antitumor efficacy of the all-active micelles was also demonstrated in the 4T1 tumor-bearing mice in vivo. The current work provides a facile approach to enhance the antitumor efficacy of PDT nanomedicine using the biocompatible fatty acids, which can be applied to various antitumor drugs and unsaturated lipids.
... The micelles showed a NO release profile over 14 days, a significant improvement in stability. Similarly, Gao et al. developed a micelle platform for the sustained release of NO [81]. This work estabilished a relationship between polymer architecture and NO release kinetics. ...
Nitric Oxide (NO) is a small molecule gasotransmitter synthesized by nitric oxide synthase in almost all types of mammalian cells. NO is synthesized by NO synthase by conversion of l-arginine to l-citrulline in the human body. NO then stimulates soluble guanylate cyclase, from which various physiological functions are mediated in a concentration-dependent manner. High concentrations of NO induce apoptosis or antibacterial responses whereas low NO circulation leads to angiogenesis. The bidirectional effect of NO has attracted considerable attention, and efforts to deliver NO in a controlled manner, especially through polymeric carriers, has been the topic of much research. This naturally produced signaling molecule has stood out as a potentially more potent therapeutic agent compared to exogenously synthesized drugs. In this review, we will focus on past efforts of using the controlled release of NO via polymer-based materials to derive specific therapeutic results. We have also added studies and our future suggestions on co-delivery methods with other gasotransmitters as a step towards developing multifunctional carriers.
... The synthesis of the mPEG− PGlu-VE employed a previously published method with slight modification. 25 In short, mPEG−PGlu (0.1 g, 0.0076 mmol), EDC· HCl (1.09 g, 5.68 mmol), and DMAP (0.69 g, 5.68 mmol) were mixed in 10 mL of DCM, and the mixture was stirred at room temperature for 1 h. Then the mixture was transferred dropwise to a VE-containing (2.45 g, 5.68 mmol) round-bottom flask and continually stirred at ambient temperature for 24 h. ...
Vitamin E (α-tocopherol) (TPGS) micelle is a robust nanocarrier in delivering hydrophobic active pharmaceutical ingredients, but is suffering from poor stability that is essential in terms of pharmaceutical and biomedical applications. Taking advantage of the chirality of vitamin E, this work reports the stereoselective stabilization of polymer-vitamin E conjugate micelles. Vitamin E was covalently linked to multivalent methoxy poly(ethylene glycol)-co-poly(glutamic acid), generating amphiphilic conjugates that could self-assemble into micelles. Eight types of micelles were produced via tailored combination of polymer backbone and side chain with different chirality. The particle size and critical micelle concentration analysis demonstrated a correlation between conjugate chirality and micelle stability. The most stable micelles were obtained when poly(glutamic acid) and vitamin E both are dextrorotatory, because of the high degree of α-helix revealed by both circular dichroism spectroscopy and molecular dynamics simulation. This phenomenon was further verified by the fluorescence resonance energy transfer (FRET) analysis in HepG2 cells. The current work not only provides a method to enhance the stability of vitamin E micelles, but also adds an additional facile tool in regulating the stability of polymer conjugate micelles without changing the conjugate composition.
Tumor cell-induced platelet aggregation (TCIPA) is known as a critical step in hematogenous tumor metastasis. The endogenous nitric oxide (NO) plays an important role in anticoagulation, which might have great potential to inhibit TCIPA. Herein, a glutathione-sensitive supramolecular nanocarrier is prepared via host-guest interaction for effective delivery of NO and chemotherapeutic agent gemcitabine (GEM). NO could be effectively released in tumor cells and inhibits platelet activation and aggregation. The inhibition of TCIPA by NO could effectively attenuate the migration and invasion of tumor cells in vitro. Furthermore, the in vivo experiments demonstrate that the NO and GEM co-delivered supramolecular nanocarriers can suppress the growth of primary tumor. More importantly, although NO-containing nanocarriers cannot inhibit the growth of primary tumors effectively, they can significantly inhibit tumor metastasis. This NO-based nano-delivery system not only provides new inspiration for multifunctional applications of NO in cancer therapy but also shows great potential in clinical antimetastatic applications.
Despite nearly 30 years of development and recent highlights of nitric oxide (NO) donors and NO delivery systems in anticancer therapy, the limited understanding of exogenous NO's effects on the immune system has prevented their advancement into clinical use. In particular, the effects of exogenously delivered NO differing from that of endogenous NO has obscured how the potential and functions of NO in anticancer therapy may be estimated and exploited despite the accumulating evidence of NO's cancer therapy-potentiating effects on the immune system. After introducing their fundamentals and characteristics, this review discusses the current mechanistic understanding of NO donors and delivery systems in modulating the immunogenicity of cancer cells as well as the differentiation and functions of innate and adaptive immune cells. Lastly, the potential for the complex modulatory effects of NO with the immune system to be leveraged for therapeutic applications is discussed in the context of recent advancements in the implementation of NO delivery systems for anticancer immunotherapy applications. SIGNIFICANCE STATEMENT: Despite a 30-year history and recent highlights of nitric oxide (NO) donors and delivery systems as anticancer therapeutics, their clinical translation has been limited. Increasing evidence of the complex interactions between NO and the immune system has revealed both the potential and hurdles in their clinical translation. This review summarizes the effects of exogenous NO on cancer and immune cells in vitro and elaborates these effects in the context of recent reports exploiting NO delivery systems in vivo in cancer therapy applications.
Nanoparticle‐based drug delivery has become one of the most popular approaches for maximising drug therapeutic potentials. With the notable improvements, a greater challenge hinges on the formulation of gasotransmitters with unique challenges that are not met in liquid and solid active ingredients. Gas molecules upon release from formulations for therapeutic purposes have not really been discussed extensively. Herein, we take a critical look at four key gasotransmitters, that is, carbon monoxide (CO), nitric oxide (NO), hydrogen sulphide (H2S) and sulphur dioxide (SO2), their possible modification into prodrugs known as gas‐releasing molecules (GRMs), and their release from GRMs. Different nanosystems and their mediatory roles for efficient shuttling, targeting and release of these therapeutic gases are also reviewed extensively. This review thoroughly looks at the diverse ways in which these GRM prodrugs in delivery nanosystems are designed to respond to intrinsic and extrinsic stimuli for sustained release. In this review, we seek to provide a succinct summary for the development of therapeutic gases into potent prodrugs that can be adapted in nanomedicine for potential clinical use. This review takes a critical look at four key gasotransmitters (CO, NO, H2S and SO2) with their incorporation into prodrugs known as gas‐releasing molecule. Different nanosystems and their mediatory roles for efficient shuttling, targeting and cleavage of therapeutic gases and the responsiveness to typical internal and external stimuli for gas release from prodrugs have been reviewed extensively.
Chronic wounds, such as pressure ulcers, vascular ulcers and diabetic foot ulcers (DFUs), often stay in a state of pathological inflammation and suffer from persistent infection, excess inflammation, and hypoxia, thus they are difficult to be healed. Nitric oxide (NO) plays a critical role in the regulation of various wound healing processes, including inflammatory response, cell proliferation, collagen formation, antimicrobial action and angiogenesis. The important role of NO in wound healing attracts intensive research focus on NO-based wound healing therapy. However, the application of NO gas therapy needs to resolve the intrinsic shortcomings of gas therapy, such as short storage and release times as well as temporal and spatial uncontrollability of the release mode. So far, various types of NO donors, including organic nitrates (RONO2), nitrites (RONO), S-nitrosothiols (RSNOs), nitrosamines, N-diazeniumdiolates (NONOates), and metal-NO complexes, have been developed to solidify gaseous NO and they were further encapsulated in or conjugated onto a variety of biomaterial vectors to develop NO delivery systems. NO synthetic enzyme mimics to catalyze the production and release of NO from l-arginine have also been developed. This paper reviews recent advances of NO donors, biomaterial vectors, thus-formed NO delivery systems, as well as recently emerged NO synthetic enzyme mimics. Furthermore, this review also summarizes the functions of NO releasing biomaterials that would benefit chronic wound healing, including antibacterial properties and the promotion of angiogenesis, as well as the convenient combination of light/thermal induced NO release with light/thermal therapies, and the prospects for future developing trends in this area.
Nitric oxide (NO), as a crucial signaling biomolecule, is closely involved in the cardiovascular, immune, and central nervous system. NO not only participates in the proliferation, differentiation, and activation of immune cells but also regulates the secretion and function of immune‐related cytokines. Meanwhile, NO plays an important role in regulating diversified pathological processes, such as cancer, autoimmune disease, pathogenic infection, and so on. Therefore, the intensive immunological study of NO has been expected to provide valuable approaches to the clinical prevention and treatment of these related diseases. Since NO has a wide range of chemical activities and biological functions, the pleiotropic effects of NO are affected by its production, concentration and duration, target cell types and subtypes, species, and pathogenesis of the immune‐related diseases. It is thus necessary to create and develop certain platforms of drugs and related preparations that can precisely regulate NO for immunotherapy. This review summarizes the regulatory functions exerted by NO in immune response, and the pathological mechanisms of tumor, autoimmune disease, and pathogenic infection in which NO is involved. The application and trend of therapeutic strategies based on the direct regulation of NO in immunotherapy are further discussed.
