Platinum(II) Complexes with Bioactive Carrier Ligands Having High Affinity for the Translocator Protein

Margiotta, Nicola; Denora, Nunzio; Ostuni, Rosa; Laquintana, Valentino; Anderson, A.; Johnson, Steven W.; Trapani, Giuseppe; Natile, Giovanni

doi:10.1021/jm100429r

Cited by 63 publications

(43 citation statements)

References 37 publications

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“…For example, of the 20 most recent papers reporting new chemical entities based on platinum in the Journal of Medicinal Chemistry, seven (35%) used DMF to dissolve complexes for biological testing, five (25%) did not state the solvent used, and three (15%) used DMSO (Table S6). Alternative solvents such as DMF have been reported not to cause cytotoxicity below 0.5% (45), and solutions of cisplatin dissolved in DMF retain activity (46). However, while DMF is recognized as cytotoxic towards cells (47), there appears to be no comprehensive assessment of DMF's utility as a drug (or platinum complex) solvent.…”

Section: Discussionmentioning

confidence: 99%

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

et al. 2014

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The platinum drugs cisplatin, carboplatin and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11 - 34%) in prominent cancer journals utilizing cisplatin dissolved in dimethylsulfoxide (DMSO). However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes the structure of the complex. We examined the effect of DMSO on platinum complexes, including cisplatin, carboplatin and oxaliplatin, finding that DMSO reacted with the complexes, inhibited their cytotoxicity and their ability to initiate cell death. These results render a substantial portion of the literature on cisplatin uninterpretable. Raising awareness of this significant issue in the cancer biology community is critical, and we make recommendations on appropriate solvation of platinum drugs for research.

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Section: Discussionmentioning

confidence: 99%

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

et al. 2014

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“…Similar to cisplatin, these complexes also induce apoptosis but show a 10−100-fold enhanced accumulation in glioma cells. 15 …”

Section: Functionalization With Receptor-specific Ligandmentioning

confidence: 99%

Functionalization of Platinum Complexes for Biomedical Applications

2015

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Platinum-based anticancer drugs are the mainstay of chemotherapy regimens in clinic. Nevertheless, the efficacy of platinum drugs is badly affected by serious systemic toxicities and drug resistance, and the pharmacokinetics of most platinum drugs is largely unknown. In recent years, a keen interest in functionalizing platinum complexes with bioactive molecules, targeting groups, photosensitizers, fluorophores, or nanomaterials has been sparked among chemical and biomedical researchers. The motivation for functionalization comes from some of the following demands: to improve the tumor selectivity or minimize the systemic toxicity of the drugs, to enhance the cellular accumulation of the drugs, to overcome the tumor resistance to the drugs, to visualize the drug molecules in vitro or in vivo, to achieve a synergistic anticancer effect between different therapeutic modalities, or to add extra functionality to the drugs. In this Account, we present different strategies being used for functionalizing platinum complexes, including conjugation with bisphosphonates, peptides, receptor-specific ligands, polymers, nanoparticles, magnetic resonance imaging contrast agents, metal chelators, or photosensitizers. Among them, bisphosphonates, peptides, and receptor-specific ligands are used for actively targeted drug delivery, polymers and nanoparticles are for passively targeted drug delivery, magnetic resonance imaging contrast agents are for theranostic purposes, metal chelators are for the treatment or prevention of Alzheimer's disease (AD), and photosensitizers are for photodynamic therapy of cancers. The rationales behind these designs are explained and justified at the molecular or cellular level, associating with the requirements for diagnosis, therapy, and visualization of biological processes. To illustrate the wide range of opportunities and challenges that are emerging in this realm, representative examples of targeted drug delivery systems, anticancer conjugates, anticancer theranostic agents, and anti-AD compounds relevant to functionalized platinum complexes are provided. All the examples exhibit new potential of platinum complexes for future applications in biomedical areas. The emphases of this Account are placed on the functionalization for targeted drug delivery and theranostic agents. In the end, a general assessment of various strategies has been made according to their major shortcomings and defects. The original information in this Account comes entirely from literature appearing since 2010.

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“…In our previous studies, potent and selective imidazopyridine-based TSPO ligands—which could carry both a cytostatic platinum species and a rhenium complex as the precursor for introducing the 99m Tc-(CO) 3 unit—were reported [25,26,27,28,29,30]. Among the imidazopyridine-based TSPO ligands investigated so far, 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl) H imidazo [1,2- a ] pyridin-3-yl)- N , N -dipropylacetamide (CB256, 3 ) contains the TSPO-targeting moiety and a metal ion anchor, namely di-(2-picolyl)amine, for a bifunctional chelate approach [29].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Tricarbonyl 99mTc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

Choi

Iacobazzi

Perrone

et al. 2016

IJMS

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The 18-kDa translocator protein (TSPO) levels are associated with brain, breast, and prostate cancer progression and have emerged as viable targets for cancer therapy and imaging. In order to develop highly selective and active ligands with a high affinity for TSPO, imidazopyridine-based TSPO ligand (CB256, 3) was prepared as the precursor. 99mTc- and Re-CB256 (1 and 2, respectively) were synthesized in high radiochemical yield (74.5% ± 6.4%, decay-corrected, n = 5) and chemical yield (65.6%) by the incorporation of the [99mTc(CO)3(H2O)3]+ and (NEt4)2[Re(CO)3Br3] followed by HPLC separation. Radio-ligand 1 was shown to be stable (>99%) when incubated in human serum for 4 h at 37 °C with a relatively low lipophilicity (logD = 2.15 ± 0.02). The rhenium-185 and -187 complex 2 exhibited a moderate affinity (Ki = 159.3 ± 8.7 nM) for TSPO, whereas its cytotoxicity evaluated on TSPO-rich tumor cell lines was lower than that observed for the precursor. In vitro uptake studies of 1 in C6 and U87-MG cells for 60 min was found to be 9.84% ± 0.17% and 7.87% ± 0.23% ID, respectively. Our results indicated that 99mTc-CB256 can be considered as a potential new TSPO-rich cancer SPECT imaging agent and provides the foundation for further in vivo evaluation.

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Platinum(II) Complexes with Bioactive Carrier Ligands Having High Affinity for the Translocator Protein

Cited by 63 publications

References 37 publications

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

Functionalization of Platinum Complexes for Biomedical Applications

Synthesis and Evaluation of Tricarbonyl 99mTc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

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