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Review
. 2019 May 20;12(10):1643.
doi: 10.3390/ma12101643.

CO-Releasing Materials: An Emphasis on Therapeutic Implications, as Release and Subsequent Cytotoxicity Are the Part of Therapy

Muhammad Faizan  1 , Niaz Muhammad  2 , Kifayat Ullah Khan Niazi  3 , Yongxia Hu  4 , Yanyan Wang  5 , Ya Wu  6 , Huaming Sun  7 , Ruixia Liu  8 , Wensheng Dong  9 , Weiqiang Zhang  10 , Ziwei Gao  11
Affiliations
Review

CO-Releasing Materials: An Emphasis on Therapeutic Implications, as Release and Subsequent Cytotoxicity Are the Part of Therapy

Muhammad Faizan et al. Materials (Basel). .

Abstract

The CO-releasing materials (CORMats) are used as substances for producing CO molecules for therapeutic purposes. Carbon monoxide (CO) imparts toxic effects to biological organisms at higher concentration. If this characteristic is utilized in a controlled manner, it can act as a cell-signaling agent for important pathological and pharmacokinetic functions; hence offering many new applications and treatments. Recently, research on therapeutic applications using the CO treatment has gained much attention due to its nontoxic nature, and its injection into the human body using several conjugate systems. Mainly, there are two types of CO insertion techniques into the human body, i.e., direct and indirect CO insertion. Indirect CO insertion offers an advantage of avoiding toxicity as compared to direct CO insertion. For the indirect CO inhalation method, developers are facing certain problems, such as its inability to achieve the specific cellular targets and how to control the dosage of CO. To address these issues, researchers have adopted alternative strategies regarded as CO-releasing molecules (CORMs). CO is covalently attached with metal carbonyl complexes (MCCs), which generate various CORMs such as CORM-1, CORM-2, CORM-3, ALF492, CORM-A1 and ALF186. When these molecules are inserted into the human body, CO is released from these compounds at a controlled rate under certain conditions or/and triggers. Such reactions are helpful in achieving cellular level targets with a controlled release of the CO amount. However on the other hand, CORMs also produce a metal residue (termed as i-CORMs) upon degradation that can initiate harmful toxic activity inside the body. To improve the performance of the CO precursor with the restricted development of i-CORMs, several new CORMats have been developed such as micellization, peptide, vitamins, MOFs, polymerization, nanoparticles, protein, metallodendrimer, nanosheet and nanodiamond, etc. In this review article, we shall describe modern ways of CO administration; focusing primarily on exclusive features of CORM's tissue accumulations and their toxicities. This report also elaborates on the kinetic profile of the CO gas. The comprehension of developmental phases of CORMats shall be useful for exploring the ideal CO therapeutic drugs in the future of medical sciences.

Keywords: CO administration; CO kinetic profile; CO-releasing materials; CO-releasing molecules; cellular targets; heme oxygenase; organometallic complexes; pathological role; pharmaceutical drugs; pharmacokinetic functions; therapeutic agent.

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Conflict of interest statement

The authors declare that there is no conflict of interests regarding the publication of the paper.

Figures

Figure 1
Figure 1
The intracellular carbon monoxide (CO) production by heme oxygenase (HO) in the mammalian system justifies its biological role.
Figure 2
Figure 2
The coagulation and fibrinolysis scope of CO-releasing materials (CORMats).
Figure 3
Figure 3
The carboxy hemoglobin (COHb) percentage is increasing in the direct CO inhalation beyond the therapeutic zone (~10%) during the mainstream blood circulation. (This information is based on data reported in reference [44,45]).
Figure 4
Figure 4
The feasibility analysis of the CO direct and indirect inhalation shows their different biological observance inside a human body.
Scheme 1
Scheme 1
CO releases from the ligand-metal CO framework (LnM-CO).
Scheme 2
Scheme 2
Various CO-releasing molecules (CORMs) formulation associates with different functional capabilities.
Scheme 3
Scheme 3
Various organometallics MCCs incorporate with numerous conjugate systems to produce carbonylation complexes, i.e., CORMats for therapeutic CO release upon trigging.
Figure 5
Figure 5
The CO-releasing administration with different conjugate and encapsulate strategies.
Figure 6
Figure 6
Triblock copolymer assembles for releasing the CO at biological sites.
Figure 7
Figure 7
Tricarbonylchlororuthenium (II) dimer (CORM-2) synthesized with water-soluble styrene-maleic acid copolymer (SMA) for micellization CORMats.
Figure 8
Figure 8
Synthesis route of unsaturated α-diketones (α-DKs) has been activated by photons energy.
Figure 9
Figure 9
Synthesis of PA2 having CO-moiety for spontaneous release CO.
Figure 10
Figure 10
[Mo(CO)4(bpyCH3,CHO)] complex has been constructed through bio-orthogonal peptide conjugate.
Figure 11
Figure 11
The synthesis route of [Mn(bpeaNHCH2C6H4CHO)(CO)3]PF6 for Photo-CORMats.
Figure 12
Figure 12
The ionic water-soluble Iron complexes [FeII(CO)(N4Py)] (A) could be modified into Photo-CORMats by the replacement of the N4Py ligand with peptide china Ac-Ala-Gly-OBn (B) for the improvement of the cell-specific itself or tissue-specific therapeutic properties.
Figure 13
Figure 13
The hydrolytically activated Ruthenium dicarbonyl complexes CORM-2 and CORM-3 could be transformed into Photo-CORMats by peptide ligands through different functionalization: (A) Polypyridyl ligand of 2-(2-pyridyl)pyrimidine-4-carboxylic acide (CppH); (B) monomeric PNA backbone.
Figure 14
Figure 14
The reactivity of the fac-[RuL3(CO)3]2+ complex (A) and CORM-3 react with single-His protein (B).
Figure 15
Figure 15
The spontaneous CO release by metalloprotein: (A) The carbonyl reagent cis-[Ru(CO)2(H2O)4]2+ spontaneous CO release in live cells using histidine (His) metalloprotein and retained at IL-8; (B) the cis-[Ru(CO)2]2+ carbonyl segment can be produced by the aqua carbonyl cis-[RuII(CO)2(H2O)4]2+.
Figure 16
Figure 16
The recombinant L-chain apoferritin (apo-rHLFr) of Ru carbonyl complexes.
Figure 17
Figure 17
B12-ReII(CO)2 CORMats conjugate: (A) B12-ReCORM-2; (B) B12-ReCORM-4.
Figure 18
Figure 18
Synthesis route of hybrid CORMats: (A) HY-CORMats-1; (B) HY-CORMats-2.
Scheme 4
Scheme 4
The hybrid CORMats (HY-CORMats-1) has a CO moiety for various anti-inflammatory, antioxidant actions and induced nuclear accumulation of Nrf2.
Figure 19
Figure 19
Galactose chelated three carbonyl ruthenium complexes.
Figure 20
Figure 20
β-isocyanate coordinated molybdenum carbonyl complexes.
Figure 21
Figure 21
The copolymer P1 synthesized for releasing CO segment.
Figure 22
Figure 22
The copolymers HPMA-co-bis(2-pyridylmethyl)-4-vinyl-benzylamine construct through Re(CO)3 moiety.
Figure 23
Figure 23
NIR-responsive amphiphilic polymer conjugates (PhotoCORMats).
Figure 24
Figure 24
Photo-activated ALF472 CORM [Mn(tacn)(CO)3]Br simulated under physiological parameter.
Figure 25
Figure 25
The mechanism of Manganese tricarbonyl functionalized with silica nanoparticles.
Figure 26
Figure 26
Metallodendrimers photoactivated CORMats.
Figure 27
Figure 27
The [Mn(CO)3(tpm)]+-functionalized nanodiamond (ND) immobilized on azidemodified ND’surface through CuAAC ‘‘click’’ reaction.
Figure 28
Figure 28
The CO-releasing rate profile reflects the different characteristics: (a) Slow CO release has therapeutic significance; (b) fast CO release demonstrates the path of ion-channel kinetics.
Figure 29
Figure 29
The CORMs/CORMats integration exhibited the cytotoxicity of metal residue (i-CORMs/CORMats).
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