Redox activation of metal-based prodrugs as a strategy for drug delivery

Abstract

This review provides an overview of metal-based anticancer drugs and drug candidates. In particular, we focus on metal complexes that can be activated in the reducing environment of cancer cells, thus serving as prodrugs. There are many reports of Pt and Ru complexes as redox-activatable drug candidates, but other d-block elements with variable oxidation states have a similar potential to serve as prodrugs in this manner. In this context are compounds based on Fe, Co, or Cu chemistry, which are also covered. A trend in the field of medicinal inorganic chemistry has been toward molecularly targeted, metal-based drugs obtained by functionalizing complexes with biologically active ligands. Another recent activity is the use of nanomaterials for drug delivery, exploiting passive targeting of tumors with nano-sized constructs made from Au, Fe, carbon, or organic polymers. Although complexes of all of the above mentioned metals will be described, this review focuses primarily on Pt compounds, including constructs containing nanomaterials.

Figure 1

Pt-based drugs in worldwide clinical use: cis- (1), carbo- (2), and oxaliplatin (3), and clinical use only in some Asian countries: neda- (4), loba- (5) and heptaplatin (6).

Figure 2

Pt(IV) compounds with bioactive ligands (in blue, 7–11): estrogen-tethered Pt(IV) complex (7, n=1–5), ethacraplatin (8), mitaplatin (9), peptide tethered Pt(IV) (10, R¹ = RGD, NGR, c(CRGDC), c(RGDfK)), platinacyclobutane (11, L = pyridine for R² = thymidine, proline, and L = 2,2′-bipyridine for R² = glucose, cholesterol). Tetra- (12), ipro- (13), satraplatin (14), LA-12 (15), cis,cis,trans-[PtCl₂(NH₃)(NH₂R³)(OOCCH₃)₂] (16, R³ = H, isopropyl, cyclohexyl), [PtCl₄(R⁴₂eddp)] (17, R⁴ = ethyl, n-propyl).

Figure 3

Ru(III) compounds NAMI-A (18) and KP1019 (19).

Figure 4

Ferrocifen (20), a ferrocene derivative of tamoxifen, shown in blue. The third phenyl ring in tamoxifen is replaced by ferrocene. At the right is an Fe(III) complex (21) of the MMP inhibitor marimastat, depicted in blue.

Figure 5

Examples of Co(III) complexes with marimastat (22), N₂O donor ligands (23), and acetylacetonato ligands (24).

Figure 6

Examples of Cu(II) complexes for releasing nitrogen mustards based on cyclen (25), cyclam (26), and tacn (27).

Figure 7

Metal-based prodrugs based on carbon nanotubes (28, 29), Au nanoparticles and -rods (30, 31), polymeric nanoparticles made of PLGA-PEG (32) and PLA-PEG (33), and iron-carboxylate nanoscale metal-organic frameworks with silica coating (34). Loaded or coupled Pt(IV) compounds are shown below. As above (Figures 2, 4 and 5), targeting units are shown in blue.

Scheme 1

Activation by reduction: A Pt(IV) prodrug carrying axial ligands L, ammine ligands NH₃, and chlorido ligands Cl⁻ in the equatorial positions yields cisplatin (1) upon reduction accompanied by the loss of both axial ligands. Most probably, a Pt(II) species then binds to nuclear DNA.

Scheme 2

Possible products following reduction of isoptopically labeled 16*.

Scheme 3

Reduction pathways of Ru(III) compounds inside and outside the cell.

Scheme 4

Prodrug mechanism based on Co(III) complexes [1]. Redox cycling in the presence of oxygen and release of the active drug by substitution with aqua ligands under hypoxic conditions.

Scheme 5

Mechanism of prodrugs based on a Cu(II) nitrogen mustard cyclen complex (25).