*2.5. Polymers*

The aforementioned most promising anticancer drug agen<sup>t</sup> is a macromolecular conjugate. Ruth Duncan et al. reported for the first time a polymer-anticancer conjugate [154]. These macromolecular drugs consist of at least three (3) parts: One is a polymer carrier (HPMA), which transports metal organic drugs such as Mn(CO)3 light-induced CORMs; the second is a biodegradable polymer drug connector; the third is an anti-tumor agent. The Bruckmann and Kunz groups reported that N-(2-hydroxypropyl)methacrylamide (HPMA) and pentacarbonyl bromide were heated under the re-flux of a dry acetone solution to obtain a copolymer P1 at high yield (Figure 21) [155]. Inducing CORMs can passively transport CO to release metal drugs for tumor cells or sites of inflammation. The polymer conjugate P1 releases CO at 365 nm light, which is not cytotoxic to the HCT116 human colon cancer and HepG2 liver cancer cells.

**Figure 21.** The copolymer P1 synthesized for releasing CO segment.

HPMA-copolymer has a grea<sup>t</sup> nature of water solubility. Bernhard Spingler et al. discovered the copolymer materials [156]. The bis(2-pyridylmethyl)benzylamine ligand was prepared from picolyl chloride and benzylamine, then this ligand coordinated with Re(CO)3 moiety to construct the HPMA-co-bis(2-pyridylmethyl)-4-vinylbenzylamine copolymers (Figure 22). HPMA-copolymer characteristics such as the average molecular weight can be modified according to the requirement by replacing the radical starter and co-monomers. For instance, the molecular weight 52KDa is the appropriate choice for remarkably enhancing the permeability and retention (EPR) effect. The established copolymer system with the Re(CO)3 fragment has an ability to diagnose the used 99mTc. Moreover, the identical behavior in IR spectra and X-ray crystallography have shown their resemblance in the binding sites of Re(CO)3-labelled copolymer and bis(2-pyridylmethyl)-amine-derived complexes (solid-state structures (SSS) of ·CH2Cl2 and·CH2Cl2·H2O). HPMA-morphology can be efficient for targeting the tumor sites for the EPR effect.

**Figure 22.** The copolymers HPMA-co-bis(2-pyridylmethyl)-4-vinyl-benzylamine construct through Re(CO)3 moiety.

*Materials* **2019**, *12*, 1643

Not only solvent exchange triggers complexes have been reported but photons energy has also been explored in this research area. Pierri et al. have shown that the water-soluble photo-CORM can be controlled through NIR photons energy. They utilized the amphiphilic polymer for encapsulating the Photo-CORM *trans*-Mn(bpy)(PPh3)(CO2)2 (Figure 23) [47]. Since CO has a strong ligand field (L.F), so its absorption bands lies in higher energy zone almost closer to the UV-region [162]. Usually Photo-CORMats belongs to the MCCs family and having CO photolysis-lability from the excited states of LF associated metal-centered [163]. Although the higher MLCT transitions obviate the ligand re-configuration, during the MLCT exhibition, the photolysis might be a ffected due to π-back-bonding of metal-to-CO configuration [164]. The energy gaps were found between the MLCT and LF excited states. The lower excitation states of MCLT have reduced the ligand lability as compared to LF states [163]. Thus, it is di fficult to construct the Photo-induced-CO-release upon NIR or longer visible wavelengths. Up-conversion nanoparticles (UCNPs), (i.e., lanthanide ion doped) have a utility of uncaging from NIR photolysis wavelengths. UCNPs are already claimed as photodynamic therapy [165,166]. Those research analysts firstly developed the polymer matrix UNCPs@PL-PEG (an amphiphilic phospholipid-functionalized poly(ethylene glycol) then used NIR photons energy as a trigger to release the CO segmen<sup>t</sup> for biological purposes. PL-PEG shows a remarkable characteristic of water solubility and it has also provided space for incoming other soluble photo-organic CORMs. These organic compounds might be helpful for searching the special physiological targets.

**Figure 23.** NIR-responsive amphiphilic polymer conjugates (PhotoCORMats).

#### *2.6. Metal Organic Frameworks (MOFs-CORMats)*

Metzler-Nolte et al. synthesized the hybrid material metal-organic framework as a class of porous coordinated polymer to encapsulate the CO segment. [138]. They established the bio-compatibility with MOFs; NH2-MIL-88B (Fe) andMIL-88B (Fe) by capturing the CO at susceptible FeII and FeIII coordinative unsaturated metal sites (CUSs). Unfavorably, it requires higher activation temperature [167] (≥ 550 K). An adventuring feature of MOF has a breathing e ffect while providing accommodation for CO at the adjacent site; probably having a controlled CO release, potential through the opening/closing gesture of porous MOF.

Instead, it encapsulates the mere CO segment. The research can also accommodate the CORM's fragment inside MOFs. A new class of Manganese carbonyl complex Photo-CORMs has been explored from Zr(IV) based MOF. MnBr(bpydc)(CO)3 (bpydc=5,5'-dicarboxylate-2,2'-bipyridine) embedded into Zr(IV) MOFs [137]. This photo-activated commodity has been evaluated into cellular substrates along with the biocompatible polymer matrix, claimed to be controlled and e fficient light-induced CO-release. After the successful CO release from CORMats, the inability in containment of metal degradation growth, this leads to scientists being reluctant for the employment of genuine medication. The CO has played its own role e ffectively; how other body organisms responds remains questionable.

#### *2.7. Porous Structure Materials*

Porous structure materials have already been in use for encapsulation of the CORMs commodity for the usage of the CO release. Maldonado, Elisa Barea et al. shared the amazing research work about the organometallic community by embedding the anion porous framework with the exhibition of the cation exchange strategy (Figure 24) [50]. This innovation invigorates under physiological condition while it is triggered by visible light. At first, they developed the air-stable, nontoxic, photoactive and water-soluble cation species CORM [Mn(tacn)(CO)3] + (ALF472+) then encapsulates

into anionic porous matrixes belonging to the inorganic framework. Anionic silica matrix exerts the good administration by reducing the CO release kinetics and providing the control-able rate. The ALF472@hybrid silica-SO3 material might support the on/off switch delivery management, probably experiencing the command and control on the released CO. For ensuring the safety of the CORMats, the process metal degradation fragment was examined for ALF472@MCM-41-SO3 up to 72 h and no significant appearance was reported. This silica framework is providing an 80% CORMs metal fragment containment. In phototherapies, the CO supplied is a provocative feature in the controlled manner, such as many inflammatory skin issues and topical skin cancer treatment.

**Figure 24.** Photo-activated ALF472 CORM [Mn(tacn)(CO)3]Br simulated under physiological parameter.

Although many of the CORMats have been explored for therapeutic purposes, but the lack of biocompatibility and inconvenient features like solubility and toxicity from organometallic compounds, it could not be used as a drug agent. To overcome this dilemma, CORM-1 has been embedded into the nonporous fibers structure poly(L-lactide-co-D/L-lactide). The bioavailability and water accessibility were confidently achieved by photo-activated electro-spinning [111]. Specifically, there was no toxicity observed during the mouse fibroblast 3T3 cells culture. This feature might be promoting the CORMats into viable drug materials in the future.
