The effect of charge on the uptake and resistance to reduction of platinum(<scp>iv</scp>) complexes in human serum and whole blood models

Chen, Catherine K. J.; Xiao, Gui; Kappen, Peter; Renfrew, Anna K.; Hambley, Trevor W.

doi:10.1039/d0mt00157k

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…Intracellularly, a platinum(IV) complex is reduced into its platinum(II) congener and axial ligands in the presence of biological reducing agents such as AsA or glutathione [ 33 , 61 , 70 , 71 , 72 , 73 ]. This report followed the reduction in PCLB , 5CLB , and 56CLB using 1 H-NMR and 1D- 195 Pt-NMR spectroscopy.…”

Section: Resultsmentioning

confidence: 99%

Potent Chlorambucil-Platinum(IV) Prodrugs

Aputen

Elias

Gilbert

et al. 2022

IJMS

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The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.

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Section: Resultsmentioning

confidence: 99%

Potent Chlorambucil-Platinum(IV) Prodrugs

Aputen

Elias

Gilbert

et al. 2022

IJMS

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“…Platinum(IV) complexes are reduced to their platinum(II) precursors by intracellular biological reducing agents such as AsA or GSH in tumour cells [ 33 , 83 , 84 , 85 ]. However, the precise mechanism by which reduction occurs is not fully understood.…”

Section: Resultsmentioning

confidence: 99%

Bioactive Platinum(IV) Complexes Incorporating Halogenated Phenylacetates

et al. 2022

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A new series of cytotoxic platinum(IV) complexes (1–8) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes 1–8 were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely 4 and 6, eliciting an average GI50 value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, 4 exhibited the highest degree of potency amongst the derivatives, displaying a GI50 value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, 56MESS (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, 4 (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes’ solubility, stability, lipophilicity, and reactive oxygen species production.

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“…Since the proposed ITI approach is dependent on the kinetic competition between cellular uptake and extracellular decomposition, and this is characteristic for transition metal complexes, these complexes are ideal for such ITI applications (Figures 2-6) [33,36]. In addition, Pt(IV) and Co(III) prodrugs that are activated by the reduction in the hypoxic environment of solid tumors (Figure 8) [49][50][51]53,56,190] can benefit from ITI by avoiding reduction in red blood cells before reaching the tumor target [54][55][56]. Generally, any cytotoxic metal complex can be considered for the use in ITI if it decomposes in an extracellular medium at a comparable rate with its cellular uptake and the decomposition products show lower toxicity compared with the initial complex [57].…”

Section: Conclusion and Future Potential Applicationsmentioning

confidence: 99%

Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections

2022

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Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous route. Such hydrophobic metal-containing complexes are rapidly taken up into cancer cells and cause cell death, while the release of their relatively non-toxic decomposition products into the blood has low systemic toxicity and, in some cases, may even be beneficial. This concept was recently proposed for V(V) complexes with hydrophobic organic ligands, but it can potentially be applied to other metal complexes, such as Ti(IV), Ga(III) and Ru(III) complexes, some of which were previously unsuccessful in human clinical trials when administered via intravenous injections. The potential beneficial effects include antidiabetic, neuroprotective and tissue-regenerating activities for V(V/IV); antimicrobial activities for Ga(III); and antimetastatic and potentially immunogenic activities for Ru(III). Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, further enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections. However, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor.

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The effect of charge on the uptake and resistance to reduction of platinum(iv) complexes in human serum and whole blood models

Abstract: Platinum(iv) complexes can be modified by incorporating negatively charged ligands in order to inhibit cellular uptake and reduction in whole blood.

Cited by 8 publications

References 44 publications

Potent Chlorambucil-Platinum(IV) Prodrugs

Potent Chlorambucil-Platinum(IV) Prodrugs

Bioactive Platinum(IV) Complexes Incorporating Halogenated Phenylacetates

Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections

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