Design and development of polynuclear ruthenium and platinum polypyridyl complexes in search of new anticancer agents

The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long and flexible linker. The complexes are characterized and have been studied for anticancer activity. The ruthenium unit of the dinuclear complexes varies in molecular structure, which may result in different interactions with DNA, the target of anticancer platinum and ruthenium antitumor compounds. The monofunctional ruthenium unit coordinates to the DNA-model base 9-ethylguanine. Variable temperature 1H NMR experiments prove that the base is hindered in its free rotation at room temperature. The crystal structure of a dinuclear ruthenium-platinum complex shows that the platinum unit is capable of intercalation and coordination (in)to DNA. Trinuclear and tetranuclear ruthenium and ruthenium-platinum complexes show higher activity than the dinuclear derivatives. A tetranuclear ruthenium complex displays interesting biological features. Human ovarian cisplatin sensitive carcinoma cells adhere together and form clots upon incubation of the complex. The effect possibly indicates antimetastatic activity. Dinuclear and trinuclear ruthenium-platinum complexes of short and semi-rigid linkers do not show significant activity against different cancer cell lines.Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO). Financial support of COST Chemistry D20 for the stay in Brno is gratefully acknowledged.UBL - phd migration 201

[²¹²Pb]Pb-eSOMA-01:A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A series of ligands based on octreotate was developed. Lead-203 was used as an imaging surrogate for the selection of the best candidate for the studies with lead-212. 203/212Pb radiolabeling and in vitro assays were carried out, followed by SPECT/CT imaging and ex vivo biodistribution in NCI-H69 tumor-bearing mice. High radiochemical yields (≥99%) and purity (≥96%) were obtained for all ligands. [203Pb]Pb-eSOMA-01 and [203Pb]Pb-eSOMA-02 showed high stability in PBS and mouse serum up to 24 h, whereas [203Pb]Pb-eSOMA-03 was unstable in those conditions. All compounds exhibited a nanomolar affinity (2.5–3.1 nM) for SSTR2. SPECT/CT images revealed high tumor uptake at 1, 4, and 24 h post-injection of [203Pb]Pb-eSOMA-01/02. Ex vivo biodistribution studies confirmed that the highest uptake in tumors was observed with [212Pb]Pb-eSOMA-01. [212Pb]Pb-eESOMA-01 displayed the highest absorbed dose in the tumor (35.49 Gy/MBq) and the lowest absorbed dose in the kidneys (121.73 Gy/MBq) among the three tested radioligands. [212Pb]Pb-eSOMA-01 is a promising candidate for targeted alpha therapy of NETs. Further investigations are required to confirm its potential.</p

Novel heteronuclear ruthenium-copper coordination compounds as efficient DNA-cleaving agents.

The DNA-cleavage ability of novel bifunctional heterobimetallic copper-ruthenium complexes is demonstrated by using gel electrophoresis.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Additional file 1 of Pharmacodynamics and biodistribution of [195mPt]cisplatin(CISSPECT®) in head and neck squamous cell carcinoma

Additional file 1. Supplementary materials and methods describing the production of Pt-195m radiolabeled cisplatin

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia