Recent progress in stimuli-activable metallo-prodrugs for cancer therapy

Abstract

The clinical approval of platinum-based drugs has prompted the development of novel metallo-complexes during the last several decades, while severe problems, especially for poor water solubility, drug resistance and toxicity in patients, greatly hindered the clinical trials and curative efficacy. To address these issues, the concept of metallo-prodrugs has been proposed for oncology. Some stimuli-activable metallo-prodrugs provide new insights for designing and preparing site-specific prodrugs with maximized therapeutic efficacy and negligible unfavorable by-effects. In this review, recent progress in stimuli-activable metallo-prodrugs in the past 20 years has been overviewed, where endogenous and exogenous stimuli have been involved. Typical examples of smart stimuli-activable metallo-prodrugs are discussed regarding to their molecular structure, activation mechanism, and promising biomedical applications. In the end, challenges and future perspectives in metallo-prodrugs have been discussed.

Keywords: cancer therapy; metallo‐prodrugs; stimuli‐activable.

SCHEME 1

Schematic illustration of stimuli‐responsive metallo‐prodrugs for cancer therapy.

FIGURE 1

FDA‐approved anti‐cancer Pt(II) metallodrugs and Pt(IV) complexes in clinical trials.

SCHEME 2

Schematic illustration of endogenous‐ and exogenous‐stimuli‐activable metallo‐prodrugs for cancer therapy.

FIGURE 2

Chemical structures of pH‐responsive metallo‐prodrugs 1–3.

FIGURE 3

(a) Mechanism scheme of the ADEPT system utilizing β‐lactamase enzyme and platinum complex. (b) Chemical structures of two anti‐tumor Pt prodrugs, DACCP and DACH. (c) Hydrolysis reaction of a β‐glucuronide‐based Pt metallo‐prodrug 5.

FIGURE 4

(a) H₂O₂‐activable aminoferrocene prodrug 6. (b) Schematic illustration of the Fe³⁺‐responsive FerriIridium 7.

FIGURE 5

Chemical structures of redox‐activable Pt(IV) prodrugs 8–11 conjugated with SWCNT/MWCNT.

FIGURE 6

(a) Chemical structure of Pt(IV) prodrug 12 and lowest energy docked conformation of HSA‐Pt nanocomposite. Reproduced with permission: Copyright 2014, American Chemical Society. (b) Chemical structure of Pt(IV) prodrug PFL 13. (c) Schematic illustration of redox‐activable Pt(IV) prodrug 13 and the subsequent cellular toxicity mechanism. Reproduced with permission: Copyright 2020, American Chemical Society. (d) Chemical structures of hypercarbon‐centered polynuclear Au(I) clusters PAA4 (14a) and PAA5 (14b).

FIGURE 7

(a) Schematic mechanism of ultraviolet‐light‐responsive Ir(III) prodrugs 15 a‐b. (b) Chemical structure of Pt(IV) complex 16.

FIGURE 8

(a) The proposed responsive mechanism of coumaplatin 17 by 450 nm blue light in PBS buffer. (b) Photo‐responsive BODIPY–Pt prodrug 18.

FIGURE 9

Chemical structures of Pt(IV) prodrug 19 (phorbiplatin) and Ru(II)‐based prodrugs 20a‐b.

FIGURE 10

(a, b) Mechanistic scheme of the action of the Ir(III) prodrug 21 by synergistic photodynamic therapy/photo‐activated chemotherapy. Reproduced with permission: Copyright 2022, American Chemical Society. ^[34a]

FIGURE 11

(a) Chemical structures of Pt 22a and 22b. (b) Chemical structure of the functionalized polyplatin 23 (P1), which consists of the Pt(IV) complex, the aggregation‐induced emission (AIE) moiety, and terminal targeting peptides R⁸K. (c) In an aqueous solution, the polyplatin can self‐assemble into NPsT. The dissociation of the NPsT is triggered by the NIR‐I laser. Reproduced with permission: Copyright 2022, WILEY‐VCH. ^[34c]

FIGURE 12

(a) Chemical structure of cyaninplatin, Pt(IV) complex 24. (b) Illustration of self‐assembly of HGB with a hydrophobic Pt(IV) complex (Pt 25) into nanoparticles. Reproduced with permission: Copyright 2023, WILEY‐VCH. ^[35b] (c) Schematic illustration of degradation of Ru‐Si 26 exposed by X‐ray radiation. Reproduced with permission: Copyright 2023, WILEY‐VCH.

FIGURE 13

(a, b) Chemical structures of redox/light‐activable (a) Pt(II) complexes 27a‐c and (b) dinuclear ruthenium(II)‐azo complex 28. (c) Scheme of NIR‐I laser induced light‐inducible nano‐cargo (LINC) for self‐amplified strategy and chemoimmunotherapy. Reproduced with permission: Copyright 2019, WILEY‐VCH. (d) Synthetic scheme and mechanism of action of Ir@SeNPs@CC nanocomposite for synergistic chemotherapy and two‐photon photodynamic therapy.

FIGURE 14

(a) Chemical structures of pH/light‐activable Ru(II) complex 31–32. (b) Photocatalytic transformation of Au prodrug 33 into the resulting Au(III)–S adduct under the existence of a 100‐fold excess of NAC.

FIGURE 15

(a) Chemical structure of clustered PCL‐CDM‐PAMAM/Pt 34 and the pH/redox dual‐activable mechanism of iCluster/Pt in tumor microenvironment. Reproduced with permission: Copyright 2016, National Academy of Sciences. (b) Synthetic scheme of the Pt–HSA/CaP nanocomposites and the release of active cisplatin in response to low pH and cellular reductants. Reproduced with permission: Copyright 2015, WILEY‐VCH. (c, d) Schematic illustration of (c) physical adsorption and oxidative polymerization of a cisplatin‐based prodrug 36, termed Pt(IV)SS@CaCO₃@Biotin, and (d) Pt(IV)SS@CaCO₃@Biotin‐induced chemoimmunotherapy by releasing cisplatin drug, producing ROS and exhausting GSH to stimulate synergistic anti‐cancer effect of apoptosis and ferroptosis. Reproduced with permission: Copyright 2021, Elsevier.

FIGURE 16

(a) Scheme of Caspase‐3/NIR‐light dual activation of Pt(IV) prodrug 37. Reproduced with permission: Copyright 2014, WILEY‐VCH. (b) Light activation of Pt(IV) prodrug 38. Reproduced with permission: Copyright 2015, American Chemical Society.

FIGURE 17

(a) Chemical structure of P‐CyPt 39, which undergoes membrane‐bound ALP‐triggered dephosphorylation and in‐situ self‐assembly process into Pt(IV) nanoparticles, followed by GSH‐stimulated disassembly to rapidly release the fluorescent Cy‐COOH and cytotoxic cisplatin. (b) Mechanism of intravenous injection of P‐CyPt for in vivo fluorescent/photoacoustic bimodal imaging‐guided chemotherapy of HepG2 tumors. Reproduced with permission: Copyright 2023, Springer Nature.

FIGURE 18

Design and activation of the azoreductase/hypoxia/redox‐responsive organo‐Ir(III) prodrug 40, IrCpNM. Reproduced with permission: Copyright 2024, American Chemical Society.

FIGURE 19

Chemical structure of esterase/pH/radiation multi‐stimuli‐activable Ir(III)‐based prodrug 41, Ir‐NB.