Macromolecular and Inorganic Nanomaterials Scaffolds for Carbon

Review pubs.acs.org/journal/abseba

Macromolecular and Inorganic Nanomaterials Scaffolds for Carbon Monoxide Delivery: Recent Developments and Future Trends Diep Nguyen† and Cyrille Boyer*,†,‡ †

Australian Centre for Nanomedicine, School of Chemical Engineering, and ‡Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University of New South Wales, Gate 2, High Street, Sydney, Australia 2052 ABSTRACT: Carbon monoxide (CO) is as an important biological gasomediator. It plays significant roles in anti-inflammatory, antihypertensive, and antiapoptotic pathways. Preclinical evidence in animal models has proven the beneficial effects of controlled CO gas administration. However, the medical use of CO gas has been hindered due to its administration. Indeed, its toxicity at high concentrations and the challenging delivery to specific target sites are the limiting factors. To overcome these problems, a wide range of CO-releasing molecules have been designed, and some have emerged as potential therapeutic agents. Despite some successes, these small CO-releasing molecules have limited stability in biologic media resulting in an unspecific release of CO, which could result in side effects. CO-releasing macromolecular and inorganic nanomaterial scaffolds have emerged as promising carriers due to their ability to encapsulate and deliver high amounts of CO-releasing molecules. Furthermore, polymer architecture could be designed for the controlled release of CO under specific stimuli. After highlighting some recent developments in the design of CO-releasing scaffolds, this review will discuss strategies and possible future directions of CO releasing macromolecules and inorganic nanomaterials for potential therapeutic applications. KEYWORDS: carbon monoxide (CO), CO-releasing molecules (CORMs), macromolecular CORMs, inorganic hybrid scaffolds and drug delivery

1. INTRODUCTION Carbon monoxide (CO), a colorless and odorless gas, is a product of partially oxidized organic matter that forms because of the lack of oxygen. The biological activity of CO is dependent on its concentration. High concentrations of CO are toxic to humans and animals because of its strong affinity for hemoglobin (it binds approximately 220 times more strongly than oxygen (O2)).1 CO replaces oxygen from oxyhemoglobin, resulting in the formation of carboxyhemoglobin (COHb).1 Consequently, there is a reduction in the oxygen transport capacity of the red blood cells with an inhibition of oxygen delivery in the tissue. It has been reported that with 50−60% of human hemoglobin occupied by CO, coma, convulsions, depressed respiration, and depressed cardiovascular status may occur, and with >70% of COHb, respiratory failure and death may result.1 However, CO is now increasingly accepted as an important messenger molecule in mammalian cells and presents similar properties to hydrogen sulfide (H2S) and nitric oxide (NO). CO has been reported to exhibit significant biological effects, such as anti-inflammatory, antiapoptotic, antiatherogenic, antiproliferative and cytoprotective effects, at low concentrations ranging from 10 to 500 ppm.2,3 Additionally, CO has been shown to protect against hepatic ischemia,4,5 prevent pancreatic beta cells from apoptosis,6 and modulate spermatogenesis under conditions of stress.7 Furthermore, CO has been demonstrated to provide protection against sepsis8 and lung injury9 in animals as well as mediate vascular smooth muscle cell proliferation.10 There are some © XXXX American Chemical Society

reports that suggest that CO may have a potential role in the neural pathophysiology of Alzheimer’ disease11 and ovulation.12 Thus, CO is a good candidate for therapeutic applications with respect to its effects in the human body. However, because of the difficulties in handling and delivering CO gas, which are associated with its toxicity at high concentrations, the synthesis of CO-releasing molecules has become an important research area. The use of macromolecular vehicles for CO delivery is particularly attractive because of their unique characteristics, such as the targeted delivery to a specific site by passive (enhanced permeation retention) or active targeting, longer lifetime for the CO molecules, low toxicity of macromolecules, and high CO payloads compared with low-molecular- weight CO donors.13−16 This review will specifically discuss some recent progress in the design and potential therapeutic applications of macromolecular and inorganic CO-releasing vehicles. Strategies and possible future directions for the therapeutic applications of CO-releasing macromolecular and inorganic nanomaterial scaffolds will then be discussed. The endogenous production, the biological properties, the therapeutic applications of CO, the main types of current low-molecular-weight CO donors, and the method for detection of CO will be also described in this review. Received: May 31, 2015 Accepted: August 27, 2015

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DOI: 10.1021/acsbiomaterials.5b00230 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Review

ACS Biomaterials Science & Engineering Scheme 1. Enzymatic Production of CO via Heme Degradation (a)

a

Adapted with permission from ref 17. Copyright 1988 Federation of American Societies for Experimental Biology.

malaria, diabetes, and acute hepatitis.2 The anti-inflammatory effect of CO was demonstrated to be mediated through either mitogen-activated protein kinase (MAPK)-related pathways29 or c-Jun N-terminal kinase (JNK) signaling pathway and activator protein 1 (AP-1).30 For example, Pamplona et al.31 applied inhaled CO to a mouse model of cerebral malaria to examine the potential anti-inflammatory effect of CO. After 3 days treatment with CO gas, the authors demonstrated that the treatment prevented the development of experimental cerebral malaria (ECM). More importantly, all animals survived the disease. The anti-inflammatory activity of CO has been studied in phase II clinical trials and show promising results. For instance, administration of 100 to 125 ppm of inhaled CO to patients with chronic obstructive pulmonary disease (COPD) has been reported to result in a decrease in the sputum eosinophils and enhancement of responsiveness,32 suggesting CO inhalation is a possible therapeutic approach for COPD disease. Furthermore, CO has shown potential in treating vascular diseases, which has been attributed to multiple pathways including cGMP-dependent pathway, potassium channels, p38 MAPK, or inhibition of cytochrome P450.33 The effects of CO on vascular diseases were observed in three rodent models having pulmonary arterial hypertension (PAH).34 In this model, inhaled CO was reported to reverse the established PAH by the stimulation of NO production, supporting its application for the treatment of pulmonary hypertension and other cardiovascular diseases.35 Moreover, inhalation of CO has been applied in the field of organ transplantation and preservation. Yoshida et al.36 reported that CO exhibited remarkable protection against transplantinduced renal ischemia/reperfusion (I/R) injury in pigs. Therefore, the ex-vivo treatment of kidney grafts with CO during cold preservation is a possible approach to protect against I/R injury. It has been established that CO increases the stability of cytochrome P450 (CYP) (a group of heme proteins present in

2. MOLECULAR BIOLOGY OF CARBON MONOXIDE Carbon monoxide is produced endogenously from the degradation of heme that is catalyzed by heme oxygenase enzyme (HO). The porphyrin ring of heme (ferroprotoporphyrin IX) is cleaved owing to the presence of functional HO, and then it is oxidized at the α-methene bridge, producing biliverdin, CO, and ferric iron (Scheme 1).17 The HO-catalyzed heme metabolism pathway requires the cofactors nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) and O2.17 Once synthesized, CO diffuses to neighboring cells and reacts with soluble guanylyl cyclase (sGC). CO is known to be capable of activating sGC by binding to a heme moiety of this enzyme, which leads to an increase in cyclic guanosine monophosphate (cGMP) formation.18 cGMP then serves as a second messenger that governs many important cellular functions, such as smooth muscle cell relaxation23,24 and the inhibition of platelet aggregation.19 In addition, the role of CO in the non-cGMP pathways has recently gained increasing attention. CO has been demonstrated to activate big potassium (BK) channels, leading to cell membrane hyperpolarization,20,21 resulting by a vasodilatation effect.21−23 Another ion channels, ion cardiac L-type Ca2+ channel can be modulated by CO,24 which confers the cardioprotective properties of CO.24 Finally, CO can modulate mitochondrial respiratory chain, NADPH oxidase,25 nitric oxide synthase,26,27 and cytochrome P450 (CYP).28 The study of the biological functions of CO is a new topic that is progressing. New biological activities and molecular mechanisms in which CO plays a role will be likely introduced in the future. 3. THERAPEUTIC APPLICATION OF CARBON MONOXIDE The administration of gaseous CO has been demonstrated as a novel therapeutic application for some diseases. CO inhalation has been shown to have potential therapeutic applications in animal models for inflammatory diseases, such as cerebral B


Review

ACS Biomaterials Science & Engineering Table 1. Solvent-Induced Ligand Exchange on CORMs versus PhotoCORMs class solvent-induced ligand exchange on CORMs photoCORMs

common transition metal

representatives

Ru

CORM-2, CORM-3, ALF492

Mn, Re, W, Mo, Fe

(OC)3Re(bpy) (thp)+, ALF794, B12− MnCORM-1

release condition releases CO spontaneously by exchange of CO by solvent molecule requires photolysis (such as UV light, visible light) to release CO

the kidney), which prevents I/R injury.37−39 Nakao et al.40 suggested that CO binding to CYP could inhibit CYP degradation and thus iron release from heme in renal grafts. The suppression of iron release prevents the formation of reactive oxygen species (ROS).41 CO also exhibits interesting properties for the treatment of infectious diseases, which is growing health care concern.42 Indeed, the emergence and widespread resistance to antibiotics in bacteria poses a serious threat to global public health. It could cost several billions dollars every year and cause the death of a hundred thousand people.43 Owing to its antimicrobial activity,44 CO could in the future help in the design of new therapeutic solutions for the treatment of infectious diseases caused by bacteria resistance to antibiotics.44−46 CO exhibits antimicrobial activity due to its inhibition of the respiratory chain in bacteria and its action on adenosine triphosphate (ATP) production.47 Besides, CO has been shown to promote phagocytosis of bacteria,47 such as Escherichia coli via p38-mediated surface expression of toll-like receptor 4 (TLR4)48 and to activate the host immune response.49 More details on the potential therapeutic applications of carbon monoxide have been described elsewhere.2,50,51

carbonyls vibrate in a region where signals from biomolecules are not observed. Furthermore, they are suggested to be potential therapeutic agents in human medicine57 because of their presence in the active center of enzymes, such as the hydrogenases. A wide range of metal carbonyl compounds exist, such as solvent-induced ligand exchange on CORMs, photoCORMs, thermal-triggered CORMs, oxidation-triggered CORMs, enzyme-triggered CORMs (ET-CORMs) and pH-triggered CORMs.50,58,59 Two types of metal carbonyl compounds have gained extensive attention in biological studies and have been utilized in combination with nanomaterials: solvent-induced ligand exchange on CORMs and photoCORMs (Table 1). 4.1. Solvent-Induced Ligand Exchange on CORMs. CORM-2 and CORM-3 (Figure 1) are the compounds most commonly used in biological and medicinal studies.

4. LOW-MOLECULAR-WEIGHT CO DONORS CO has interesting therapeutic applications because of its beneficial role in the body. However, the development of approaches for transporting and delivering CO is still at an early stage. The simplest approach is the inhalation of CO at appreciable concentrations. Despite the commercialization of a delivery device for inhaled CO, it is considered difficult to store and deliver CO in a controlled manner because CO is a gas. Moreover, it is known that prolonged inhalation of CO may cause adverse effects in the patients owing to its toxicity at high concentrations, which limits the use of this method in a medical context. These limitations led to the development of molecules capable of releasing CO (CORMs) as a pharmaceutical agent. Such molecules improve the efficiency, safety and delivery of CO. More details about the CO-releasing molecules (CORMs) have been described extensively elsewhere.50,52−55 In this review, we present the most common CORM compounds. Diverse compound classes that can release CO under mild conditions have been identified: organometallic compounds, aldehydes, oxalates, boroncarboxylates, and silacarboxylates.52 Among the classes of CORMs, metal carbonyl complexes with CO bound to a transition metal in a low oxidation state have gained increasing interest due to the large number of studies that have shown strong evidence for the potential of these complexes in medical treatment. Organometallic compounds are suitable reagents that can act as carriers of CO because they offer many advantages. First, they have a versatile chemistry, such as the nature and oxidation state of the metal center, the number of carbonyl ligands, the nature of the coligands and the outer coordination sphere, as well as structural variety.50,52,53,56,57 Additionally, their distinct spectroscopic features make the detection of carbonyl species easy because the bands of metal

Figure 1. Chemical structures of three solvent-induced ligand exchange on CORMs.

CORM-2 (Figure 1) is a commercially available complex that was first introduced in 2002 by Motterlini et al.35 It has been demonstrated that CORM-2 that is freshly dissolved in dimethyl sulfoxide (DMSO) exists as isomers (Scheme 2), not as dimers.35 Scheme 2. Isomers Formed from CORM-2 in DMSOa

a

Adapted with permission from ref 35. Copyright 2002 American Heart Association.

CORM-2 has been exploited to synthesize compounds containing Ru(CO)3 moieties. One of the simplest complexes, CORM-3 [Ru(CO)3Cl(glycinate)], is water-soluble and was prepared from the reaction of CORM-2 and glycine (Scheme 3) by the Motterlini group in 2003. CORM-3 represents the first known air-stable and water-soluble CORM. It releases CO by ligand substitution with water molecule.60,61 CORM-3 (Figure 1) has been reported to show interesting biological effects, including vasodilatory, anti-inflammatory, antibacterial, anti-ischemic and antiapoptotic effects in preclinical studies.2,45,53,62,63 In 2012, a novel water-soluble ruthenium complex (ALF492) (Figure 1) that has excellent biological properties was designed and generated by Pena et al.58 ALF492, synthesized through the reaction of CORM-2 and β-DC


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ACS Biomaterials Science & Engineering Scheme 3. Synthesis of CORM-3a

Scheme 5. Decomposition of PhotoCORMsa

a

Adapted with permission from ref 60. Copyright 2007 Royal Society of Chemistry.

a

thiogalactopyranoside (Scheme 4), is capable of transferring CO to heme without affecting the oxygen transportation by hemoglobin and is distributed in vivo with a significant affinity for the liver. Additionally, the treatment of cerebral cells with ALF492 allows the protection of these cells against cerebral malaria in mice. More importantly, when used in combination with antimalarial drugs, ALF492 demonstrated synergistic effects for the treatment of cerebral malaria. 4.2. PhotoCORMs. PhotoCORMs are metal carbonyl complexes that are stable in the dark in aqueous solution. Upon photoactivation, these compounds release one (or more) carbon monoxide equivalents at an appropriate wavelength.64 In contrast to solvent-induced CORMs, photoCORMs are more specific, which allows a spatial and temporal control in the CO delivery. Although solvent-induced CORMs release CO spontaneously, photoCORMs decompose via a light trigger. For example, metal−carbonyl complex A (Scheme 5) is stable in the dark, but upon exposure to light, it releases one (or more) equivalent of CO, resulting in the formation of the intermediate species B, whereas the coligands L remain bound. The intermediate species B further binds to a solvent molecule (sol) to yield compound C.64 Motterlini et al.35 performed the first study in 2002 on COreleasing molecules, which dealt with the light-induced release of CO from iron pentacarbonyl and dimanganese decacarbonyl (Figure 2A). Although both compounds did not release CO in the dark, they released CO upon extended photolysis as determined by a myoglobin assay. However, the study was not continued because of the poor bioavailability and high toxicity of both complexes. To improve the solubility and stability in aqueous solutions, a strategy involving solvent-separated ions containing noncoordinating anions was employed. Several groups used this strategy to generate a new series of photoCORMs.65−70 In 2008, Schatzschneider65 reported [Mn(CO)3(tpm)]+ (tpm = tris(1pyrazolyl)methane) to be a photoCORM with improved activity. The compound was stable in the dark in aqueous buffer and released two equivalents of CO upon excitation at 365 nm with UV. The complex exhibited an efficient cellular internalization in HT29 human colon cancer cells as shown by graphite furnace atomic absorption spectroscopy and cell viability. At 100 μM, [Mn(CO)3(tpm)]+ led to a significant decrease in cell biomass after exposure 10 min to UV light in comparison with 5-

fluorouracil (5-FU), a common anticancer drug used in this type of cancer. In contrast, the complex had no effect on the number of viable cells in the absence of UV light, which demonstrates its specificity.65 Additionally, the efficient cellular internalization of [Mn(CO)3(tpm)]+ was also demonstrated in living human cancer cells by Raman microspectroscopy.66 To develop the selective delivery of the manganese tricarbonyl complex to a cancer cell, the attachment of functionalized amino acids and model peptides (Figure 2B) using Sonogashira coupling reaction and copper-catalyzed azide−alkyne, i.e., 1,3-dipolar cycloaddition (CuAAC “click” reaction) was explored.67 A tungsten photoCORM was reported by Rimmer70 in 2010, and the term, photoCORM, was introduced in that report for the first time. The tris-sodium salt of [W(CO)5(tppts)]3− (tppts = tris(sulfonatophenyl)phosphine) (Figure 2C) is water-soluble and stable in aqueous buffer if kept in the dark. CO can be released from the compound upon photoexcitation in the range from 300 to 370 nm. Upon irradiation at 313 nm, approximately one equivalent of CO was liberated, resulting in the formation of [W(CO)4(H2O) (tppts)]3− that then underwent further oxidation independent of the irradiation. Further details are available in previous reviews on photoCORMs.64,71,72 Although photoCORMs present several advantages for clinical use, their designs require complex study, as the cellular toxicity of these photoCORMs and their photoproducts (i.e., multiple degradation products) needs to be considered. Unfortunately, the toxic effects of photoCORMs were rarely studied in these earlier studies. In addition, these photoCORMs are probably not preferable in therapeutic applications because CO that is released from these compounds requires UV light that may have harmful effects on tissues and cells. More recently, the development of photoCORMs for biological applications focuses on the preparation of photoCORMs within a phototherapeutic window ranging from 620 to 850 nm - the range in which the light penetration depth into mammalian tissue reaches a maximum.73,74 Recently, some promising photoCORM candidates for biomedical applications with minimal toxicity have been reported. For example, the complex (OC)3Re(bpy) (thp)+ (thp = tris(hydroxymethyl)phosphine, bpy = bipyridine)75 (Figure 2D) is water-soluble, airstable and nontoxic. The advantages of this complex include the following: First, it displays a relative high quantum yield. Second, both (OC)3Re(bpy) (thp)+ (Figure 2D) and its product after photoactivation are fluorescent, which permits the detection of

Adapted with permission from ref 64. Copyright 2011 Elsevier

Scheme 4. Synthesis of ALF492a

a

Adapted with permission from ref 58. Copyright 2012 American Society for Microbiology. D


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ACS Biomaterials Science & Engineering

Figure 2. Chemical structures of several photoCORMs.

these compounds in a biological medium using fluorescence microscopy and allows to visualize the release of CO. Another interesting photoCORM that possesses a low toxicity is molybdenum carbonyl ALF794 (Figure 2E). This photoCORM has been shown to be efficient for the treatment of acetaminophen-induced acute liver failure in mice.76 Finally, photoCORM B12−MnCORM-1 (Figure 2F), which can release CO after exposure to visible light, was prepared by Zobi et al.77 Light-activated B12−MnCORM-1 (Figure 2F) has been shown to prevent fibroblasts from death under conditions of hypoxia and metabolic depletion. As mentioned above, some CORMs, including CORM-3, ALF492, ALF794, and B12−MnCORM-1, exert remarkable biological activities, and they are now in the early stages of preclinical studies. Thus, CORMs are promising candidates for therapeutic applications.

tion signal at 557 nm. After reaction with CO to yield MbCO, there are two new signals at 540 and 577 nm from MbCO, whereas the signal at 557 nm disappears. Therefore, this conversion can be monitored by UV−vis spectroscopy. Although myoglobin assay is the common method for CO detection, it suffers some disadvantages. First, the CO release from this assay is conducted in the presence of an excess reducing agent sodium dithionite and this reducing agent is responsible for facilitating the release of CO from CORM-2 and CORM-3,78 and consequently, enhancing their release rates.78 In addition, some issues such as turbidity due to poor-solubility of CORMs or CORM absorbance can also lead incorrect determination of MbCO concentration.79 Two new modified myoglobin methods79 have recently been developed by Fairlamb et al. to get reliable and correct concentration of CO release. In the first method, one assay with added myoglobin (standard assay) and one without myoglobin (control assay) are carried out in parallel, then CORM absorbance in the nonmyoglobin reaction mixture is subtracted from the one with myoglobin, giving more reliable measurements. In the second method, the UV spectrum of CORM is calculated based on four isosbestic points (510, 550, 570, and 585 nm) between the absorption of deoxy-Mb and MbCO. If CO release is not affected by the presence of myoglobin, the first method is suitable. In contrast, if myoglobin plays an active role in the release of CO from a CORM, the second method is preferred.

5. METHODS FOR THE DETERMINATION OF CO RELEASE Reliable and accurate methods are required to study the CO release profiles of CORMs. The common in vitro method for detection of CO released from CORMs is the myoglobin assay reported by Motterlini and co-workers in 2002.35 In this assay, CORM is added to a solution of reduced deoxy-myoglobin (deoxy-Mb) which can trap CO to form carbonmonoxy myoglobin (MbCO). Deoxy-Mb shows a characteristic absorpE


Review


Scheme 6. Current Types of CO-Releasing Macromolecular and Inorganic Nanomaterial Scaffolds: (A) Copolymer Systems;94,95 (B) Micellar Systems;96−98 (C) Inorganic Hybrid Scaffolds (Silica,99,100 Nanodiamond,101 Iron Oxide102); (D) Iron MetalOrganic Framework;103 (E) Nanofiber Gel;104 (F) Protein;105 (G) Metallodendrimers.106

impairs the detection of CO release when applying this method in aqueous solutions. CO release can also be detected by electrochemical approach. This technique takes advantage of a change of the reduction peak shape and an increase of the reduction current of the FeII/FeIII redox pair owing to the interaction between the CO release from CORMs and heminmodified electrode. Joseph et al. used this method to monitor CO release from CORM-2 as well as 1,3-dimethoxyphenyl tricarbonyl chromium.84 In a recent account, Esteban et al.85 reported that CO can be detected with both selectivity and sensitivity by chromogenic probe. The method involved the use of binuclear rhodium derivatives such as complex [Rh2(C6H4PPh2)2(O2CHCH3)2](HAc)2. The complex containing two cyclometalated phosphines ligands underwent a fast and distinct color shifts through displacement of acetic acid (HAc) by CO. The purple solutions turned into orange for low CO concentrations whereas, at high CO concentration solutions became yellow.86 An advantage of this method is the very clear color shift, enabling detection of CO concentrations as low as 0.2 pm with the naked eye. Additionally, this method can be used both in solution and in air. However, this complex is insoluble in water thereby limiting the use of this method for detection CO in live cells. In this context, Raman microspectroscopy66 and two assays based on fluorescent probes87,88 were introduced to quantify CO release in living cells. The methods for detection of CO release from CORMs have been reviewed extensively elsewhere.55,59,89 Although some progress has been made in this field with the introduction of some systems to track CO in live cells, there is still urgent need for further development to detect the CO release in more complicated biological environments, especially in vivo.

To eliminate the necessity of using reducing agent, such as sodium dithionite (in myoglobin assay), which can enhance the rate of CO release, McLean and co-workers developed an oxyhemoglobin assay.78 Unlike a myoglobin assay, there is no need to deoxygenate reduced hemoglobin because of the fact that CO strongly binds to hemoglobin. The difference in absorption spectra of oxyhemoglobin (Oxy-Hb) and carboxy hemolgobin (HbCO) in the Soret region at 442 nm suggests that it is an efficient method to determine the replacement of O2 by CO. Beside myoglobin and oxyhemoglobin assays, a number of alternative methods have been proposed to quantify the amount of CO release per CORM and to investigate the kinetics of CO release. Gas chromatography with a thermal conductivity detector (GC-TCD) is considered to be the most accurate method to measure the content of CO release from a sample.80,81 This approach offers a lot of advantages. For example, it can be utilized in different aqueous media with variable pH values and detection of carbon dioxide (CO2) can be run in parallel using this method. This method is preferable to monitor CO release from CORM-3, as one CO ligand is released in the form of CO2.82 Furthermore, detailed information can be gained about several gas species such as CO, CO2 and H2 from this method.82,83 Another method that can be used to detect the CO release is IR spectroscopy in which the characteristic carbonyl signals of CORMs appearing in the region of 1800 to 2200 cm−1 are monitored. The advantage of this method is the absence of other vibration signals from other functional groups. Furthermore, IR spectroscopy is often applied to quantify the amount of CO released from a sample in the solution or/and solid state. However, the low IR transmittance of water (due to the fact that water shows a very strong and broad IR absorption) F


Review


Figure 3. Structure of the CO-releasing copolymers: Mn(CO)3@P1 and Mn(CO)3@P2. Adapted with permission from ref 95. Copyright 2011 Wiley.

Figure 4. (A) Structure of the poly[PEG-b-OrnRu-b-nBu] triblock copolymer. (B) Schematic representation of micelle formation of the triblock copolymer. Adapted with permission from ref 96. Copyright 2010 American Chemical Society.

Figure 5. (A) Schematic illustration of SMA/CORM2 micelles structure. (B) Colon tissue damage illustration in mice treated with DSS-induced colitis and SMA/CORM2. Mice treated with SMA/CORM2 had much less tissue damage and a histological appearance that was similar to normal mice. (C) Suppression of inflammatory cytokines (MCP1, TNF-α, and IL-6) by SMA/CORM2. Reproduced with permission from ref 97. Copyright 2014 Elsevier.

6. MACROMOLECULAR AND INORGANIC NANOMATERIAL SCAFFOLDS AS CO CARRIERS

CORMs is the controlled dose-release of CO at the target tissue. The delivery of CO in target tissues is challenging because these small molecular-CORM drugs diffuse rapidly after the administration and release of CO prior to their accumulation into the specific tissue, which results in side effects and some

Although the discovery of CORMs opens up new avenues for therapeutic usage, there are still many problems to overcome. One of the major prerequisites for the practical clinical use of G


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Figure 6. Schematic representation of CO-release from a water-soluble nanocarrier upon NIR light. Adapted with permission from ref 98. Copyright 2015 Royal Society of Chemistry.

Figure 7. Covalent attachment of [Mn(CO)3 (tpm)]+ complex to the surface of the azide-functionalized silica nanoparticles via CuAAC “click” reaction and TEM micrograph of CORM-functionalized silica dioxide nanoparticles. Reproduced with permission from ref 99. Copyright 2011 American Chemical Society.

Figure 8. (A) Structure of the design manganese carbonyl complex {Mn-CO}. (B) SEM-EDX maps of {Mn-CO}@ Al-MCM-41 (B) Si; (C) O; (D) Al and (E) Mn. Reproduced with permission from ref 100. Copyright 2014 Royal Society of Chemistry.

drug activity by temporal control or distribution control (via ether passive or active targeting approaches).107,108 Another advantage of polymers is their ability to increase the circulation time in the blood and maintain the concentration of the drug to achieve therapeutic levels over an extended period of time. a. Copolymer. The first successful incorporation of a polymeric backbone with a CORM was achieved in 2007. Kunz et al.94 reported the synthesis and characterization of N-(2hydroxypropyl) methacrylamide poly[(HPMA)-co-bis(2-pyridylmethyl)-4-vinylbenzylamine] copolymers containing the Re(CO)3 fragment. HPMA was used as a copolymer because of its water solubility, biocompatibility, and nonimmunostimulatory nature.109−111 Poly[HPMA-co-bis(2-pyridylmethyl)-4-vinylbenzylamine] copolymer was first prepared using conventional radical polymerization conditions. The resulting polymer was then coordinated with the Re(CO)3 fragment by refluxing (nBu4N)2[Re(CO)3Br3] and AgOTf in methanol. The IR spectrum confirmed the presence of carbonyl groups at approximately 1900 and 2100 cm−1 in the nanocarriers. Although the CO-release property of these CO nanocarriers was not examined, this study opens up a new method for CO delivery to biological systems. Four years later, another group also exploited

toxicity. This problem can be addressed by using macromolecular carrier and inorganic nanocarrier systems (Scheme 6). Macromolecular and inorganic carriers, such as polymeric nanoparticles and iron oxide nanoparticles, appear to be an ideal vehicle for the transport of drugs because their sizes can be easily tuned, permitting the passive accumulation in a tumor tissue via the enhanced permeability and retention (EPR) effect.90−92 Additionally, macromolecular carriers offer a high CO-loading capacity due to the attachment of several CO per macromolecule, resulting in a significant increase in the CO concentration. Furthermore, nanocarriers not only enhance the therapeutic efficacy, but they also reduce the systemic toxicity of drugs, which results in a reduction in side effects.93 Therefore, the use of macromolecular and inorganic systems as CO carriers has recently gained increasing attention. Recent development of CO releasing macromolecular and inorganic nanomaterial scaffolds over the past few years are discussed in this section. 6.1. Polymeric Organic Scaffolds. Polymeric nanocarriers have been widely investigated as potential drug carriers. The application of polymers in a medical context shows promising results because of their properties. Polymers can be used to enhance the solubility and stability of drugs as well as improve the H


Review


Figure 9. (A) Covalent attachment of [Mn(CO)3 (tpm)]+ complex to the azide-modified nanodiamond surface via CuAAC “click” reaction; (B) TEM micrograph of [Mn(CO)3(tpm)]+ -based nanodiamond and (C) EDX spectrum of [Mn(CO)3(tpm)]+ -based nanodiamond. Reproduced with permission from ref 101. Copyright 2012 Royal Society of Chemistry.

oligolactide side chain that was coordinated with ligand moieties (Mn(CO)3@P2) (Figure 3). Myoglobin assay showed that these polymers were photoinducible CO-releasing molecules (PhotoCORMs), and the CO release from the polymers took place on the same time scale as the release from the free complexes. The toxicity of the resulting Mn(CO)3-polymer conjugates was tested in the Hct116 human colon carcinoma and in HepG2 human hepatoma cells. Interestingly, Mn(CO)3@P2 exhibited cytotoxic effects, whereas the Mn(CO)3@P1 did not exhibit any cytotoxicity because of the differences in the cellular uptake and intracellular distribution.The size and molecular weight of the polymers were designed to be suitable for the passive accumulation and drug delivery (EPR effect) as well as degradability to aid in renal clearance. Brückmann’s results suggest that polymer conjugates can be used for the passive delivery of CO to the tumor tissue and site of inflammation. b. Micelles. The encapsulation of CORMs into polymeric micelles has also been investigated. For instance, Hasegawa and

Figure 10. Structure of CORM-functionalized iron oxide nanoparticles and TEM micrograph of CORM-functionalized iron oxide nanoparticles. Left panel adapted and right panel reproduced with permission from ref 102. Copyright 2013 Royal Society of Chemistry.

HPMA as the polymeric backbone for the coordination of CORM. Brückmann et al.95 presented a method of attaching the manganese tricarbonyl moiety to 2-hydroxypropyl methacrylamide (HPMA)-based copolymers. The polymers consisted of either a HMPA backbone attached to ligand units (Mn(CO)3@ P1) (Figure 3) or HPMA backbones with a biodegradable

Figure 11. MIL-88B−Fe for the loading and delivery of CO. (A, B) SEM micrographs of crystals of MIL-88B−Fe (C) Structure of MIL-88B−Fe, (viewed along the c axis). Empty circles represent the positions of the terminal ligand; Fe atoms, light-gray spheres; O atoms, gray spheres; and C atoms, black spheres. Reproduced with permission from ref 103. Copyright 2011 American Chemical Society. I


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Figure 12. (A) Structure of CO-releasing peptide amphiphile (PA2) (adapted from ref ) (B) SEM image of PA2 with diluent PA C16 V2A2E2 and gelled by presence of CaCl2. Panel A adapted and panel B reproduced with permission from ref 104. Copyright 2014 Royal Society of Chemistry.

CORM-3, which is due to the encapsulation of CORM in hydrophobic part of the micelles. The anti-inflammatory property of the CO-releasing micelles was investigated using THP-1 Blue cells (derived from human monocyte THP-1 cells). These micelles successfully attenuated the lipopolysaccharideinduced monocyte cell line and notably decreased the cytotoxicity of the Ru(CO)3Cl (amino acidate) moiety attributed to the stealth feature of poly(ethylene glycol) polymer. In another approach, Yin et al.97 designed and prepared micelles (SMA/CORM2) comprising poly(styrene-alt-maleic acid) copolymer (SMA) encapsulating CORM-2 (Figure 5A). These micelles not only had the ability to release CO in a sustained and slow fashion but also exerted superior in vivo pharmacokinetics, that is, prolonged circulation time and selective accumulation in inflammatory tissue due to EPR effect. Interestingly, this system was found to remarkably suppress the generation of inflammatory cytokines (including monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)) (Figure 5C), suggesting therapeutic utilization of SMA/CORM2 for the treatment of reactive oxygen species related disease including inflammatory bowel disease. This is the first example of the application of a CO releasing carrier in vivo. Another type of CO-releasing micelle has recently been reported by Pierri et al.98 In this approach, the authors developed a water-soluble photoCORM nanocarrier capable of triggering the release of CO using near-infrared (NIR) light (Figure 6). This approach overcomes the previous limitations of the systems described by Hasegawa,96 Yin and co-workers,97 that is their poor spatial and temporal control. The nanocarriers were prepared by the encapsulation of NIR upconverting nanomaterials (which are materials capable to absorb low energy wavelength and emit higher energy wavelength) in the core of micelles using an amphiphilic phospholipid-functionalized poly(ethylene glycol) (DSPE-PEG-2000) as the stabilizing macromolecule and photoCORM, [Mn(bpy) (CO2) (PPh3)2]+. Inductively coupled

Figure 13. (A) Structure of [(lysozyme)Mn(CO)3(OH2)2]2. (B) X-ray crystal structure of [(lysozyme)Mn(CO)3(OH2)2]2.145. Panel A adapted and panel B reproduced with permission from ref 145. Copyright 2007 Royal Society of Chemistry RSC.

co-workers96 prepared the first CO-releasing polymeric micelles capable of targeting tumor tissues, suggesting that these scaffolds can be useful for the therapeutic application of CO. In this approach, the micelles, poly[PEG-b-OrnRu-b-nBu] (Figure 4) were constituted of a poly(ethylene glycol) block, a poly(ornithine acrylamide) block bearing Ru(CO)3Cl (ornithinate) moieties and poly(n-butylacrylamide) blocks, where the poly(ethylene glycol) is the hydrophilic block utilized to stabilize the micelle. Ru(CO)3Cl (ornithinate) is the fragment that liberates the CO, and poly(n-butylacrylamide) is the hydrophobic block used to drive self-assembly. First, poly[PEG-b-(Boc-Orn-OtBu)b-nBu] triblock copolymers were synthesized using reversible addition−fragmentation chain transfer (RAFT) polymerization. Boc and OtBu protecting groups were removed to yield the poly[PEG-b-OrnNa-b-nBu] triblock copolymer, which was then reacted with CORM-2. The copolymers self-assembled into spherical micelles that had an average diameter of approximately 30−40 nm. The micelles that were synthesized following this route were reported to be stable in buffer and serum solutions. CO-release studies showed that micelles only release CO via the addition of thiol-compounds, such as cysteine or glutathione. The release rate of CO from micelles was slower than for

Figure 14. (A) Schematic illustration of the synthesis of Ru·CL-HEWL. (B) Representation of CO release from Ru·CL-HEWL in the vicinity of cells. Reproduced with permission from ref 105. Copyright 2015 American Chemical Society. J


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Figure 15. CORM-dendrimer conjugates. Adapted with permission from ref 106. Copyright 2103 American Chemical Society.

41-bearing manganese carbonyl complex ({Mn-CO}@AlMCM-41) was analyzed using several techniques, such as inductively coupled plasma-optical emission spectroscopy (ICPOES), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy coupled with energy-dispersive X-ray (SEM-EDX) and transmission electron microscopy (TEM) (Figure 8). The amount of {Mn-CO} grafted on the Al-MCM-41 was determined to be approximately 2.06 wt % of the Mn by acid digestion followed by ICP-OES. The CORMfunctionalized mesoporous silica nanoparticles were thermally stable, and CO release took place only upon exposure to visible light. Because of its specific CO release in time and space, {MnCO}@Al-MCM-41 could be employed in the treatment of cardiovascular diseases, where a local delivery is desirable. The authors successfully demonstrated vasorelaxation by {Mn-CO} @Al-MCM-41 in rat aortic muscle. This system showed advantage over the previously mentioned CO-releasing silica nanoparticles because the CO release was induced by visible light which is not harmful to the cell and gives greater penetration depth in tissue compared with UV light. b. Nanodiamond (ND). The interest in utilizing nanodiamond (ND) as a drug delivery vehicle has emerged over the past decade due to its unique properties, such as low toxicity, facile functionalization with biomolecules and high cell uptake.117−119 Nanodiamonds are promising drug carriers for the delivery of anticancer chemotherapeutics as it allows to track these nanomaterials by fluorescence microscopy.117,119−122 The first generation of CORM-functionalized nanodiamond was achieved by Dördelmann et al.101 They used a similar approach in which silica nanoparticles were functionalized by the COreleasing molecule. Briefly, the [Mn(CO)3(tpm)]+ (PhotoCORM) complex was attached to the nanodiamond bearing the surface-bound azido groups by a CuAAC “click” reaction (Figure 9A). The complete reaction was followed by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), atomic absorption spectroscopy (AAS) and energy dispersive X-ray (EDX). IR spectrum showed the absence of the azide band at 2100 cm−1 and the presence of new signals at 1961 and 2051 cm−1 attributed to the carbonyl groups of Mn(CO)3 moiety, indicating the successful attachment with [Mn(CO)3(tpm)]+ complex. TEM micrograph revealed the average diameter of CORM-functionalized nanodiamond approximately 10 nm (Figure 9B). The appearance of manganese on

plasma-optical emission spectroscopy (ICP-OES) analysis confirmed the loading efficiency of Mn in the nanocarriers to be approximately 80%. The nanocarriers were stable in an aqueous solution in the dark, whereas the release of CO was triggered upon NIR excitation. This approach presents several advantages in comparison with previous systems, such as the spatial and temporal controlled delivery of CO using an external stimulus (NIR) light. Indeed, NIR presents a high penetration in the biological tissue (several centimeters) due to its low absorption. Furthermore, it does not provoke serious damage in contrast with the shorter wavelengths, such as UV. 6.2. Inorganic Hybrid Scaffolds. a. Silica Nanoparticles. Among the many types of materials that have been employed for drug delivery, the utilization of silica nanoparticles in biomedical research is of great interest because of their well-defined structures, simple synthesis, stability, biodegradability, and nontoxicity.112−115 Silica-based diagnostic nanoparticles in the form of Cornell dots have just recently received the first Food and Drug Administration (FDA)-approval in-human clinical trials,116 opening up the possibility of utilizing silica nanoparticles in clinical assessments. The first silica as a CO-releasing macromolecular scaffold was generated by Dördelmann et al.99 in 2011 (Figure 7). A modified [Mn(CO)3(tpm)]+ complex (tpm = tris(pyrazolyl)methane) was coupled to silica nanoparticles via the copper-catalyzed azide−alkyne 1,3-dipolar cycloaddition (CuAAC “click” reaction). Azide groups were conjugated to the surface of the silica, and then the azidefunctionalized nanoparticles were reacted with modified [Mn(tmp) (CO)3]+ using copper(II) sulfate as the catalyst. The successful coupling on the nanoparticles was characterized using IR spectroscopy by the formation of the two characteristic bands of the Mn(CO)3 moiety. CORM-functionalized silica was demonstrated to have similar photoinducible CO-releasing properties compared with the free complexes, as observed using the myoglobin assay. The CORM-functionalized silica may be used as a CO delivery agent in tumor tissues in the future. Loading of the manganese carbonyl complex fac-[Mn(pqa) (CO)3]ClO4 (pqa = (2-pyridylmethyl)(2-quinolylmethyl)amine) (abbreviated as {Mn-CO}) (Figure 8) to Al-containing mesostructured materials (Al-MCM-41) has recently been reported by Gonzales and co-workers (Figure 8).100 Al-MCM41 was chosen as the carrier for CORM because of its potential intravenous or intracellular applications. The resulting Al-MCMK


L

a

CO gas

MIL-88B−Fe and NH2-MIL-88B−Fe

human serum albumin, hen egg white lysozyme horse heart myoglobin, human hemoglobin, human albumin, human transferrin and hen egg white lysozyme cross-linked hen egg white lysozyme polypyridyl dendritic CORM-2 Mn(CO)5Br

CORM-2 [Mn(CO)3(acetone)3](CF3SO3), [Et4N]2[Re(CO)3(Br)3], [Ru(CO)3Cl2(1,3-thiazole)]) fac-[Mo(CO)3(histidinate)]Na (ALF186) CORM-3

UV light magnetic field

[Mn(CO)3(tpm)]+ CORM-2

nanodiamond Fe2O3

peptide amphiphile hen egg white lysozyme

UV light visible light

[Mn(CO)3(tpm)]+ fac-[Mn(pqa) (CO)3]ClO4

release CO spontaneously UV light

normoxic conditions

release CO spontaneously in physiological conditions release CO spontaneously

NIR light

[Mn(bpy) (CO2) (PPh3)2]+

amphiphilic phospholipid-functionalized poly(ethylene glycol) silica nanoparticles Al-MCM-41

CO release UV light thiol moieties release CO spontaneously

CO/CORMs (nBu4N)2[Re(CO)3Br3] Mn(CO)5Br CORM-2 CORM-2

materials

HPMA-based copolymers HPMA-based copolymers poly[PEG-b-OrnRu-b-nBu] poly(styrene-alt-maleic acid) (SMA)

The CO-releasing scaffolds were tested in vivo.

metallodendrimer

nanofiber gel protein

nanodiamond magnetite nanoparticles iron metal organicframework

silica nanoparticles

micelles

polymers

CO-releasing scaffolds

display as an extracellular scaffold to active nuclear factor kappa B (NF-κB)

improve in the cardiomyocyte viability

relax rat aorta muscle rings → potential for the treatment of cardiovascular diseasesa

attenuate the LPS-induced inflammatory response of human monocytes suppress the generation of inflammatory cytokines→ potential for the treatment of reactive oxygen species related disease including inflammatory bowel diseasea

potential therapeutic application

Table 2. Summary of Current Types of CO-Releasing Scaffolds with Various Materials and Their Potential for Biological Application ref

106

105

82

149

145,147,148

104

103

102

101

100

99

98

97

96

95

94

ACS Biomaterials Science & Engineering Review


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assemble into a range of well-defined complex structures and their simple synthesis.137 PA can self-assemble into fibrous hydrogels that are advantageous over other polymeric biomaterials because they are easily injectable in the solid state, and they are rapidly biodegradable.137,138 Additionally, their natural nanofibrous morphology has the ability to mimic the threedimensional (3D) structural features of the native extracellular matrix to assist in the integration with the host tissue and to serve as a regeneration template for the specific tissue.137,139,140 The first design of a CO-releasing peptide material (Figure 12) was achieved by Matson et al.104 This material was prepared from a nanofiber gel containing PA that was covalently coordinated to ruthenium tricarbonyl. The CO-release studies showed that the self-assembled nanofiber gel containing the PA released the CO spontaneously, and the half-life of CO release from the nanofiber gel was more than 8 times longer than that of the CORM-3. Additionally, treatment with this peptide-based material resulted in a considerable improvement in the cardiomyocyte viability compared with both an H2O2 control and non-CO-releasing PA control, thus highlighting its potential as a biodegradable gel for localized CO delivery platforms in therapeutic applications. 6.5. Proteins. Proteins have received increasing attention for fabrication drug delivery systems owing to their unique characteristics, namely low toxicity, stability, biodegradability, nonimmunogenicity and their ease of preparation and scale up.141−144 In addition, they exhibit high drug binding capacity and considerable cellular uptake ability.143 The fist CORMfunctionalized protein was generated in 2007. Razavet and coworkers145 developed a lysozyme containing manganese− carbonyl fragment {Mn(CO) 3 } + , [(lysozyme)Mn(CO)3(OH2)2]2 (Figure 13A) that can react with a nickel complex and thus resulted in a compound mimicking the structure of the active site of [NiFe] hydrogenase. The system was prepared by treating hen egg white lysozyme (HEWL) with excess [Mn(CO)3(acetone)3](CF3SO3) in acetate buffer pH 4.4 solution at room temperature in the absence of light. The resulting lysozyme containing Mn(CO)3 moiety was confirmed by several techniques such as IR (infrared spectroscopy), AAS (atomic absorption spectroscopy), X-radiation (X-ray) (Figure 13B). AAS determined that {Mn(CO)3}+-lysozyme comprising approximately 0.6 Mn atom per protein chain. The CORMbased lysozyme can be used to investigate the structure and the reactivity of the {Fe(CO) (CN)2}146 intermediate during [NiFe] hydrogenase maturation. In a subsequent study, Santos-Silva and co-workers82 reported the interaction of CORM-3 with various proteins including horse heart myoglobin, human hemoglobin, human albumin, human transferrin and hen egg white lysozyme (HEWL). All the above proteins were first incubated with an excess CORM-3 for 1 h and then was dialyzed to remove all the unbound compounds. The rapid formation of protein-Ru(II)(CO)2 adducts as the products from the reaction of CORM-3 and proteins, was characterized by inductively coupled plasma-atomic emission spectroscopy (ICPAES), infrared spectroscopy (IR), liquid chromatography mass spectrometry (LC-MS) and X-ray crystallography. The reactions were fast, losing all non-CO ligands (including a chloride ion and glycinate) and one CO ligand. The interaction of other COreleasing molecules (such as [Et4N]2[Re(CO)3(Br)3], [Ru(CO)3Cl2(1,3-thiazole)] and fac-[Mo(CO)3(histidinate)]Na (ALF186)) to proteins was also investigated.147−149 These findings may play an important role in the design and synthesis of CO-releasing scaffolds for therapeutic applications. Recently, Tabe et al.105 developed a CO-releasing scaffold Ru·CL-HEWL

nanodiamond was further confirmed by EDX technique (Figure 9C). In this approach, the authors showed a photoactivation CO release under UV at 365 nm. The need of high energy wavelength (i.e., 365 nm) to activate the release could limit its application for medical application, as UV light presents a low penetration into biological tissue and can damage DNA, and thus leads to some side effects. c. Iron Oxide Nanoparticles. Maghemite nanoparticles (NP) have attracted considerable interest as a carrier system for drugs in recent years. The potential of magnetic NPs as carriers of drugs is due to their distinct properties, such as superparamagnetism, drug loading capability, bioassimilation, nontoxicity, controllable high surface area, and low cost.123−127 Recently, the concept of magnetic-nanoparticle control for triggered CO-release (Figure 10) was introduced by Kunz et al.102 The magnetic (Fe2O3) nanoparticle surface was first grafted with D / L -3(3,4dihydroxyphenyl)amine to introduce an anchor group for subsequent attachment of the CORM moiety. A suitable CORM-2 was then immobilized on the surface of the magnetite nanoparticles via its catechol unit to yield CORM-functionalized iron oxide nanoparticles (CORM@IONP). IR spectroscopy showed intense bands at approximately 2059 and 1986 cm−1, indicating the presence of carbonyl groups in the CORM@ IONP. CO-releasing magnetite nanoparticles provide the main possibility for triggered CO-release in target tissue via an external alternating magnetic field. Under a high frequency magnetic field, a rapid CO release is observed due to the increase of temperature of iron oxide core.102 This approach allows a temporal control CO release. In contrast to NIR-photoactivated CO release, this approach is less affected by the biological tissue absorption. However, the spatial control is inferior in comparison with the photoactivation approach. 6.3. Iron Metal Organic Framework. Metal−organic frameworks (MOFs), also known as porous coordination polymers, form porous structures with a large inner surface area and have an ordered pore channel with different sizes;128 thus, they are good candidates for gas storage.129−131 Because they possess no toxicity, a high drug-loading capacity, a long release time and biodegradable activity,132−134 some MOFs have potential biomedical uses. Very recently, Ma et al.103 reported the first iron metal−organic frameworks as nanocarriers for CO (Figure 11). High-quality crystals of MIL-88B-Fe and NH2-MIL88B-Fe with a high dispersibility and homogeneous size were synthesized from iron(III) chloride hexahydrate and terephthalic acid or 2-aminoterephthalic acid using a microwave-assisted solvothermal method. Then, the MIL-88B-Fe and NH2-MIL88B-Fe samples were activated using heat in UHV, followed by incubation under a CO atmosphere at 98 K. Vacuum Fourier transform infrared (UHV-FTIR) spectroscopy was used to study the successful binding of CO to the MOFs. The signals of the carbonyl vibrations of the MIL-88B-Fe and NH2-MIL-88B-Fe in the UHV-FTIR spectrum occurred at 2181 and 2169 cm−1, respectively. These materials exhibited good biocompatibility, and the carbon monoxide was released under physiological conditions during the degradation of the materials, demonstrating their applicability as novel CO-delivery systems in biological applications. 6.4. Self-Assembling Peptide Amphiphiles (PA). Peptide amphiphiles (PA) are a class of self-assembling peptide systems that consist of a hydrophobic alkyl tail that is covalently bound to a hydrophilic peptide sequence.135,136 Their application in medicine has gained increasing attention over the past decade because of the advantages they offer, such as the ability to selfM


Review


7. CONCLUSION AND OUTLOOK In this review, we highlighted some of the recent advances in the utilization of macromolecules and nanomaterials as CO carriers (Table 2). The first encouraging studies confirm that nanoparticles have significant benefits, such as high CO payloads, targeted CO delivery to the site of action, and delayed CO release in comparison with CORMs. For instance, the encapsulation of CORM-2 in micelle allows the extension of half-life from a few minutes to several hours, which offers the opportunity for bioapplications. Indeed, the most significant challenge in the CO delivery is to obtain a sustainable and controlled release of CO, and thereby limits its side effects. CORMs have always been limited by their short half-lives (a few minutes) and their poor biodistribution for biomedical application. The encapsulation of these molecules in a single nanoparticle tackles this major limitation by offering an opportunity to control its release and localization. In addition, CO-releasing nanoparticles also enhanced the potency and efficacy of CORMs. For example, scaffolds in the form of micellar and silica nanoparticles have proved to be promising CO nanocarriers as these systems have potential for the treatment of inflammatory bowel disease and cardiovascular disease. Therefore, it is expected that COreleasing materials based on macromolecular and inorganic nanoparticles will be applied for the treatment of these diseases in clinical trials in the not too distant future. Furthermore, the numerous potential applications of CO for the treatment of hardto-treat diseases, such as malaria, hypertension, etc., will also motivate researchers to develop treatments using CO, and by consequence CO-releasing materials. Perhaps, one of the opportunities of these CO-releasing materials will be in the preparation of new antimicrobial agents for the treatment of infectious diseases. Therefore, new breakthrough systems for CO delivery are needed for the therapeutic applications. Other types of nanomaterials and macromolecules, such as ADN, polymer dendrimers, nanogels, liposomes, gold, and graphene oxide, can be exploited as CO carriers. This field is very new, and there are many opportunities for designing and synthesizing new CO-based nanocarriers for drug delivery purposes. We anticipate that the development of macromolecular and inorganic nanomaterial-derived CO delivery systems will definitely expand the new generation of COreleasing materials that will likely be introduced for future clinical use.

(Figure 14) by mixing CORM-2 and cross-linked hen egg white lysozyme (CL-HEWL). The half-life of CO release from Ru·CLHEWL was 10 times greater than the half-life of CORM-2 as shown by myoglobin assay. In vitro studies demonstrated that Ru·CL-HEWL, as an extracellular scaffold, was able activate nuclear factor kappa-B (NF-κB) in living cells. Thus, this system holds promise for construction of an artificial extracellular scaffold for CO delivery in biological system. 6.6. Dendrimers. Dendrimers are macromolecules with highly branched and three-dimensional structures that are composed of a series of dendritic wedges that extend outward from the inner core.150−152 Dendrimers have been extensively investigated as nanocarriers for drug delivery owing to their many advantages, such as low polydispersity, high degree of molecular uniformity, precisely controlled structure, and the ability to cross cell membranes.152 Metallodendrimers are dendrimers coordinated to metalcontaining fragments, and have recently been used in biological studies.153,154 The first CO-releasing metallodendrimers (Figure 15), comprised of polypyridyl dendritic scaffolds that are functionalized with a Mn(CO)3 fragment, were described by Govender et al.106 The metallodendrimers-based CORMs show photoCORM activity, and they release approximately 65% of the total number of CO ligands per molecule, as observed using the myoglobin assay. Thus, [Mn(CO)3]-functionalized metallodendrimers represent a new method for the delivery of high-dose CO to biological systems. Overall, not many CO-releasing scaffolds based on macromolecular and inorganic nanoparticles have been reported (Table 2). Among materials explored for CO delivery, polymeric micelles have shown a lot of benefits such as prolonging CO halflive, improving the solubility of CORM, decreasing the toxicity of CORM and exhibiting excellent anti-inflammatory activity both in vitro and in vivo. Inorganic nanoparticles scaffolds such as silica, nanodiamond, iron oxide nanoparticles also showed advantages for the delivery of CO in vivo. It is relatively easy to functionalize inorganic nanomaterials with CORMs and to prepare different nanoparticle morphologies with a good control of size and shapes. Recently, shapes and sizes have been demonstrated to be critical for the cell-uptake and biodistribution.155,156 However, the use of these materials raises concerns regarding their instability in biological media. This problem can be overcome by conjugation with polymers. In addition, the incorporation of inorganic nanomaterials into polymeric systems could confer additional properties. For instance, the attachment of magnetic iron oxide nanoparticles could be employed as imaging contrast agents157−159 or for hyperthermia,160,161 whereas nanodiamond could be employed for bioimaging.162,163 Another material, such protein, has also showed promise for CO delivery. However, protein-based nanocarriers pose problems due to their inability to achieve a sustained drug release because of their rapid clearance.143 It is difficult to ascertain which system is the best for the delivery of CO and which has the best chance of reaching the clinic because the exploration of macromolecular and inorganic nanomaterial for CO delivery is still in its infancy. Perhaps, the use of polymeric systems is a good choice because of their ease of functionalization, better colloidal stability, and lower immune response. In the future, consistent research may facilitate CO-releasing scaffolds based on polymer material for clinical use.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS C.B. acknowledges the Australian Research Council for his Future Fellowship (FT1200096) and UNSW for internal funding.

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ABBREVIATION AcA, acetic acid AP-1, activator protein 1 NF-κB, activate nuclear factor kappa-B ATP, adenosine triphosphate (Al-MCM-41), Al-containing mesostructured materials AAS, atomic absorbance spectroscopy DOI: 10.1021/acsbiomaterials.5b00230 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Review


(3) Mann, B. E.; Motterlini, R. CO and NO in medicine. Chem. Commun. 2007, 43, 4197−4208. (4) Stupfel, M.; Bouley, G. Physiological and Biochemical Effects on Rats and Mice Exposed to Small Concentrations of Carbon Monoxide for Long Periods. Ann. N. Y. Acad. Sci. 1970, 174, 342−368. (5) Amersi, F.; Shen, X.-D.; Anselmo, D.; Melinek, J.; Iyer, S.; Southard, D. J.; Katori, M.; Volk, H.-D.; Busuttil, R. W.; Buelow, R.; Kupiec-Weglinski, J. W. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 2002, 35, 815−823. (6) Günther, L.; Berberat, P. O.; Haga, M.; Brouard, S.; Smith, R. N.; Soares, M. P.; Bach, F. H.; Tobiasch, E. Carbon Monoxide Protects Pancreatic β-Cells From Apoptosis and Improves Islet Function/ Survival After Transplantation. Diabetes 2002, 51, 994−999. (7) Ozawa, N.; Goda, N.; Makino, N.; Yamaguchi, T.; Yoshimura, Y.; Suematsu, M. Leydig cell−derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress. J. Clin. Invest. 2002, 109, 457−467. (8) Morse, D.; Sethi, J.; Choi, A. M. K. Carbon monoxide-dependent signaling. Crit. Care Med. 2002, 30, S12−S17. (9) Otterbein, L. E.; Mantell, L. L.; Choi, A. M. Carbon monoxide provides protection against hyperoxic lung injury. Am. J. Physiol. 1999, 276, L688−694. (10) Morita, T.; Mitsialis, S. A.; Koike, H.; Liu, Y.; Kourembanas, S. Carbon Monoxide Controls the Proliferation of Hypoxic Vascular Smooth Muscle Cells. J. Biol. Chem. 1997, 272, 32804−32809. (11) Barañano, D. E.; Doré, S.; Ferris, C. D.; Snyder, S. H. Physiologic roles for the heme oxygenase products carbon monoxide, bilirubin and iron: links to neuroprotection in stroke and Alzheimer’s disease. Clin. Neurosci. Res. 2001, 1, 46−52. (12) Tschugguel, W.; Stonek, F.; Zhegu, Z.; Dietrich, W.; Schneeberger, C.; Stimpfl, T.; Waldhoer, T.; Vycudilik, W.; Huber, J. C. Estrogen Increases Endothelial Carbon Monoxide, Heme Oxygenase 2, and Carbon Monoxide-Derived cGMP by a Receptor-Mediated System. J. Clin. Endocrinol. Metab. 2001, 86, 3833−3839. (13) Seymour, L. W. Passive tumor targeting of soluble macromolecules and drug conjugates. Crit. Rev. Ther. Drug Carrier Syst. 1992, 9, 135−187. (14) Maeda, H.; Nakamura, H.; Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Delivery Rev. 2013, 65, 71−79. (15) Nakamura, H.; Jun, F.; Maeda, H. Development of nextgeneration macromolecular drugs based on the EPR effect: challenges and pitfalls. Expert Opin. Drug Delivery 2015, 12, 53−64. (16) Torchilin, V. P. Multifunctional nanocarriers. Adv. Drug Delivery Rev. 2012, 64, 302−315. (17) Maines, M. D. Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988, 2, 2557−2568. (18) Stone, J. R.; Marletta, M. A. Soluble Guanylate Cyclase from Bovine Lung: Activation with Nitric Oxide and Carbon Monoxide and Spectral Characterization of the Ferrous and Ferric States. Biochemistry 1994, 33, 5636−5640. (19) Brune, B.; Ullrich, V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol. Pharmacol. 1987, 32, 497−504. (20) Hoshi, T.; Pantazis, A.; Olcese, R. Transduction of Voltage and Ca2+ Signals by Slo1 BK Channels. Physiology 2013, 28, 172−189. (21) Patterson, A. J.; Henrie-Olson, J.; Brenner, R. Vasoregulation at the Molecular Level: A Role for the β1 Subunit of the Calcium-Activated Potassium (BK) Channel. Trends Cardiovasc. Med. 2002, 12, 78−82. (22) Nelson, M. T.; Quayle, J. M. Physiological roles and properties of potassium channels in arterial smooth muscle. Am. J. Physiol. 1995, 268, 799−822. (23) Brenner, R.; Perez, G. J.; Bonev, A. D.; Eckman, D. M.; Kosek, J. C.; Wiler, S. W.; Patterson, A. J.; Nelson, M. T.; Aldrich, R. W. Vasoregulation by the [beta]1 subunit of the calcium-activated potassium channel. Nature 2000, 407, 870−876.

BK, big potassium CORMs, CO-releasing molecules CO, carbon monoxide MbCO, carbonmonoxy myoglobin COHb, carboxyhemoglobin COPD, chronic obstructive pulmonary disease JNK, c-Jun N-terminal kinase CuAAC “click” reaction, Copper-catalyzed azide−alkyne 1,3dipolar cycloaddition CL-HEWL, cross-linked hen egg white lysozyme CYP, cytochrome P450 cGMP, cyclic guanosine monophosphate deoxy-Mb, deoxy-myoglobin DSS, dextran sulfate sodium EPR, enhanced permeability and retention EDX, energy-dispersive X-ray ET-CORMs, enzyme-triggered CORMs ECM, experimental cerebral malaria FDA, Food and Drug Administration FTIR, Fourier transform infrared spectroscopy HO, heme oxygenase HEWL, hen egg white lysozyme H2S, hydrogen sulfide ICP-AES, inductively coupled plasma-atomic emission spectroscopy ICP-OES, inductively coupled plasma-optical emission spectroscopy IR, infrared spectroscopy IL-6, interleukin-6 IONP, iron oxide nanoparticles I/R, ischemia/reperfusion LC-MS, liquid chromatography mass spectrometry NP, maghemite nanoparticles MOFs, metal−organic frameworks (MAPK, mitogen-activated protein kinase MCP-1, monocyte chemotactic protein-1 HPMA, N-(2-hydroxypropyl) methacrylamide ND, nanodiamond NIR, near infrared NADPH, nicotinamide adenine dinucleotide phosphateoxidase NO, nitric oxide PA, peptide amphiphiles SMA, Poly(styrene-alt-maleic acid) copolymer PAH, pulmonary arterial hypertension pqa, (2-pyridylmethyl)(2-quinolylmethyl)amine) ROS, reactive oxygen species RAFT, reversible addition−fragmentation chain transfer SEM-EDX, scanning electron microscopy coupled with energy dispersive X-ray sGC, soluble guanylyl cyclase TLR4, toll-like receptor 4 3D, three-dimensional TEM, transmission electron microscopy TNF-α, tumor necrosis factor-α UHV-FTIR, vacuum Fourier transform infrared spectroscopy

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