5.1 Aquation of cisplatin

After intravenous administration, the cisplatin complex dissolves in the water of the bloodstream, in which it is carried and passes into cells, crossing their membrane by passive diffusion.

As the complex is neutral, it can easily pass through the lipophilic cell membrane.

Recent research has also suggested that the copper transporters CRT1 and CRT2 may also play a role in the uptake of cisplatin.

Fortunately, in practice, the high concentration of chloride ions in the blood suppresses the hydration of cisplatin, and it passes into the cells mostly unchanged.

However, once in the cells, it is a different story.

The concentration of chloride is now much lower (4 mmol  inside, compared with 100 mmol  outside). Cisplatin slowly reacts stepwise with the water in the cells to form first the monosubstituted aqua complex and then the disubstituted ion.

Equation 2 shows the hydration equilibria involved.

and studies have shown that the mono-aqua square-planar complex is the active species.

This is illustrated in the next video, in which Professor Stephen Lippard (MIT) describes some of the work completed to help understand the chemistry involved.

There is a 2–3 h delay in sensitisation after the administration of cisplatin due to the slow formation of this substituted complex.

The positive charge on the substituted complex means that it is attracted to the negatively charged surface of the DNA in the cell. This was confirmed by treatment of cancer cell cultures with a high dose of -radiolabelled cisplatin, which shows where cisplatin binds in the cells.

Analyses indicated there were about 9 Pt per 1 DNA molecule, compared with ~1 Pt in protein molecules and ~1 Pt per 10–1000 RNA molecules.

In addition, it was found that there is a correlation between Pt–DNA adducts in circulating (peripheral) blood cells and disease response in patients given cisplatin.

So Pt–DNA binding has been the main focus of further studies.