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Review
. 2022 Nov 22;23(23):14511.
doi: 10.3390/ijms232314511.

Recent Advances in Light-Controlled Activation of Pt(IV) Prodrugs

Daniil Spector  1   2 , Kirill Pavlov  1 , Elena Beloglazkina  1 , Olga Krasnovskaya  1   2
Affiliations
Review

Recent Advances in Light-Controlled Activation of Pt(IV) Prodrugs

Daniil Spector et al. Int J Mol Sci. .

Abstract

Pt(IV) prodrugs remain one of the most promising alternatives to conventional Pt(II) therapy due to their versatility in axial ligand choice and delayed mode of action. Selective activation from an external source is especially attractive due to the opportunity to control the activity of an antitumor drug in space and time and avoid damage to normal tissues. In this review, we discuss recent advances in photoabsorber-mediated photocontrollable activation of Pt(IV) prodrugs. Two main approaches developed are the focus of the review. The first one is the photocatalytic strategy based on the flavin derivatives that are not covalently bound to the Pt(IV) substrate. The second one is the conjugation of photoactive molecules with the Pt(II) drug via axial position, yielding dual-action Pt(IV) molecules capable of the controllable release of Pt(II) cytotoxic agents. Thus, Pt(IV) prodrugs with a light-controlled mode of activation are non-toxic in the absence of light, but show high antiproliferative activity when irradiated. The susceptibility of Pt(IV) prodrugs to photoreduction, photoactivation mechanisms, and biological activity is considered in this review.

Keywords: photoactivatable platinum prodrugs; photocatalysis; photocontrolled chemotherapeutics; photodynamic therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Substrates of photoreduction cisplatin- and carboplatin-based Pt(IV) prodrugs 1–5, electron donors, and photoreduction catalysts flavins and flavoproteins. Flavoproteins used in the photocatalytic studies: miniSOG (mini singlet oxygen generator, NOX (NADH oxidase), GOX (glucose oxidase), GR (glutathione reductase).
Figure 2
Figure 2
Proposed mechanism of photocatalytic reduction of Pt(IV) prodrug 1 by riboflavin (Rf). The mechanism was proposed based on density functional theory and includes the stages of riboflavin excitation, its reduction to RfH- form, conjugation with Pt(IV) prodrug 1 by hydrogen bonding, and further reductive electron transfer to Pt(IV) prodrug core with the formation of cisplatin and initial riboflavin.
Figure 3
Figure 3
Carboplatin and oxaliplatin-based Pt(IV) prodrugs used as a substrate in rhodamine B-promoted photoreduction studies.
Figure 4
Figure 4
Synthesis of the Pt(IV) prodrug hPhorbiplatin 8 with pyropheophorbide a in axial position.
Figure 5
Figure 5
Proposed photoreduction mechanism of Phorbiplatin 8.
Figure 6
Figure 6
Structure of nanocrystals 10–12, modified with PPA-containing Pt(IV) prodrug 9.
Figure 7
Figure 7
Cytotoxicity of NCs 10 on A2780 (A) and A2780cisR (B) cell lines. **, p < 0.01; ***, p < 0.001. Reproduced with permission from Ref. [61]. Copyright 2021 The Royal Society of Chemistry.
Figure 8
Figure 8
Antitumor activity of complexes 9, 11, 12 on 4T1 tumor. Irradiation conditions: 660 nm laser (100 mW cm−2) for 10 min per mouse for prodrug 9, 808 nm laser (0.5 W cm−2) for 30 min (5 min irradiation with 5 min intervals) per mouse for NCs 11 and 12. ***, p < 0.001 Reproduced with permission from [61]. Copyright 2021 The Royal Society of Chemistry.
Figure 9
Figure 9
Synthesis of the Pt(IV) prodrug Coumaplatin 14 and its complex-precursor 13 with coumarin in axial position.
Figure 10
Figure 10
Proposed mechanism of the Pt(IV) prodrug 13 photoreduction.
Figure 11
Figure 11
Synthesis of Pt(IV) prodrugs Rhodaplatin 15 and structures of Pt(IV) prodrugs Rhodaplatins 15 and 16 with rhodamine B in axial position.
Figure 12
Figure 12
Synthesis of the Pt(IV) prodrug Bodi-Pt 17 with bodipy derivative in axial position.
Figure 13
Figure 13
Structures of Pt(IV) prodrugs 17–26 with bodipy derivative in the axial position.
Figure 14
Figure 14
Synthesis of the Pt(IV) prodrug Oxoplatin-B 27 with bodipy derivative in axial position.
Figure 15
Figure 15
Synthesis of the Pt(IV) prodrug 28 with red-light absorbing bodipy derivative in axial position.
Figure 16
Figure 16
Synthesis of the Pt(IV) prodrug 29 with cyanine derivative in axial position.
Figure 17
Figure 17
Synthesis of the polymer Pt(IV) prodrug 30 (exemplary monomer) with poly(phenylene ethynylene in axial position.
Figure 18
Figure 18
SKOV-3 cells viability, incubated with the Pt(IV) prodrug 30, PPE, and oxaliplatin under irradiation (20 min, 460 nm, 7 mW/cm2) or in the dark. (A) 24 h of incubation before irradiation, no removal of residual compound prior to the irradiation. (B) 1 h of incubation before removal of residual compounds and irradiation in fresh media. **** p < 0.0001, *** p = 0.0003, ** p < 0.01, and * p < 0.05. Reproduced with permission from Ref. [64]. Copyright 2022 American Chemical Society.
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