Abstract
The management of patient pain associated from bone or metastatic cancer requires a multidisciplinary approach, and necessitates the use of chemotherapy, hormone treatment, radiotherapy, surgery, bisphosphonate chelators and radioisotopes. All these treatment options attempt to provide palliative treatment to widespread painful bone lesions while simultaneously avoiding additional unwanted side effects to the patient. There is thus room for treatment improvement to provide mankind with the best quality of life. Among these, radiopharmaceuticals provide a promising, tailor-made treatment option as it utilizes bone-seeking functionalities that contains suitable radiometal isotopes. The d-block metals utilised in radiopharmaceuticals as bone cancer palliation agents are numerous, e.g., indium, thallium, chromium, barium, strontium, rhenium, ruthenium and molybdenum, but f-block elements from the lanthanide series have several advantages over the above, which include the ability to accumulate at rapid bone growth sites, a feature that is associated with either fracture or cancer. This selectivity results in delivering a highly region-specific radiation dose, mainly through β-particle emission that does not penetrate deep enough to affect healthy bone marrow.
To utilize these elements as radiopharmaceuticals, the accompanying ligands need to be tailored for physiological stability and additional guidance to the bone lesions. In this study, N-nitroso-N-phenylhydroxylamine (cupferron, L1) was selected as the core for the accompanying ligand. Our attempts towards derivatization at the phenyl ring through halogenation, methylation or phosphonation to promote water-solubility and bone-seeking ability did not have the desired effect. Instead, an alternative route where L1 and its halogen derivatives, i.e., chlorocupferron (L2) and bromo cupferron (L3) were combined with 1-aminoethanol-1,1-diyldiphosphonic acid (bisphosphonate) to generated heteroleptic complexes of Sm (III), Ho (III) and Tb (III), forming
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a series of water-soluble complexes (C1–C9). Prior to the complexation, computational study was used to investigate the suitability of the ligands for complexation. These ligands and their complexes were characterized by elemental analysis (CHN, Sm, Ho, Tb and P), IR, 1H, 31P, 15N and 13C{H}NMR, HRMS, TGA, SEM-EDX and UV-Vis spectroscopic techniques, confirming the mixed ligand complexes in 1:1:1 mole ratio of ligands to metal. The presence of halogens offers some structural advantage such as increase binding affinity, membrane permeability, and bioavailability.
To maximise their potential by undertaking scoping biological studies, the ligands and their complexes were screened for antimicrobial on selected Gram-positive bacteria and Gram-negative bacteria, and cyto-toxicity studies using osteosarcoma-MG-63 (bone cancer) and osteoblast-MG-63 (healthy) cell lines. The result of the antimicrobial studies showed that the complexes are more potent than the free ligands on all the organisms at the concentrations tested. The order of antimicrobial strength of the complexes is Sm (III) > Ho (III) > Tb (III), while the cyto-toxicity studies of complexes on osteosarcoma cell line and osteoblast cell line showed marked toxicity effects on osteosarcoma cells with limited toxicity effect on the osteoblast cells. This means that, even in the absence of radioisotopes, these complexes show promise for the specific indications.
The octanol-water partition coefficient study revealed that all the ligands and their complexes are lipophilic with the bisphosphonate showing hydrophilic properties. Bone adsorption studies on hydroxyapatite (HAP) as in vitro bone model revealed that all the complexes have high binding affinity to HAP and release of calcium as characterized by PXRD, TGA, FTIR and SEM-EDX.