Carbon Monoxide and Its Controlled Release - American Chemical

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Carbon Monoxide and Its Controlled Release: Therapeutic Application, Detection, and Development of Carbon Monoxide Releasing Molecules (CORMs) Miniperspective Ken Ling,†,‡,# Fang Men,§ Wei-Ci Wang,⊥,# Ya-Qun Zhou,∥,# Hao-Wen Zhang,† and Da-Wei Ye*,† †

Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China § College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China ⊥ Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ∥ Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ‡

ABSTRACT: Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.

1. INTRODUCTION

antihypertensive, vasodilative, antiatherogenic, and cytoprotective effects.4,5 Carbon monoxide is endogenously produced via the breakdown of heme, which is catalyzed by a family of enzymes known as hemeoxygenases (HOs). In a tightly controlled manner, the porphyrin IX ring of heme collapses in the presence of the cofactors NADP and O2 to yield CO, Fe2+, biliverdin IX (first step product), and bilirubin IX (second step product)6 (Figure 1). Approximately 16 μmol CO/h is produced by this route in a healthy human. HO has been thoroughly studied by many researchers, and three isoforms of this enzyme have been identified: HO-1, HO-2, and HO-3. HO-1 is an inducible isoform triggered by free heme molecules and carries out heme decomposition. It is mainly found in the spleen and the liver. HO-2 and HO-3 are constitutively expressed and mainly found in the brain and testes.6 Ample evidence has demonstrated that the dysfunction of HOs and associated metabolic processes may be linked to various diseases.6−8 One study also claimed that heme oxygenase

At temperatures above −190 °C, carbon monoxide (CO) is an odorless and colorless gas that is produced by insufficient oxidation among carbon-containing compounds, which is typically caused by a lack of oxygen. CO has great affinity to hemoglobin, a protein tuned to remove CO from circulation, which is approximately 220 times stronger than the affinity between oxygen and hemoglobin, thereby resulting in the formation of carboxyhemoglobin1 (COHb). Some studies claimed that high levels of COHb lacked proper oxygen transport capacities and once it occupied up to 50−60% of the total hemoglobin, coma, convulsions, respiratory depression, and other fatal consequences may follow.2 Thus, a negative stigma is attached to CO. However, an extraordinary study led by Goldbaum et al.3 suggested that a high concentration of COHb does not necessarily interfere with the oxygen-carrying ability of the blood. CO shares similar properties with the gas messenger molecules hydrogen sulfide (H2S) and nitric oxide (NO), and low concentrations of CO have received increasing attention as a cell-signaling molecule that exhibits pleiotropic biological functions, including anti-inflammatory, antiapoptotic, © 2017 American Chemical Society

Received: July 31, 2016 Published: September 6, 2017 2611

DOI: 10.1021/acs.jmedchem.6b01153 J. Med. Chem. 2018, 61, 2611−2635

Journal of Medicinal Chemistry

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Motterlini et al.17 first addressed the use of CO-releasing molecules (CORMs) as proper pharmaceutical agents and investigated the first generated CORMs: transition-metal carbonyl complexes 1 (CORM-1) and 2 (CORM-2) (see Table 1). The use of these molecules as CO-donating reagents improves the efficiency, safety, and delivery of CO. Diverse compounds can be used as CORMs, including organometallic compounds,18 oxalates, aldehydes, boranocarboxylates, unsaturated cyclic α-diketones,137 xanthene-9-carboxylic acid (XCA), and silacarboxylates. Organometallic compounds, such as metal carbonyl complexes that present a transition metal core, have gained increasing popularity because they present several advantages: structural diversity for tunable chemistry; natural variations and different oxidation states of the metal center; variations in the number of carbonyl ligands and nature of the coligands and the outer coordination sphere; distinct spectroscopic features that are convenient for tracking and detection because of the presence of essential trace elements, such as manganese, iron, cobalt, tungsten, ruthenium, and rhenium.18

Figure 1. Heme degradation. Heme (Fe2+ protoporphyrin IX) is degraded to carbon monoxide (CO), ferrous ions (Fe2+), and biliverdin IX catalyzed by heme oxygenase. Then a following step catalyzed by biliverdin reductase yields bilirubin IX.

2. THERAPEUTIC USE OF CO AND CORMS Since the initial discovery of the relationship between CO and HO metabolic pathways, CO has been underestimated as merely a “byproduct” of these pathways. Only recently has this diatomic molecule been rerecognized as a gasotransmitter and, along with its carriers, considered as potential therapeutic agents. CO and CORMs produce cytoprotective effects and restore homeostasis mainly by modulating inflammation, cellular proliferation, and apoptosis1 as demonstrated in multiple preclinical models. Herein, we briefly describe these therapeutic and biological effects in six clinical indications (Figure 2) and list these preclinical data in a well-scheduled comprehensive table (Table 1). 2.1. Inflammation. Many animal models of inflammatory diseases and several phase II clinical trials19,20have corroborated the anti-inflammatory properties of CO and CORMs. These anti-inflammatory properties are mediated by the involvement of mitogen-activated protein kinase (MAPK) related signaling pathways,21 c-Jun N-terminal kinase (JNK) pathways, and activator protein 1 (AP-1).22 Moreover, the mitochondria respiratory chain23 has been reported to play a central role in this effect. For example, in a mouse experimental cerebral malaria (ECM) model8 in which plasmodium infected the brain and aroused an inflammatory cascade in the nearby tissue, inhaled CO administration 3 days after the plasmodium infection significantly prevented mouse brain edema and increased the survival rate, whereas the control group suffered heavy casualties. The use of CO and its carriers may represent a potential treatment for inflammatory disorders, such as rheumatoid arthritis and osteoarthritis, and a study has shown that the intraperitoneal administration of 3 (CORM-3) to mice with collagen-induced arthritis significantly alleviated the clinical and histopathological manifestations of the disease.24 Treatment with 3 inhibits the expression of synergistic inflammatory factors, such as interleukin 1β (IL-1β), IL2, IL6, IL10, prostaglandin-2 (PGE-2), and tumor necrosis factor α (TNFα), as well as cyclooxygenase 2 (COX-2), intercellular adhesion molecule 1 (ICAM-1), and the receptor activator of nuclear factor κB ligand (RANKL). Moreover, 3 lowers cellular infiltration and mitigates cartilage destruction. In septic mice models in which cecal ligation and puncture (CLP) were performed to induce sepsis,25−27 the admin-

signaling pathway products are important factors in modulating the risk of cardiovascular disease.9 Once CO has diffused across tissue, it activates soluble guanylyl cyclase (sGC) via a reaction with its heme moiety, resulting in the production of cyclic guanosine monophosphate (cGMP).10 cGMP then acts as a second messenger for a plethora of cellular function signals, such as vasodilation and platelet aggregation inhibition.11 Recent studies on the conformational changes of sGC activation showed that there is a heme in every β subunit of sGC with propionate groups showing intertwined Tyr-X-Ser-X-Arg sequences (X can be any amino acid).12 This heme usually coordinates with His ligands in the iron center and binds CO transiently to peel off the His residue, thus creating a pentacoordinated sCG10 and switching on its biological effects. The non-cGMP pathway has been the subject of increasing investigation because CO stimulates largeconductance voltage-gated K+ channels, which are referred to as BK (big potassium) channels,13−15 via the non-cGMP pathway and initiates hyperpolarization of the membrane. Another channel, the ion cardiac L-type Ca2+channel, confers CO cardioprotective properties.16 As stated above, although CO possesses promising therapeutic properties, clinical applications of inhaled CO are severely hampered because of the difficulty in storing and delivering gaseous CO. Moreover, as a result of great affinity between CO and hemoglobin, high COHb concentrations are needed to allow small amount of CO to leave the circulation and enter tissues in need, thus putting a thermodynamic constraint for the use of CO gas. The total lack of tissue specificity and targeting of COHb transport also raises concerns for utilization of gaseous CO. Moreover, the exact respiratory function and hemoglobin level of patient will largely interfere with the therapeutic effects of CO inhalation. The ideal clinical therapeutic agent is a nontoxic, easy-ambulant, and highly biocompatible molecular entity that releases low doses of CO that can be dispersed in a controlled manner at predetermined location and time and keep the values of COHb in circulation to baseline values (≤5% COHb). 2612



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Table 1. Preclinical Efficacy of Inhaled Carbon Monoxide, Carbon Monoxide-Releasing Molecules (CO-RMs), and Genetic Modulation of HO-1 models of disease Experimental cerebral malaria (ECM) in mice Collagen-induced arthritis (CIA) in mice Sepsis in mice

inhaled CO effect

CORM effect

genetic modulation of HO1 expression effect

ref

250 ppm started 3 days after parasite infection prevented cerebral injury

Not tested

Not tested

8

Not tested

CO-RM3 administered once a day from days 22 to 31 reduced joint inflammation and erosion in CIA. CO-RM3 prevented sequelae of sepsis; CORM2 prolonged survival and reduced inflammation; CO-RM2 reduced liver injury after CLP. Not tested

Not tested

24

Not tested

25−27

Not tested

28

Not tested

29−31

Not tested

32

HO1 induction upregulated anti-inflammatory activity via regulating the balance between Th17 and Treg cells. Induction of HO-1 by cobalt protoporphyrin IX (CoPPIX) administration after EAE onset reversed paralysis and disease relapse.

33

34, 35

Not tested

36

Not tested

Not tested

19, 37, 38

Not tested

Not tested

39

CORM-A1 administration at a dose of 2 mg/kg ip for 14 days showed ameliorated course of EAU. CO-RM1 had anti-inflammatory effects in the mesentery in response to carrageenan.

Not tested

40

Not tested

41

Induction of HO-1 by CoPP administration (2 mg/kg) once weekly for 6 weeks improved insulin sensitivity, downregulated the peripheral endocannabinoid system, and remodeled adipose tissue Not tested

42

56

Not tested

46, 47

Not tested

48−51

Not tested

52, 53

50−250 ppm had anti-inflammatory effects; 10−250 ppm as a pretreatment or as a post-treatment improved survival in lung and liver injury in response to LPS

LPS-induced acute lung injury in pigs Postoperative ileus in mice

250 ppm ameliorated lung derangement by endotoxin and suppressed inflammation Not tested

Chronic colitis in mice Dextran sulfate sodium induced acute colitis in mice

250 ppm given continuously from weeks 8−12 of life prevented colitis and inflammation Not tested

Experimental autoimmune encephalomyelitis (EAE) in mice

450 ppm continuously for 30 days, reversed paralysis and suppressed autoimmune neuroinflammation

Sickle cell disease in mice Pulmonary hypertension in rats and mice Asthma and airway hyper-responsiveness in mice Experimental autoimmune uveoretinitis (EAU) Carrageenan-induced mesenteric inflammation in mice Obesity-induced diabetes in rats

250 ppm for 1 h per day, 3 times a week for 10 weeks prevented leukocyte infiltration and vaso-occlusion 250 ppm, 1 h per day beginning at peak hypertension reversed right heart size and pulmonary artery pressure; 50 ppm for 21 days prevented pulmonary hypertension 250 ppm 1 h per day given to ovalbumin-sensitized mice prevented methacholine-induced bronchoconstriction and airway inflammation Not tested

Not tested

Not tested

Autoimmune (type 1) diabetes in rats

Not tested

Lung transplantation in rats and mice; IRI in rats and mice Kidney transplantation in pigs and rabbits and rats; kidney transplantinduced IRI in pigs Liver transplantation and preservation in rats

250 ppm prevented chronic rejection, IRI, and apoptosis

CORM-A1 conferred protection from diabetes in MLDS-induced mice and reduced diabetes incidence in NOD mice as confirmed by preserved insulin secretion and improved histological signs of the disease. Not tested

Not tested

University of Wisconsin (UW) solution with soluble CO prevented transplant-induced renal IRI in pigs; 40 μM soluble CO in UV solution prevented cytochrome P450 degradation and IRI of rat kidney grafts

CO-saturated blood improved liver function after transplantation

CO-RM3 (40 mg per kg, intraperitoneally) in mice before ileus reduced intestinal muscalaris inflammation. Not tested Not tested

Prophylactic administration of CORM-A1 (2 mg/kg in a final volume of 200 μL improves the clinical and histopathological signs of EAE, indicated by a reduced cumulative score, shorter duration and a lower cumulative incidence of the disease as well as milder inflammatory infiltrations of the spinal cords. Not tested

Proper dose of CORM-3 (50 and 100 μM) restored renal blood flow (RBF) and improved renal function indexes; 50 μM CORMA1 and CORM3 improved renal function after cold storage and reperfusion. CORM3 (50 μM) in preservation solution improved hepatic function after transplantation.

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Table 1. continued models of disease

inhaled CO effect

CORM effect

genetic modulation of HO1 expression effect

ref

Small intestine transplantation and IRI Pancreatic islet cell transplantation Myocardial infarction in mice and cardicac IRI in rats

250 ppm prevented transplant-induced paralytic ileus; COsaturated preservation solution prevented IRI; 250 ppm prevented rejection 250 ppm improved islet cell survival

Not tested

Not tested

54

Not tested

Not tested

55, 56

250−1000 ppm after injury prevented infarct mass induced by left anterior descending artery ligation

Not tested

57, 58

Cigarette smoke-induced vascular injury in rats

Not tested

CO-RM3 reduced injury from myocardial infarction; 25 and 50 μM CORM-3 significantly reduced the incidence of ventricular fibrillation (VF) and tachycardia (VT). Not tested

60

Angioplasty trauma in rodents and pigs; vascular access graft hyperplasia in pigs

250 ppm for 1 h before injury prevented stenosis and enhanced re-endothelialization; pre-exposure to 250 ppm of CO before injury suppressed stenosis after carotid balloon injury in rats as well as in mice; 250 ppm for 2 h induced early thrombolysis and countered intimal hyperplasia after vascular

CO-RMA1 administered 1 h before injury enhanced re-endothelialization.

Microbial infection in mice

250 ppm improved survival rate and prevented multiple-organ failure when administered after Gram-positive or -negative bacteria infection

Hepa129 cells induced hepatocellular carcinoma in mice livers

Not tested

CORM3,ALF062 and CORM2 increased survival and antimicrobial response; Trypto-CORM showed potent antibacterial effects against Escherichia coli. Not tested

Induction of HO1 activity by hemin ameliorated oxidative damage in vascular cells and HUVECs caused by cigarette smoking Upregulation of HO1 expression by hemin dropped vascular occlusion rate. Adenovirus transfected HO1 upregulation inhibited thrombus formation. Not tested

Mice injected with prostate cancer (PC3) cells

250 ppm for 1 h per day for 20 weeks inhibited growth of human prostate cancer xenografts (a possible noxious result of long CO exposure time)

Not tested

Pancreatic, ovarian, urothelial, and colon carcinomas in mice and rats CD1 athymic mice xenotransplanted with pancreatic cancer cells Aspirin/clopidogrel induced platelet inhibition and tissue-type plasminogen activator (tPA) induced fibrinolysis in rabbit

Not tested

Not tested

500 ppm for 24 h inhibited tumor proliferation and microvascular density of xenotransplanted tumors

CORM2 treatment (5 mg/kg per day) for 3 days inhibited tumor proliferation and microvascular density of xenotransplanted tumors. Addition of 100 μmol/L CORM2 to rabbit plasma significantly improved coagulation. Addition of 200, 400, and 600 μmol/L CORM2 significantly improved coagulation and attenuated fibrinolytic bleeding. Bleeding time significantly decreased after administrated CORM2 (10 mg/kg; 279 μmol/L) intravenously. Administration of CORM2 increased velocity of thrombus formation and increased clot strength.

Plasma of different coagulopathy patients

Not tested

Not tested

61−64

68−76

Small interfering RNA (siRNA) silencing of HO1 expression led to lowered tumor growth rate, reduced cell proliferation, migration, and angiogenesis. Silencing the HO1 gene by OB-24 inhibited prostate tumor growth and metastases in lymph nodes and lung. HO1 inhibition by ZnPP suppressed proliferation and invasion of these tumors. Not tested

86

Not tested

94, 95

Not tested

98−100

78

79, 80

81, 82

with bowel motility dysfunction. Postoperative ileus mice treated with 3, 4 (CORM-A1), or CO gas showed the restoration of intestinal contractility and peristalsis. Hegazi et al.32 confirmed the therapeutic use of CO in IL-10-deficient (IL-10(−/−)) mice with established T helper (Th) 1 mediated chronic colitis. In their study, CO administration prevented intestinal inflammation by inhibiting interferon γ (IFN-γ), IL12, and IFN regulatory factor 8 (IRF-8) expression in murine macrophages. A recent study performed by Zhang and colleagues33 also highlighted the therapeutic use of HO-1 in dextran sulfate sodium-induced acute murine colitis, an inflammatory bowel disease that presents inflammatory changes in the gastrointestinal tract. The induction of HO-1 weakened

istration of CO gas, 2, or 3 attenuated the migration and accumulation of polymorphonuclear leukocytes and neutrophils and inhibited the production of nuclear factor κB (NF-κB), ICAM-1, and reactive oxygen species (ROS). Most importantly, these CO carriers increased the survival rate in septic mice, which might imply the potential of these molecules for preventing lethal sepsis in human patients. Similarly, a pretreatment with 250 ppm of CO in lipopolysaccharide (LPS) induced acute lung injury pig models prevented respiratory derangement and ameliorated several acute pathological changes induced by endotoxic shock.28 CO and CORMs also have therapeutic relevance to postoperative ileus,29−31 a common complication after abdominal surgery 2614



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Figure 2. Therapeutic activity of CO and CORMs.

abdominal cavity. The kidneys that were bubbled with CO gas in their UW solutions revealed higher survival rates and less tubular fibrosis nidus or infiltrates. These results indicated the potential of using CO gas and CORMs as protective adjuvants in organ preservation solutions as complement to the current cold storage procedure. Similarly, in a rabbit kidney transplantation case,50 kidneys that were flushed with 3 or 4 displayed better renal function indexes and respiratory control indexes. Interestingly, this protective effect was blocked in the presence of a GC inhibitor, suggesting that CO performed its biological role via the GC-cGMP pathway as previously mentioned.10 Cytochrome P450 (CYP450) has long been connected to IRI prevention by CO and appears to be stabilized by CO. A renal graft model produced by Nakao et al.51 suggested that CO binding to the heme moiety of CYP450 was able to block CO degradation and the subsequent release of iron from heme, which leads to ROS formation. This lowered peroxidation significantly contributed to IRI prevention. 2.3. Cardiovascular Disease. The introduction of HO-1/ CO/CORMs has provided considerable benefits to cardiovascular disease treatment. For example, in a mouse coronary artery occlusion model,57,58 groups subjected to the intravenous infusion of 3 and exogenous exposure of CO showed a smaller myocardial infarct size, and a subsequent study using isolated rat hearts59 exhibited a significant reduction in the incidence of reperfusion-induced ventricular fibrillation (VF) and tachycardia (VT). The HO-1/CO system also demonstrated its cardioprotective role in a HO-1-deficient mice abdominal aortic transplantation model.44 In this study, HO-1-deficient aortic allograft recipients all died within 4 days of transplantation because of severe arterial thrombosis; however, treatment with 2 significantly improved the survival rate (62% of the animals survived more than 56 days) and reduced the platelet aggregation in the graft, confirming the antiaggregatory properties of CO mentioned above. Another cigarette smoke rat model60 also verified the antioxidant role of HO-1. In a recent study led by Suliman et al.,61 manipulation of HO-1/CO and utilization of 5 (B12-ReCORM-2) to enhance mitochon-

the symptoms of colitis, equilibrated the balance between T helper 17 (Th17), and regulatory T (Treg) cells, and exhibited excellent anti-inflammatory abilities. The anti-inflammatory efficacy of CO has been observed in mice models of experimental autoimmune encephalomyelitis (EAE),34 which mimics multiple sclerosis (MS) symptoms, including CNS demyelination and paralysis. In addition, the induction of HO-1 and exogenous administration of CO were found to reverse paralysis and disease relapse characterized by a dysregulated immune response,35 suggesting that CO ameliorates autoimmune neuroinflammation and has potential applications as a therapeutic approach to treating MS. CO gas and CORMs have exhibited therapeutic potential in several models of disease related to inflammatory processes, including sickle-cell anemia,36 COPD,19,37,38 asthma and airway hyper-responsiveness,39 experimental autoimmune uveoretinitis (EAU),40 carrageenan-induced mesenteric inflammation,41 and diabetes.42 2.2. Organ Transplantation and Preservation. The application of CO and CORMs in a medical context has achieved considerable progress in organ transplantation,1 including the heart,43−45 lung,46,47 kidney,48−51 liver,52,53small intestine,54 and pancreatic islet.55,56 In addition, these applications were beneficial throughout the transplantation process, including benefits to the donor, the organ, and the recipient. One profound example of therapeutic CO use is observed with heart transplantation in rodents.43 Cardiac allograft survival is prolonged with either environmental CO exposure or 3 administration each day for 8 days. CO and CORMs have been reported to function as organ protectants by reducing ischemia/reperfusion injury (IRI) during organ transplantation. In a study in which porcine kidneys underwent a 10 min warm ischemia and 18 h of cold storage, treatment with 3 restored renal blood flow (RBF) and improved renal function indexes, such as the glomerular filtration rate (GFR) and creatinine clearance rate (CCR).48 A similar result was found in a model of porcine kidney autotransplantation49 in which excised pig kidney grafts were cold flushed and stored in UW solution for 2 days and then transplanted back into the 2615



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low concentrations, HO-1 activation and CO synthesis in tumor cells were cytoprotective, proangiogenic, and proproliferative, which might be attributed to CO’s role as a gasotransmitter. However, at high levels, CO exerts antitumor effects, which are likely the result of its systemic toxicity. Generally, the physiological dose of CO produced via tumor cells or tumor-infiltrating macrophages often incurs protumor effects, which makes HO-1 an excellent antitumor target with relatively mild side effects. HO-1 overexpression has been demonstrated in many tumor types, such as prostate cancer, pancreatic cancer, Kaposi sarcoma, and melanoma.78 Such HO1 activation contributes to the proper function and progression of tumor cells. For example, in a mouse model of orthotopic hepatocellular carcinoma growth,79 silencing of HO-1 expression by small interfering RNA (siRNA) led to lowered tumor growth rates, cell proliferation, migration, and angiogenesis. A similar result was observed in an immune-deficient mouse model of a prostate tumor, in which short hairpin RNA (shRNA) diminished HO-1 expression.80 The excellent tumor suppression effects of HO-1 inhibitors confirm the oncogenic features of CO. For instance, the introduction of the HO-1 inhibitor ZnPP IX into rodent models of pancreatic, ovarian, urothelial, and colon carcinoma cells inhibited the proliferation and invasion of these tumors.81,82 Another small-molecule HO1 inhibitor, 2-[2-(4-bromophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane hydrochloride (OB-24), limited advanced prostate cancer growth and metastasis in mice.80 Interestingly, administration of this compound along with paclitaxel (Taxol) therapy showed improved antitumor effects, indicating that the HO-1/CO system might be an applicable target for chemotherapy for tumor control. Currently, many new HO-1 inhibitors are emerging, such as tin mesoporphyrin (SnMP) and polyethylene glycol (PEG)-ylated ZnPP.83 Additional studies are required to verify these inhibitors as candidates for clinical repurposing for cancer. However, the protumor effects of HO-1/CO might be highly dependent on the tumor type because HO-1 knockdown has been indicated to cause weakened tumor growth.84,85 HO-1 inhibition techniques should be applied only to tumors that express HO-1 and use “CO to create a nourishing local environment”.77 However, most HO-1 inhibitors lack proper selectivity and therefore can induce off-target pharmacological actions other than HO-1 inhibition. Moreover, HO-1 functions as more than just a CO generator by modulating cellular levels of bilirubin and heme, which would lead to changes in the cellular redox status.1 At relatively high concentrations or over long exposure time, inhaled CO or CORMs or HO-1 overexpression could be noxious to tumors. In a CD1 athymic mouse model implanted with Capan-2 pancreatic cancer cells,86 500 ppm of CO inhalation for 1 h a day or 35 mg−1 kg−1 day−1 intraperitoneal injections of 2 significantly hindered cancer cell growth rates and the corresponding angiogenesis. Similar antitumor effects of CO or CORMs have been reported,87 and their underlying mechanisms might be linked to mitochondria activity exhaustion via the acceleration of oxygen consumption, generation of mitochondrial ROS, inhibition of cellular protein synthesis, collapse of tumor cell mitochondria, and reduction of cell viability.87 Nevertheless, these preclinical data may not be clinically applicable because high levels of CO may also harm normal tissue.88 2.6. Coagulation and Fibrinolysis. The impacts of exogenous and endogenous CO exposure on clotting responses

drial biogenesis indicated a direct pathway to embryonic stem (ES) cell differentiation and maturation into energetically efficient cardiomyocytes. This capacity to augment cardiomyogenesis contributed greatly to functional cardiac repair and ameliorated degenerative cardiac diseases. More importantly, CO and its carriers have shown impressive homeostatic effects in vascular proliferative diseases. In multiple animal models,62−64 HO-1/CO/CORMs arrested the hyperproliferation of vascular smooth muscle cells, which weakened intimal hyperplasia, suppressed arteriosclerotic lesions,64 and facilitated re-endothelialization.65 In addition, a CO benefit was indicated in a more clinically serious case of pulmonary arterial hypertension (PAH) that resulted from excess intimal/medial hyperplasia in the pulmonary arterioles and led to pulmonary artery remodeling and right heart hypertrophy. In rodent models with induced PAH,37 inhaled CO restored right ventricular and pulmonary arterial pressure and pulmonary vascular architecture to near normal. These cardioprotective properties might be attributed to the mediation of the cGMPdependent pathway, BK channel, ion cardiac L-type Ca2+channel, and p38 MAPK and inhibition of CYP450.58,66,67 2.4. Microbial Infection. CO and certain CORMs, such as 3, have shown antimicrobial potential against diverse microorganisms,68 including Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli or Pseudomonas aeruginosa69−71) bacteria. CO acts as a bactericide by cutting off adenosine triphosphate (ATP) supplies in bacteria and inhibiting the respiratory chain.72 Additionally, CO facilitates phagocytosis and acts as a bactericide against Escherichia coli via the p38-mediated surface expression of Toll-like receptor 4 (TLR4)73 and activation of host immune responses.27 The potent bactericidal effect of CORMs might be derived from their metal cores. A recent study74 reported that in Escherichia coli, CORMs, such as 2 and tetraethylammonium molybdenum pentacarbonyl bromide (ALF062), improved cellular oxidative stress by ROS generation and caused DNA lesions in bacteria. Another study introduced a well-designed tryptophan-derived manganese-containing complex (Trypto-CORM),75 the first visible-light-activated CORM exhibiting potent antibacterial effects against Escherichia coli. This thermally stable CORM only releases CO and tryptophan in the presence of visible light (1.4 mol of CO at 465 nm, and 2 mol at 400 nm) and shows low toxic profile against mammalian cells. Recently, an astonishing study76 showed the antibacterial and antiparasitic activity of manganeseI tricarbonyl complexes with ketoconazole (ktz), miconazole (mcz), and clotrimazole(ctz) ligands.The general formula of these complexes is [Mn(CO)3(bpyR,R)(azole)]PF6 (R = H, COOCH3), and the clotrimazole (ctz) complex shows submicromolar activity on Staphylococcus aureus and S. epidermidis with minimal inhibitory concentration (MIC) values of 0.625 μM. The antileishmanial potential of the ctz complex is relatively low due to toxicity on mammalian cell lines 293T and J774.1. These complexes also have promising antitrypanosomal effect, and the most potent one is the complex with ktz ligands, which has an IC50 value (half maximal inhibitory concentration) on Trypanosoma brucei of 0.7 μM with selectivity on parasitic over mammalian cells as indicated by a selectivity index above 10. This study also showed that biological activity and medicinal applications of pre-existing drugs can be significantly improved with proper metal coordination. 2.5. Cancer. Intriguingly, the role of HO-1/CO in cancer experimental therapy has been shown to be dichotomous.77 At 2616



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investigation to determine whether morbidly obese patients undergoing bariatric surgery showed increased endogenous CO production and plasmatic hypercoagulability. The results indicated that the plasma coagulation kinetics of these bariatric patients was obviously upregulated and the COHb concentration and carboxy heme fibrinogen (COHF) formation were increased. In addition, increased HO activity was found in the adipocytes of the obese patients. One intriguing aspect of CO is its role in modulating plasmatic coagulation in Alzheimer’s disease (AD). This intractable disease has been postulated to have multiple etiologies. A recent study102 claimed that the pathogenesis of AD may be caused by spontaneous cerebral emboli caused by thrombi ultrastructural changes modulated by endogenous CO and increased HO activity. As for the ultrastructural changes in the thrombi, researchers have analyzed scanning electron microphotographs of platelets obtained from several human disease states103,104 that exhibit increased endogenous CO expression. These images illustrated that thin fibrin polymer formation and matting had increased, which is consistent with enhanced clot strength. However, whether CO attenuates or exacerbates thrombophilic disease remains unclear and requires further investigation. A possible reason for the lack of clarity surrounding the actions of CO in thrombophilic disease is the ability of CO to act as either an anticoagulant or a procoagulant depending on the situation and species,89 and the effect of these species-specific differences on thrombi ultrastructure, plasmatic coagulation kinetics and hemostatic responses is not well understood. Previous research has shown that CO and CORMs have a large library of biological and therapeutic effects. To better understand and evaluate these displayed effects, research should be focused on CO release detection and the chemistry and synthesis of CORMs, which will be described later.

and hemostasis have always been a controversial topic. Considerable preclinical data have indicated that CO has two disparate biological effects: anticoagulation and procoagulation.89 Evidence has shown that CO leads to weakened hemostasis in humans and rodents in vivo and in vitro via the inhibition of platelet aggregation,11 whereas other studies have claimed that increased CO exposure contributes to platelet activation, thereby enhancing coagulation and inhibiting fibrinolysis in humans and other mammalian species by activating the associated plasma proteins.90 A number of studies utilizing rodent models have demonstrated antiplatelet or profibrinolytic effects in vitro and in vivo. Using a rat model with electrical carotid injury induction and thrombus formation, Desbuards et al.91 demonstrated that the upregulation of HO-1 expression by hemin, a HO-1 inducer, effectively inhibited vascular occlusion rates. In another hypercholesteremic mice model with carotid angioplasty induction, adenovirus-transfected HO-1 upregulation or CO inhalation inhibited thrombus formation and arterial plasminogen activator inhibitor 1 (PAI-1) expression.92 Similar results were shown in the aforementioned mice allogeneic aortic transplantation model,44 and in another study, a new class of cis-ReII-dicarbonyl-vitamin B12 complexes have been shown to be antiplatelet with tunable CO releasing abilities.93 All this evidence showed decreased platelet aggregation and was dependent on cGMP pathway; however, in certain in vivo human studies,94 CO exposure or CORM administration inhibited the release of adenine diphosphate and serotonin from platelets and inhibited calcium entry94 into human platelets. Evidence demonstrating the procoagulant and antifibrinolytic effects of CO has also emerged. Preclinical animal models have shown that CO enhanced coagulation and attenuated fibrinolysis. For example, in a rabbit model with aspirin/ clopidogrel-induced platelet inhibition,95 the intravenous administration of 2 (10 mg/kg) to sedated rabbits decreased their ear bleeding time back to the baseline level. In a similar model where the rabbits were injected with tissue-type plasminogen activator (t-PA),96 which is a strong facilitator of fibrinolysis, animals administered 2 showed bleeding times that were several-fold shorter than those of untreated animals. Evidence associated with the human clotting system has drawn intense attention. Nielsen and co-workers97 reported that when human plasma was exposed to 2, the velocity of thrombus formation and the strength of the final clot increased. Similarly, a series of studies were launched in which the plasma samples of different coagulopathy patients were administered 2, and they all showed increased clot formation velocity and strength. Plasma samples were obtained from different types of patients, including patients with hemophilia A or B, patients administered heparin/argatroban/warfarin/protamine,98 patients subjected to hemodilution with either crystalloid or colloidal solutions,99 and patients subjected to cardiopulmonary bypass.100 CO was shown to attenuate coagulopathy caused by these multiple etiologies. Recently, increasing clinical evidence has demonstrated CO’s procoagulant role. For instance, patients with left ventricular assist devices (LVAD) are associated with thrombophilia despite anticoagulation. Blood samples from LVAD patients were obtained a month or more after LVAD implantation, and CO enhancement of coagulation was observed in most of them.101 Morbid obesity is associated with significant thrombophilia. In 2015, Nielsen et al.101 conducted an

3. DETECTION OF CO RELEASE Accurate and dependable methods of measuring and adjusting CO-release rates in CORMs are required, and quantifying such processes may be dependent on the assay solution or the temperature, O2, or light conditions. Assays have been established to detect the release of CO, such as gas chromatography, laser infrared absorption, colorimetric CO sensing, and electrochemical assays.105,106 To date, the deoxymyoglobin carbonylation assay has been widely used to quantify CO release.107,108 In this assay, reduced deoxymyoglobin, which absorbs light at 557 nm in absorbance spectroscopy, reacts with CO from CORMs to form carbonmonoxy myoglobin (MbCO). Two new absorption bands of MbCO increase at 540 and 577 nm, while the former absorption at 557 nm decreases and eventually disappears. Thus, this process can be monitored and quantified with spectrophotometers. However, to be reliable, this assay requires the separation of reduced deoxymyoglobin from excess reducing agent, usually sodium dithionite, before it is incubated with the CORM solution. For example, sodium dithionite was reported to be responsible for the accelerated release of CO from 2 and 3.106 In the absence of sodium dithionite neither of these CORMs reacts with deoxymyoglobin. Additionally, the turbidity of low-solubility CORMs may hinder the measurement of MbCO concentrations.109 Fairlamb et al.109 recently improved this assay with two modifications: a “contrast test” utilizing added and void myoglobin into assays in parallel; four isosbestic points (510, 550, 570, and 585 nm) in the ultraviolet−visible (UV−vis) 2617



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Table 2. Compilation of Sensor-Based Methods Applied for CO Detection

spectrum. The effects of these modifications remain to be examined, although McLean’s oxyhemoglobin assay,106 which has a similar design but does not include sodium dithionite, is an efficient method of detecting CO release. The binuclear rhodium complex [Rh 2 (C 6 H 4 PPh 2 ) 2 (O2CHCH3)2]-(HAc)2 has been reported to provide a robust, selective, and sensitive alternative to detecting CO.110 There are two cyclometalated phosphine ligands in this structure. CO

displacement of acetic acids triggers a quick and remarkable color change from purple to orange to yellow, which is both visible (even at the concentration of 0.2 ppm in air) and reversible. Unfortunately, these rhodium compounds are soluble only in organic solvents, such as chloroform, which impedes the real-time detection of CO release in vivo. Fluorescent probes have also been developed for CO detection; we can find access to these probes in many recent 2618



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Table 3. Major Chemical and Biological Properties of CORMs

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Table 3. continued

studies.111−113 Further, one assay with a biosensor and another with an organometallic palladium complex as a probe have been introduced to living cell CO release assessments. On the basis of a metal-mediated carbonylation reaction, COP-1, a cyclopalladated probe,114 quenches the fluorescence of its borondipyrromethene difluoride (BODIPY) core by heavy-atom electronic effects. After the invasion of the CO molecule, an immediate carbonylation reaction occurs and releases Pd0 and a BODIPY dye, and the release of BODIPY activates high fluorescence signals. In the presence of CO, the fluorescence intensity experiences a 10-fold enhancement, which is concentration-dependent and has a 1 μM CO detection minimum. Moreover, the palladium probe is biocompatible and shows low toxicity; however, an hour is required to reach the peak fluorescence enhancement. The other approach, which was established by Wang et al.,115 uses an iron-containing heme protein COSer as a fluorescent probe. This biosensor has two main elements: yellow fluorescent protein (YFP), which provides the fluorescence, and CooA, which is a CO-sensing hemeprotein dimer extracted from Rhodospirillum rubrum. Once exposed to CO, the long C helix of CooA pivots between Phe132 and Asp134, which binds CooA to DNA and initiates transcription of the coo operon. Once this reaction occurs, YFP shows a 2-fold fluorescence intensification within 10 min. The COP-1 probe shows improved fluorescence signal amplification, whereas the biosensor COSer has a shorter response time. Interestingly, the process by which the COSer interacts with CO is totally reversible, whereas the COP-1 process is irreversible. These characteristics confer different roles for these two probes: COSer is appropriate for real-time monitoring of CO release, whereas COP-1 is better for lowconcentration CO detection in CORMs because of its high sensitivity. Moreover, the irreversible reaction of COP-1 may sequester CO from the system, thus tilting the equilibria of the CO exchange and leading to more CO release.13 In addition to these assays, other novel methods have emerged, such as gas chromatography with a thermal conductivity detector (GCTCD)116,117 and IR spectroscopy.118,119 These methods have been thoroughly reviewed.120,121

An interesting study122 showed an attractive alternative for CO release detection and measurement in biological systems and in vitro studies. In this work, an oral carbon monoxide release system (OCORS), namely, an oral tablet with sulfiteinduced CO release from 2, was introduced, offering precise, controlled, and tunable CO delivery in vivo. Modification of the tablet shell precisely controlled CO release. It was shown that OCORS possesses a nearly linear CO release profile between the window of time from 30 to 240 min; thus an integrated CO sensor using “Ei207D” CO detectors was employed in the amperometric detection system for calibration of CO release. This work not only put forward a reliable and available CO delivery method but also inspired us to employ a brand new CO release measurement mode under some specific conditions. The advances in detecting CO release described here (Table 2) will benefit the design of CO carriers and lead to a better understanding of CORM biology.

4. PHARMACOLOGICAL FEATURES OF CORMS 4.1. Triggers of CO Release. In recent decades, CORM development has expanded, and the large library of CO release compounds can now be classified by the manner in which CO release is activated, including solvent-triggered CORMs, photoCORMs, enzyme-triggered CORMs (ET-CORMs), thermaltriggered CORMs, oxidation-triggered CORMs, pH-triggered CORMs, etc.123 (Table 3). Photo-CORMs are gaining attention because of their wide utilization and pharmaceutical potential. 4.1.1. Solvent-Triggered CORMs. Certain CORMs activate the CO release process within a solvent by initiating solventinduced ligand exchange with the solvent or solutes.124,125 Such CORMs include 217,126 and 3.127 2 is a ruthenium carbonyl compound which is dissolved in dimethyl sulfoxide (DMSO) before being added to aqueous biological solutions and buffers. Addition of a glycinate ligand to 2 gives water-soluble 3.128 When added to water, 3 is readily attacked by hydroxide above pH 3 to give [Ru(CO)2(CO2H)Cl(glycinate)]−, which is the active species for CO delivery and may lose 1 equiv of CO, as CO2, through interaction with proteins (see section 5 below). 2620



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UV light as a trigger, which is harmful for most organisms. Bohlender and co-workers137 have synthesized 11 (CORM-A1PLA), a decacarbonyl moiety incorporated into a nanofibrous poly-(L-lactide-co-D/L-lactide), and its trigger is visible light. Once absorbed into live 3T3 fibroblasts and kept under visible light, this compound releases CO and prevents fibroblasts from dying under hypoxic and metabolically depleted conditions. Novel photo-CORM syntheses have been developed with a goal of minimal toxicity. For example, compound 12 shows no apparent toxicity and remains stable in organisms. This complex and its product are fluorescent after photoactivation, which facilitates their detection and can be used to monitor CO release.138 Photo-CORMs are not always all equipped with a metal core. Recently, Antony and co-workers introduced the first watersoluble, transition-metal-free CORM 13139 (Figure 3).

Many beneficial biological effects were witnessed following administration of these CORMs, such as anti-inflammatory,31 antibacterial,68 and anti-ischemic58 effects in preclinical studies. And in a study led by Gonzalez et al.,129 three iron-based CORMs including the complex 6 were introduced. This FeII carbonyl gives a clean example of solvent triggered CO release; it dissolves in water to release CO at room temperature in the dark to yield 6, giving us a well-defined i-CORM control. CORMs designed in this study exhibit rapid vasorelaxation effect of mouse aorta muscle rings. The water-soluble 7 (ALF492) is a novel ruthenium-based CORM; it exhibits great medicinal properties and CO release profiles. The biocompatibility and solubility of CORM 7 in water are derived from the attachment of galactose ligands to the metal core. These ligands also show great affinity with liver cells by targeting asialoglycoprotein receptors. Biologically, 7 offers full protection against ECM and acute lung injury (ALI) in mice.125 This protection effect does not affect oxygen transport and is enhanced when 7 triggers HO-1 expression. Additional studies have also confirmed that 7 combined with antimalarial drugs facilitates the treatment of ECM. Hydrolytic and redox processes occasionally combine to trigger CO release by certain CORMs, such as 8 (ReCORM-1) and 5,61,130,131 which represent electronically unsaturated Re complexes. Once 8 is dissolved in aqueous media, it undergoes an exchange of three bromides for solvent molecules. This substitution process initiates a reduction of the ReII complex to its corresponding ReI species, thus facilitating the oxidation of Br− to BrO−. The ReI complex is capable of releasing CO continually within 30 min under physiological conditions before it is oxidized to a nontoxic [ReO4]− anion. Biologically, this promising rhenium-based CORM shows antioxidative properties and was shown to protect cardiomyocytes from death in a rat ischemia/reperfusion model. 4.1.2. Photo-CORMs. Photo-CORMs are complexes that remain stable in the dark in aqueous buffer and release corresponding equivalents of CO upon exposure to light with an appropriate wavelength.132,133 The first identified photoCORM with pharmacological effects was 1,17 a decacarbonyl dimanganese carbonyl complex that releases CO following stimulation by light. Undoubtedly, photo-CORMs possess better spatial and temporal control in CO delivery; however, early stage photo-CORMs, such as compounds with iron pentacarbonyl and dimanganese decacarbonyl, show poor bioavailability and high toxicity.17 One promising photo-CORM candidate is compound 9.134 This system loses two of three CO ligands and releases 2 equiv of CO when exposed to 365 nm UV. Furthermore, cell viability studies have revealed that the complex easily absorbs light and has great antineoplastic properties in HT29 human colon cancer cells. This photoinitiated cytotoxicity against tumors produced a significant reduction in cell biomass upon irradiation with UV relative to 5-fluorouracil (5-FU), a longestablished anticancer drug. In darkness, this complex stays inactive, even when the concentration is as high as 100 μM. Another study also showed the cellular internalization effect of 9 using Raman microspectroscopy.135 Another photo-CORM is 10, a tungsten-containing photo-CORM reported by Rimmer136 in 2010. This CORM is water-soluble and stable in liquids if kept in the dark, and it liberates 1 equiv of CO when irradiated at 313 nm. Notably, these photo-CORMs are not yet optimized for immediate pharmaceutical applications because they demand

Figure 3. First water-soluble, transition-metal-free CORM that can be activated by visible light.

Complex 13 is able to release CO in water and methanol under a radiation wavelength of 500 nm, which is within the visible light spectrum. This CORM possesses desirable biological features, such as an appropriate photoactivated trigger, good solubility in water, and a nontoxic metal-free photoproduct. But the short wavelength needed to trigger CO release and relatively poor light penetrating power into biological tissues may confine this complex to topical therapeutic application. What’s worse, the above complex is hard to synthesize and it is also difficult to modify the corresponding chromophore to shift the absorption window toward longer wavelengths. In a goal of utilizing an alternative easy-synthesizing chromophore, Palao and co-workers140 reported a new generation of organic CORMs constituted of BODIPY chromophores (COR-BDPs) (14a, 14b, and 14c) that could be activated by visible-to-NIR light. This wavelength range suited individual physiological activities well and presented deeper penetration of light into tissues (tissuetransparent). By modifying the structure of COR-BDPs, we can enable fine-tuning of the physicochemical properties. For example, in synthesizing 14b, the 3,5-distyryl groups extended the π conjugation and bathochromically shifted absorption band by about 150 nm in comparison with 14a. The PEG chains in 14b contributed to the overall aqueous solubility. Another valuable property of these complexes is the fluorescence of BODIPY chromophores, which allows for simultaneous monitoring in vivo. 2621



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tuning of their visible absorption maxima between 630 and 693 nm (red light). Second, employment of photosensitizers, such as organic dyes or metal complexes, in CORM design will enhance the CO release process. And finally, photolytic liberation of CO by two-photon absorption (TPA) would represent a considerable advance. Mascharak and his group significantly contributed to the synthesis and improvement of photo-CORMs;150 some of their recent studies were interesting because they introduced photoCORMs whose CO delivery to biological targets, especially malignant cells, was trackable. In one of their studies,151 a “turn-on” photo-CORM (18) they designed augments COinduced death of MDA-MB-231 human breast cancer cells when triggered by broadband visible light. CO released from this complex gives rise to fluorescence within the cellular matrix due to deligation of the pbt ligand and is easy to track. In another study, 152 a ReI carbonyl complex, [Re(H2O)(CO)3(pbt)](CF3SO3), was synthesized. This complex releases CO under low-power UV illumination, accompanied by a luminescence change from orange to deep blue. Such theranostic two-tone luminescent feature enables this complex to be tracked all the way from the entry into cancer cells to CO delivery step. In summary, phototriggered CORMs have a bright future in therapeutic applications, and the ideal behaviors of these CORMs should include the following. (1) Precise spatialtemporal control of release. In photo-CORMs, this means releasing CO in response to irradiation. CO dosage should not leak in any way until exposed to light. (2) Satisfactory physiochemical properties, like water solubility, oxygen tolerance, good permeability, and resistance from enzymatic attacks. (3) Low cytotoxicity of both CORMs and their byproducts. (4) Appropriate absorption and CO release wavelength. Many early photo-CORMs are activated by UV light, which is both harmful to cells and has poor penetration depth. CO release should be triggered by infrared, nearinfrared, or visible light, which suits practical usage. To make a great leap from putative ideal photo-CORMs to realistic ones, more innovative CO release systems should be synthesized and their properties should be fine-tuned by modification of the molecule architecture with different substituent groups. And new photo-CORMs may be equipped with more biomaterials for intracellular delivery.153 More detailed summary about photo-CORMs can be found elsewhere.146,154 4.1.3. Enzyme-Triggered CORMs. Enzyme-triggered systems (ET-CORMs) are tissue- or cell-specific CORMs that allow for tissue-specific CO release in response to an appropriate stimulus, such as disease-related enzymes. For example, the η4-acyloxybutadiene-Fe(CO)3 complex is stable in buffer and activated by an esterase. This esterase attacks the targeting ester group and leads to a tautomeric dienol-Fe(CO)3 complex intermediate, which breaks the Fe−CO bond and induces the CO release process155 (Figure 4). The synthesis of a new η4oxidiene-Fe(CO)3 complex 19 linked to a penicillin G amidase (PGA) cleavable side chain through a p-aminobenzyl or a Nmethyl-1,2-ethylenediaminecarbonyl unit as self-immolative linker has also been reported.156 These units decay via PGAinduced cleavage of the corresponding amide bond, which finally released CO. Romanski et al. also synthesized a phosphatase-triggered CORM η4-cyclohexadiene-Fe(CO)3 complex (compound 20),155 which exhibits moderate antiinflammatory effects.

Another set of novel organic photo-CORMs 15, which consisted of micelle-encapsulated unsaturated cyclic αdiketones, were reported by Liao et al.141 In their study, three cyclic α-diketones compounds (15a−c) were synthesized and exposed under visible light. All three complexes managed to release CO under 470 nm irradiation within 10 min in organic solvents but failed to release CO in aqueous solution. This might be partly due to the hydrated form of the diketone groups, which was insensitive to visible light. To address this problem, Pluronic F127 micelles were introduced to be the “capsule” of 15, which served to provide a hydrophobic milieu for the carbonyl. The encapsulated complexes successfully released CO in aqueous solution under 470 nm irradiation and yielded 78%, 71%, and 90% of CO, respectively. Like CORBDPs mentioned above, the byproduct of this kind of complexes was fluorescent, which enabled “real-time” imaging. Further, 15c was confirmed to be absorbable by acute myeloid leukemia (AML) KG-1 cells and could release CO quantum within the cells under 470 nm irradiation (shown by bright blue fluorescence in the cells). In spite of all these advantages to using unsaturated diketones 11a−c in vitro, they also have issues when applied in vivo. There existed many difficulties in tuning the CO release rate, and the encapsulation process undermined light penetration efficiency. Recently, Ruggi and co-workers142 developed a new method of conferring increased photodegradation kinetics and a better spectrum signature to photo-CORMs by connecting CORMs such as fac-[Mn(CO)3bpyBr] derivatives with semiconductor CdSe/ZnS core/shell quantum dots (QDs), which yielded the first QD-sensitized CORM system 16. This system presented a photodecomposition rate that was 2- to 6-fold faster under visible light (510 nm) than other photo-CORMs. In a recent study, 3-hydroxyflavone-based CORMs (17a− d)143 were introduced; they could emit CO in aerobic environment when exposed to visible light. By modulation of the substituent on the 3-hydroxyflavone scaffold 17a, the absorption wavelength could be regulated from 419 to 546 nm. After CO emission, these compounds would undergo fluorescent changes, allowing for “real time” CO release monitoring. The efficacy of CO release would drop sharply when placed in hypoxia condition, which might undermine the application of these CORMs in anoxic pathological processes. Interestingly, complexes with 3-hydroxyflavone scaffold are reported to be antioxidative, anti-inflammative, and anticancer in some areas.144,145 Photo-CORMs represent a promising pharmaceutical tool, and their ideal phototherapeutic window might be within the range 620−1100 nm, which represents the red end of the visible light spectrum and near-infrared rays.17,146 Within this range, the light penetration depth into mammalian tissues is at its maximum.147 To enable such near-infrared ray (NIR) excitation, three strategies summarized by Schatzschneider et al.148 should be employed for CORM design. First, the absorption maximum of the photo-CORMs can be shifted to the NIR spectrum by suitable metal coligand combinations, such as chelators with an extended aromatic π system. In a recent study, Kottelat et al.149 reported a series of carbonyl MnI complexes capable of releasing CO when triggered with red light. Electron-donating or electron-withdrawing substituents were introduced into their 2,2′-azopyridine ligands, indicating that electron deficient ligands decrease the HOMO−1 (highest occupied molecular orbital)/LUMO (lowest unoccupied molecular orbital) gap of the species, thus enabling a fine2622



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Oxygen also acts as a CORM trigger in certain cases. Complex 22 (ALF186), a protein-containing complex that is oxidative-triggered, remains soluble and stable in water and shows neuroprotective,162 anti-inflammation,163 and gastric ulcer prevention164 effects. When injected in vivo, it acts as a “CO bolus” that maintains well-defined COHb level in circulation. And 10, a photo-CORM that was described above, is air stable, although its photoproduct [W(CO)4(H2O)(tppts)]3− is not. This photoproduct undergoes an oxidative cascade in air and continues to yield CO.136 This same stepwise activation is observed in manganeseI complexes 9.134 After photolytic release of the first CO quantum, the last two carbonyl ligands of these complexes are liberated and accompanied by manganese oxidation to MnII, thus netting μ-O-MnIII compounds as the final products. Recently, Kunz et al.165 reported the attachment of a [RuCl-(p-DOPA)(CO)3] moiety to magnetic Fe2O3 nanoparticles, which resulted in a compound triggered to release CO through heating in an alternating magnetic field. If this system is exposed to an appropriate magnetic field, CO will be released through heating. In certain cases, CORMs can be administered in vivo and release CO to the target organs via metabolism. Molybdenum carbonyl 23 (ALF794) has low toxicity and can be bioactivated in the liver. In addition, this compound was found to have curative effects in acetaminophen-induced animal models of acute liver disease.166 In 2014, Wang and co-workers167,168 reported the “click and release” approach, in which two strictly organic and nontoxic components were mixed under biological conditions to yield CO bubble formation (Figure 5). The two components were tetraphenylcyclopentadienone (TPCPD) and bicyclo[6.1.0]nonyne (BCN), and they generated a pericyclic reaction that converted the energy in the double bonds to strained energy, thus releasing CO molecules. An increasingly accelerated reaction rate was observed in polar solvents and at a temperature of 37 °C compared with the reaction at ambient temperature. This approach was extremely convenient and promising because it represents the first step toward synthesiz-

Figure 4. Degradation and CO liberation from acyloxybutadiene− Fe(CO)3 complex (an enzyme-triggered CORM, ET-CORM).

The innovative and clever enzyme triggers represent very promising controlled CO delivery approaches. But by now, most studies concerning ET-CORMs are based upon metal complexes, which would unavoidably possess toxicological profiles and lead to iron accumulation due to everyday administration of these prodrugs. 4.1.4. Other CORM Triggers. Apart from the abovedescribed triggers, additional CORM triggers have also resulted in promising preclinical data. In [(OC)5Cr(L)] (L= halide/ aminoester) chromium complexes,157,158 L can be replaced by solvent molecules such as DMSO, thus leading to CO release. In addition, complex 21 can react with cysteamine and release CO in QSG-7701 and HepG2 cell lines.159 For rheniumII-based CORMs that contain bromide anions, CO release is pH dependent and presents half-lives ranging from 6 to 43 min. The lower the pH value, the faster the CO is liberated from the metal complexes.130,160 Acidification is also a trigger for CO release in the transition-metal-free complex 4.161 During the activation process of this CORM, the protonation of the carboxylate or the amide group yields Na[H3B-CO2H], which is followed by water or amine cleavage. The neutral H3B−CO molecule that is generated hydrolyzes to CO and the boronhydride-hydroxy byproduct. This CO release process is also pH dependent, and the rate increases sharply with decreasing pH.

Figure 5. Inverse-electron demanded Diels−Alder reaction between TPCPD and exo-BCN. Adapted with permission from ref 167 (http://dx.doi. org/10.1039/C4CC07748B) with permission of The Royal Society of Chemistry. Copyright 2014 The Royal Society of Chemistry. 2623



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Figure 6. Representation of CORM cytotoxicity. Once transported to target sites and released CO, its CO-absent analogue (i-CORM) left in situ, with a heavy metal core, harbors cofactor and has uncontrolled reactions with cell membrane, mitochondria, and cell nucleus, leading to severe cell damage.

ing a metal-free, organic, in vivo compatible CORM.169 In this system, the generation of CO was tunable by changing the electron density of TPCPD, but because of the concentrationdependent nature of bimolecular process, this system failed to function as a CO-prodrug. It will be a great breakthrough if we can figure out a unimolecular system that integrates the alkyne and the cyclopentadienone moieties into a single molecule. This system will be capable of undergoing intramolecular click reactions and releasing CO under physiological conditions. In all, more triggers of CORMs are there to be found to enhance better therapeutic use of CO-donating reagents. 4.2. Toxicity and Tissue Accumulation of CORMs. Despite the pharmaceutical effects of CORMs, they also present undesired side effects because of the toxicological profile of CORMs or the accumulation of the metal-containing residues (i-CORMs) in CORMs after release of CO.17,170−172 Thus, one major shortcoming of CORMs is that after the CO release process, their CO-absent analogues are left in situ, and the heavy metal core backbone often harbors cofactors that may generate uncontrolled reactions with adjacent cells, thereby leading to severe cell damage (Figure 6). In a study led by Wang et al.,173 cytotoxicity, in vivo toxicity, and biodistribution of two series of CORMs with Ru(CO)3 and M(CO)5 (M = Cr) moieties were evaluated. In vivo toxicity, especially, was shown by IC50 and LD50 values. According to the study, these

complexes were distributed unevenly into tissues and organs and did subsequent harm by oxidation of metal ions. In addition, the use of different cytotoxicity determination assays for a single CORM may present different levels of toxicity or even contradictory cytoprotective effects because metal carbonyls may interfere with the assays. To elucidate this toxicity issue, Winburn et al.174 performed a comparative analysis of the effects of gaseous CO, 2, and its CO-depleted metabolite (iCORM-2) in primary rat cardiomyocytes and two cell lines (HeK 293 and MDCK). The study revealed that the cytoprotective (100 mM) concentration. Furthermore, both 2 and i-CORM-2 showed cellular toxicity in the form of reduced cell viability, abnormal cell cytology, increased apoptosis and necrosis, cell cycle arrest, and suppressed mitochondrial enzyme activity. These results are consistent with metal-core mediated toxicity. Studies have also suggested that increasing the polarity of CORMs would minimize their permeation across the cellular membrane, thus weakening their toxicity.138,175 As a result, metal toxicity of transition metal complexes seemed to be an unbridgeable stigma for CORM, limiting CORM use only to short-term therapy or dying situations like terminal cancer. We should also note the presence of transition metal does not necessarily rule a complex out of clinical application. For example, the deadly arsenic 2624



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Figure 7. Use of different CO release profiles.

tion, tissue distribution, and PK. An analogy can be drawn between Romão’s model and a guided missile. Part A is the body of the missile, part B is the adaptor and stabilizer, and part C corresponds to the warhead and guidance system (Figure 8). Following this model, additional CORMs with potential pharmacological value can be logically designed and synthesized in the future.

trioxide, a highly toxic poison, has been approved to treat specific types of leukemia176 and received good effects. Therefore, future investigations must stringently profile the toxicology of metal-related CORMs with better cytotoxicity assays and assess i-CORMs independently by investigating their physiological properties. 4.3. CO Release Kinetics of CORMs. CO release kinetics of CORMs primarily involves the speed at which CO is released after it is triggered, and it represents a key parameter in CORM clinical applications. For example,128 the estimated t1/2 of 3 in human plasma is only 3.6 min. When it dissolves in plasma, it reacts with albumin, releases CO2, and attaches the Ru(CO)2 fragment to the protein which, when in vivo, carries it in circulation slowly delivering CO nonspecifically.187 This nonspecific release fails to fulfill pharmaceutical purposes. Additionally, both fast and slow CO release molecules should be developed to serve different study designs (Figure 7). Fast CO releasers with a t1/2 of seconds or even milliseconds are designed for transient CO release observations, such as in studies of ion-channel kinetics,177 whereas relatively slower CO releasers are more useful in therapeutic applications, which require a longer time frame to deliver CO to the target tissues.130,148,157,158,160 To improve the pharmacokinetic properties, macromolecular systems and inorganic nanomaterials can also be exploited as CO carriers, which will be discussed below. The triggers of CO release, the kinetics of CO liberation, the solubility of CORMs in aqueous media, and the toxicity of CORMs and their metal-containing residues play major roles in CORM design. To improve the pharmaceutical design of CORMs, Romão and co-workers178 introduced an elegantly conceptualized model of a metal carbonyl complex (MCC). This model contains three different components: (A) a metal core179,180 in charge of the intrinsic properties and toxicity of the complex; (B) a coordination sphere with CO and ancillary ligands that confer thermodynamic and kinetic stability to the MCC,160 which responds to a specific trigger and leads to CO release; (C) a drug sphere that is composed of organic substituents and responsible for the druglike features of CORMs via modification of the ancillary ligands at their distal sites; in addition, this sphere is responsible for the pharmacological parameters, such as water solubility, absorp-

Figure 8. Conceptual model for the development of pharmaceutical CORMs: (A) a metal core, which is analogous to the body of a missile; (B) a coordination sphere, corresponding to the adaptor and stabilizer of the missile; (C) a drug sphere, corresponding to the warhead and guidance system. Adapted with permission from ref 178 (http://dx. doi.org/10.1039/c2cs15317c) with permission of The Royal Society of Chemistry. Copyright 2012 The Royal Society of Chemistry.

CO release kinetics is crucial to pharmaceutical acceptability of CO prodrugs because for gasotransmitters, the dosage issue is not just about concentration; it also involves release and further exposure rates of CO. The same dosage with differing release rates may end up with totally different topical concentrations. And for metal-containing CORMs, CO release kinetics is dependent on the electronic structure of the metal and the atoms directly bound to it. Thus, selection of ligands and modification of the coordination sphere may tune the structures of CORMs to achieve controllable specific kinetics. Further, to fulfill different therapeutic indications, CO-prodrug designers can equip CORMs with different CO-releasing profiles to support either a rapid or a continual therapeutic 2625



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action as discusses above. Fine-tuning of the drug sphere for better permeability, solubility, or suitable redox properties can also benefit these medical indications. One big problem that hurdles the precise spatial-temporal CO release of CORMs is the insufficient targetability. CO molecule is highly diffusive and affinitive to hemoproteins, which is prone to bind to multiple tissue targets. To target CO to a specific location or tissue, it is desirable to introduce some “target ligands” conjugated to the metal carbonyl scaffold or even some “capsule” encapsulating the whole complex. Herein, macromolecular and nanomaterials can be utilized, which will be discussed in the next section.

5. MACROMOLECULES AND NANOMATERIALS AS CO-RELEASING SCAFFOLDS One of the major obstacles for the clinical use of CORMs is the difficulty of controlling the CO dose release to the biological targets. Traditional low-molecular-weight CORMs diffuse rapidly after administration and release CO instantly; thus, they fail to meet the minimum valid concentration (MVC) in the target tissues. To address this problem, macromolecular and nanosized materials have been exploited as CO-releasing scaffolds because they can avoid rapid kidney elimination and target organs with capturable nanoparticles and ligands.181,182 Materials such as micelles, copolymers, inorganic hybrid scaffolds, iron metal organic frameworks, proteins, and dendrimers are being used as CO carriers. Detailed reviews of this system can be found elsewhere.153,183,184 Here, we briefly introduce several typical macromolecular carriers and nanomaterial scaffolds. Polymeric organic scaffolds185−189 have been widely studied as drug carriers. Brückmann et al.190 successfully bound a polymeric backbone with a CORM. The authors synthesized [(hydroxypropyl methacrylate)-co-bis(2-pyridylmethyl)-4-vinylbenzylamine] copolymers with a Re(CO)3 moiety. Hydroxypropyl methacrylate (HPMA) confers properties such as water solubility, biocompatibility, and nonimmunostimulation. Subsequently, Brückmann et al.190 proposed attaching a manganese tricarbonyl fragment to HPMA-backbone copolymers that presented Mn(CO)3@P1 and Mn(CO)3@P2. The sizes and molecular weights were designed for passive accumulation and drug delivery to the tumor inflammation sites. The proposed compounds also showed proper degradability. A recent study announced that electrospun poly(ε-caprolactone) scaffolds loaded with an organic photo-CORM191 could serve as a nontoxic, biocompatible CORM that releases CO once exposed to visible 470 nm light under dry or cell culture conditions. A similar CORM was used for the first time for tissue-engineering small-diameter vascular grafts. Metal organic frameworks (MOFs), which are also called porous coordination polymers, are a collection of metal centers or inorganic clusters bridged by simple organic linkers via metal−ligand coordination bonds.192−194 The large inner surface of these polymers confers a high molecular-loading capacity and the clinical properties of traditional polymers. Ma et al.195 reported the design of the first MOF CO carriers, MIL88B-Fe and NH2-MIL-88B-Fe (Figure 9), elucidated the chemistry of CO binding to MOFs, and provided insights into a unique trigger of CO release: the degradation of MOFs under physiological conditions. Proteins represent the most intriguing modality of CO carriers because of their considerable biocompatibility and cellular intake; therefore, they are the subject of increasing

Figure 9. 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 stand for the positions of the terminal ligand: Fe atoms, light-gray spheres; O atoms, gray spheres; C atoms, black spheres. Reproduced with permission from ChemistryA European Journal (Ma, M.; Noei, H.; Mienert, B.; Niesel, J.; Bill, E.; Muhler, M.; Fischer, R. A.; Wang, Y.; Schatzschneider, U.; MetzlerNolte, N. Iron metal-organic frameworks MIL-88B and NH2-MIL-88B for the loading and delivery of the gasotransmitter carbon monoxide. 2013, Volume 19, pp 6785−6790).195 Copyright 2013 Wiley.

interest for research into drug-delivery systems.196−198 In 2007, Razavet and co-workers199 synthesized the first protein CORM: a lysozyme bearing manganese−carbonyl complex [(lysozyme)Mn(CO)3(OH2)2]2. Subsequently, another protein-containing complex 22200 was reported, and it released all of its CO equivalents once exposed to O2. Interactions between 3 and various proteins, such as hen egg-white lysozyme (HEWL), have also been found,201 and protein-RuII(CO)2 adducts were derived.202 Recently, Tabe et al.203 developed a ruthenium carbonyl incorporated cross-linked hen egg-white lysozyme (Ru·CL-HEWL), which represents a brand new CORM with a t1/2 of CO release 10 times longer than that of 2. These authors also discovered that treating cells with Ru·CL-HEWL induces stronger NF-κB activity. In another study,204 a series of RuII(CO)2-HEWL complexes, where hydrolytic decomposition products of 3 react with histidine residues on the surface of proteins, were introduced. These complexes release CO in aqueous solution, cells, and mice spontaneously. Further in this study, RuII(CO)2 complex was combined with bovine serum albumin (BSA), and administration of BSA-RuII(CO)2 into mice with colon carcinoma led to enhanced CO accumulation at the tumor, suggesting that RuII(CO)2−protein complexes could be used as viable alternatives for therapeutic CO delivery in vivo. In 2015, Fujita et al.205 introduced a photoactive CORM protein cage for CO delivery in living cells and constructed an architecture of ferritin (Fr) containing manganese carbonyl complexes. When substituting Arg52 adjacent to Cys48 of Fr with Cys, the Fr mutant coordinated with 48 Mn-carbonyl (MnCO) moieties and released CO 2626



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ligands under light irradiation. The contribution of protein CO carriers to NF-kB activation in mammalian cells was also demonstrated. However, the pharmaceutical use of protein CO carriers in vivo may be threatened by their rapid clearance. The encapsulation of CORMs into polymeric micelles is also of great value because these micelles prevent early CO release and facilitate tissue targeting.206 Hasegawa et al.105 first developed CO-releasing polymeric micelles, including poly[PEG-b -OrnRu-b-nBu] with a CO liberation block Ru(CO)3Cl(ornithinate), which presents high CO-loading storage and slow CO release and has a particular trigger of thiol compounds, such as cysteine or glutathione. Micelle CO carriers have shown anti-inflammatory properties in THP-1 Blue cell lines via the inhibition of lipopolysaccharide-induced NF-kB activation of monocytes, which alleviates the cytotoxicity of Ru(CO)3Cl(amino acid). Micelles have also become an alternative for improved photo-CORM design as described above, such as [Mn(bpy)(CO2)(PPh3)2]+ reported by Pierri et al.207 In this system, NIR absorbing up-conversion nanoparticles (UCNP) were coated with amphiphilic phospholipidfunctionalized poly(ethylene glycol) (DSPE-PEG2000), thus forming the UCNP@PL-PEG (dried DSPE-PEG2000 powder). This compound specialized in absorbing low-energy wavelengths and converting this light into higher energy wavelengths, thus enabling the NIR light trigger and improving CO delivery (Figure 10). Another study led by Yin et al.208

Figure 11. Covalent attachment of [Mn(CO)3(tpm)] + complex to the azide-modified nanodiamond surface via CuAAC “click” reaction.

nanofiber gels with PA were covalently coordinated to ruthenium tricarbonyl, and CO bubbled out spontaneously over a long period, thus indicating localized CO delivery. This localization may account for the improved viability of cardiomyocytes when this material is added to oxidatively stressed cardiomyocytes. Metallodendrimers are macromolecules with dendritic structures and a metal moiety, and they have emerged as promising CORM candidates because of their advantages, such as low polydispersity, good molecular uniformity, and defined structure as well as their ability to delivery large amounts of CO across cell membranes to cellular systems.219−223 Govender et al.224 described the first CO-releasing metallodendrimer, which combined the polypyridyl dendritic scaffolds with a Mn(CO)3 fragment to form a formula [DAB-PPI-{MnBr-(bpyCH3,CHN)(CO) 3 } 4 ], [DAB = 1,4-diaminobutane, PPI = poly(propyleneimine)]. This metallodendrimer was photoinducible and had a high CO-loading capacity. Subsequent studies by this group introduced second generation polypyridyl dendritic ligands, yielding metallodendrimers with eight [MnBr(bpyCH3,CHN)(CO)3] end groups. Both the first- and second-generation metallodendrimers share similar t1/2 and quantum yields of CO release, implying that scaling effects were not involved in these systems and that each [MnBr(bpyCH3,CHN)(CO)3] end group operated independently. Overall, the study of tissue-specific CO release is at a bottleneck, and traditional CORM applications often result in unspecific CO release. The introduction of macromolecular and inorganic nanosized materials into CORM design opened novel avenues for precise CO treatment by tethering specific targeting molecules onto the surface of the “capsule”, thus facilitating site-directed drug uptake. The “encapsulated CORMs” were also able to improve the bioavailability of the parent CORMs and avoid metal leakage and further toxicity by trapping the metal core within the insoluble matrix materials.

Figure 10. Schematic representation of CO release from a watersoluble nanocarrier exposed to NIR light. Adapted with permission from ref 207 (http://dx.doi.org/10.1039/C4CC06766E) of The Royal Society of Chemistry. Copyright 2015 The Royal Society of Chemistry.

demonstrated the encapsulation of a poly(styrene-alt-maleic acid) copolymer into 2, which showed prolonged circulation and anti-inflammatory effects. Silica-based nanoparticles209,210 and nanodiamonds211−213 have gained increasing popularity in CORM design over the past decade because of their stability, nontoxicity, biodegradability, and easy production.210,214 In 2011, Dördelmann and co-workers215 first combined modified 9 fragments with silica nanoparticles via the copper-catalyzed azide−alkyne 1,3-dipolar cycloaddition (CuAAC “click” reaction) (Figure 11). These CORM-functionalized nanoparticles were photoinducible and could be effective at targeting solid tumors. Matson et al.216 recently used peptide amphiphiles (PAs), a self-assembling peptide system with a hydrophobic alkyl tail,217,218 as a CO carrier. PA is able to self-assemble into fibrous hydrogels. These biodegradable nanofibrous gels share similar structural features with the native extracellular matrix and facilitate the regenerative process. In Matson’s research,

6. CONCLUSIONS Carbon monoxide is an endogenous messenger produced by HO-catalyzed heme degradation, and although it presents cytoprotective effects, it also has many toxic adverse effects when present in large amounts, namely, through inhalation. Therefore, CORMs, or prodrugs that deliver and release CO in a spatially and temporally controlled manner, have been investigated to reach better therapeutic goals. The therapeutic 2627



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absorption, half-lives, and triggers of CORMs are required to fulfill different clinical roles. The variety of CORMs has been expanding, although the evolution of CORMs from prodrugs to qualified clinical drugs is still in its infancy because more in vivo research is required with a focus on enhancing CO delivery efficiency and biocompatibility.

effects of CO and CORMs include reducing inflammation, protecting transplanted organs from IRI, easing cardiovascular disease, preventing microbial infection, hindering cancers, and affecting hemostasis as described above. To date, most CORMs are transition metal carbonyl complexes and possess versatile biological advantages, such as anti-inflammatory, antiapoptotic, and vasodilator effects. However, their different CO release rates and different physicochemical properties like permeability and solubility set up obstacles for us to further facilitate their clinical applications and generate improved CORM designs. Measuring the CO release rate of CORMs in cells and tissues accurately is very important. Traditional deoxymyoglobin carbonylation assays are inappropriate for this purpose, and improvements over the presently available CO biosensors (rhodium complexes, fluorescent biosensors and palladium complexes) are required. Cutting-edge CO release detectors/ reporters must be rapid, selective, and sensitive within the lower micromolar range to enable real-time detection inside live cells and tissues. To draw a full picture of CORM characteristics, new insights are needed into the activation of CO release and the toxicity, sensitivity, and release kinetics of CO. The methods for CO release, or the triggers of CORMs, are used to classify metal carbonyl complexes as solvent-triggered CORMs, photoCORMs, ET-CORMs, thermal-triggered CORMs, oxidationtriggered CORMs, pH-triggered CORMs, and so on. These CORMs show promising pharmaceutical potential and deserve extensive investigation.225 Other than their therapeutic effects, CORMs occasionally present toxic effects in organisms, which result mainly from the uncontrolled reactivity of the heavymetal core and accumulation of their CO-depleted metalcontaining residues (metabolites). In addition, the kinetics of CO release is of great importance for CORM clinical usage. A defined CO release speed from CORMs will serve different clinical purposes, for example, a fast-release CORM for ionchannel studies and a slow release CORM for tissue targeting. For tissue targeting to be effective, traditional low molecular weight CORMs must be carefully designed to (1) survive systemic circulation and avoid the corresponding sequestering of CO by Hb; (2) reach the disease tissue/site and accumulate with marked specificity; (3) respond to a trigger of the diseased tissue in order to release CO; (4) generate nontoxic molecular residues that can be safely eliminated.226 All these require strenuous medicinal chemistry efforts, and each CORM is made to target only one disease and one location. On the other hand, the application of macromolecular and inorganic-nanosized materials as CO carriers is gaining momentum because of their favorable properties with regard to certain biological targets and the possibility of their use in implants and in combination with surgical praxis. This is particularly true in cases where the ESR effect can be explored, like in tumors, to favor higher specificity and tissue accumulation. It is also important to favor the removal of the metal-based CO-depleted residues in certain applications like skin or GI tract treatments or even in cancer treatment followed by tumor resection. Another important property of some of these nanosized materials is the circumventing of rapid metabolism in the liver. In all, CORMs are systematic prodrugs with CO as their active ingredient. CORMs do not target specific receptors but only serve as carriers that survive long enough under physiological conditions to distribute CO preferentially to the disease site and release their CO load quickly after triggering. CO is then able to perform its therapeutic effects. Proper

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AUTHOR INFORMATION

Corresponding Author

*Phone: 00862783663409. Fax: 00862783662853. E-mail: [email protected]. ORCID

Da-Wei Ye: 0000-0002-5114-1378 Author Contributions #

K.L., W.-C.W., and Y.-Q.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Ken Ling received his Bachelor of Medicine degree in Hainan Medical College in 2014. He is currently a student of the Ph.D. in Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. His main research interests concern carbon monoxide preclinical development. Fang Men is a Ph.D. student at College of Chemistry and Molecular Sciences, Wuhan University. Wei-Ci Wang studied Medicine at the Tongji Medical College, Huazhong University of Science and Technology, where she graduated in 2012 after a visiting fellowship at Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School (U.S.). Her research has mainly been focused on the molecular mechanisms underlying signal transduction pathways of carbon monoxide. Ya-Qun Zhou is a Ph.D. student at Anesthesiology Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Hao-Wen Zhang is a Ph.D. student at Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Da-Wei Ye received his Medical Doctor degree in 2007 and pursued the Ph.D. degree at Tongji Medical College, Huazhong University of Science and Technology. After a clinical fellowship at City of Hope Medical Center (U.S.), he is now Associate Professor at Cancer Center, Tongji Hospital. His current research focuses on the design, synthesis, and biological evaluation of clinical application of carbon monoxide.

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ACKNOWLEDGMENTS Research work related to this field was supported by funding from the Nature Science Foundation of China (Nos: 81400917, 81500376, 81371250, and 81571053) and the Nature Science Foundation of Hubei Province, China (NO.2016CFB108).

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