The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Abstract

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.

Figure 1

NIH-registered clinical trials involving cisplatin in various parts of the world as of 2015. The numbers reflect only those trials that are open and whose activity has been verified by the NIH within the past two years. Graphic generated using search tools from www.clinicaltrials.gov.

Figure 2

Schematic summary of the topics discussed in this review.

Figure 3

The four steps of the mechanism of cisplatin and, by extension, related platinum anticancer drugs. (i) Cellular uptake, (ii) aquation/activation, (iii) DNA binding, and (iv) cellular processing of DNA lesions leading to apoptosis. Reproduced from reference . Copyright © 2015, The Royal Society.

Figure 3

The structures of double-stranded DNA adducts of different platinum anticancer agents as determined by X-ray crystallography or NMR spectroscopy. (a) Cisplatin 1,2-d(GpG) intrastrand cross-link (PDB 1AIO). (b) Cisplatin 1,3-d(GpTpG) intrastrand cross-link (PDB 1DA4). (c) Cisplatin interstrand cross-link (PDB 1A2E). (d) Oxaliplatin 1,2-d(GpG) intrastrand cross-link (PDB 1PG9). (e) Satraplatin 1,2-d(GpG) intrastrand cross-link (PDB 1LU5). (f) cDPCP monofunctional adduct (PDB 3CO3). Reproduced from reference . Copyright © 2009, The Royal Society of Chemistry.

Figure 4

The paths travelled by cisplatin before and after entering the cell. Attention is drawn to instances where deactivation/sequestration can occur. Reproduced from . Copyright © 2013, The American Chemical Society.

Figure 5

The composition of platinum(IV) prodrugs. Adapted from reference. Copyright © 2014, The American Chemical Society.

Figure 6

Schematic representation of the accumulation of nanoparticles in tumor tissues as a result of the enhanced permeation and retention effect. Reproduced from reference. Copyright © 2014, A. M. Jhaveri and V. P. Torchilin (Creative Commons Attribution License).

Figure 7

Formation of a supramolecular drug delivery device driven by host-guest interactions between a platinum(IV) prodrug and a platinum(II) cage. Reproduced from reference. Copyright © 2015, The Royal Society of Chemistry.

Figure 8

A) A platinum(IV) prodrug designed to mimic a fatty acid. B) The modelled complex of the platinum(IV) prodrug in human serum albumin. Adapted from reference. Copyright © 2014, The American Chemical Society.

Figure 9

Artistic rendition of lipoplatin. The cisplatin core is shown as a blue, roughly spherical ball surrounded by a vesicular lipid bilayer. PEG chains protrude from the surface of the liposome. Adapted from reference. Copyright © 2012, G. P. Stathopoulos and T. Boulikas (Creative Commons Attribution License).

Chart 1

Chemical structures of clinically-approved and marketed platinum anticancer drugs.

Chart 2

Chemical structures of cugar-conjugated platinum(II) complexes.

Chart 3

Chemical structures of estrogen receptor ligands tethered to platinum(II) complexes.

Chart 4

Chemical structures of bile-acid tethered platinum(II) agents.

Chart 5

Chemical structures of folate-targeted platinum(II) complexes.

Chart 6

Chemical structures of platinum(II) complexes tethered to peptides.

Chart 7

Chemical structures of biologically inactive and active trans-platinum(II) agents.

Chart 8

Chemical structures of trans-platinum(II) agents with one or two iminoether ligands.

Chart 9

Chemical structures of trans-platinum(II) agents with one or two aliphatic amine ligands.

Chart 10

Chemical structures of di- and tri-nuclear platinum agents. The pendent aliphatic groups of TriplatinNC-A are shown in the protonated state, raising the overall charge of the complex to 8+.

Chart 11

Chemical structure of platinum(II) complexes that bind to DNA through non-covalent interactions.

Chart 12

Chemical structures of monofunctional platinum(II) complexes.

Chart 13

Chemical structures of platinum(IV) agents that have undergone clinical trials.

Chart 14

Chemical structure of dual-treat platinum(IV) agents.

Chart 15

Chemical structure of dual-treat platinum(IV) agents bearing vitamin E (A) or estrogen (B) derivatives.

Chart 16

Chemical structures of photoactivable platinum(II)-diiodo complexes.

Chart 17

Chemical structures of photoactivable cis- and trans-platinum(II)-diazido complexes.

Chart 18

Carbon-based delivery systems for platinum(IV) prodrugs including single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), and spherical carbon nanoparticles.

Chart 19

Chemical structures of platinum(IV) prodrugs used in the preparation of gold nanoparticle delivery constructs.

Chart 20

Chemical structures of platinum(IV) complexes conjugated to inorganic nanoparticles including lanthanide-based upconversion nanoparticles, quantum dots, iron oxide nanoparticles, and layered double hydroxides.

Chart 21

Depiction of the formation of coordination polymers using metal units to link platinum(IV) prodrugs bearing axial ligands with coordinating motifs.

Chart 22

Depiction of the polymerization of platinum(IV) prodrugs bearing axial ligands with pendent trialkoxysilanes to form platinum-containing polysilsesquioxane nanoparticles.

Chart 23

Platinum complexes encapsulated within polymeric micelles using non-covalent interactions. The complexes are shown next to the polymer (blue) that was used to make the nanoparticle. In the case of the PLGA nanoparticle, PEGylated lipids were used to stabilize the particles formed from the non-amphiphilic polymer.