**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 1, Yanyan Wang 1, Ya Wu 1, Huaming Sun 1, Ruixia Liu 4, Wensheng Dong 1, Weiqiang Zhang 1,\* and Ziwei Gao 1,\***


Received: 7 April 2019; Accepted: 14 May 2019; Published: 20 May 2019

**Abstract:** The CO-releasing materials (CORMats) are used as substances for producing CO molecules for therapeutic purposes. Carbon monoxide (CO) imparts toxic e ffects to biological organisms at higher concentration. If this characteristic is utilized in a controlled manner, it can act as a cell-signaling agen<sup>t</sup> for important pathological and pharmacokinetic functions; hence o ffering 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 o ffers 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; therapeutic agent; pharmaceutical drugs; heme oxygenase; CO-releasing materials; CO-releasing molecules; organometallic complexes; pharmacokinetic functions; pathological role; CO kinetic profile; cellular targets
