Nedaplatin

Available forms

Nedaplatin comes as a powder, since it is unstable in a solution.^[7] For clinical administration, it is dissolved in a liquid and administered intravenously.^[3][8]

Mechanism of action

Disruption of the DNA structure caused by the crosslinksobstructs the DNA polymerases, preventing DNA replication and transcription. This causes the cell to go into cell cycle arrest it cannot go on from the G2 to the M phase and stops at the G2/M checkpoint. The cell tries to repair the DNA before dividing.^[1]

The intrastrand crosslinks are normally repaired by the excision repair pathway. It attempts to remove the platinum adducts. If repair fails or is insufficient, apoptosis is induced and leads to cell death. However, cancer cells have impaired apoptosis pathways limited DNA repair pathways. This can decrease the efficacy of the drug and can lead to resistance to the drug.^[1][12]

It has been observed that radiotherapy pairs well with administration with the drug, but how this works is not entirely established. It is known that cells that cells that are stuck at the G2/M phase of the cell cycle and have impaired DNA repair system are more sensitive to radiotherapy. This suggests that nedaplatin is a radiosensitizer,^[10]

Pharmacokinetics

Nedaplatin is administered in its active form and is removed from the bloodstream by the kidneys to leave the body via the urine.^[8]  

The recommended therapeutic dose of nedaplatin is 80–100 mg/m² of body surface area. Optimal dosing is determined using measurements of unbound platinum concentrations following intravenous infusion together with an assessment of renal function using creatinine clearance. The dose can be estimated using Ishibashi’s formula:^[1] Dose_NDP = AUC × CL_NDP, where CL_NDP = 0.0738 × creatinine clearance + 4.47 The precise mechanism of cellular uptake is not fully understood, and substantially less information is available compared with cisplatin. However, nedaplatin does not interact with the Oct2 transporter or apical multidrug and toxin extrusion (MATE) transporters, which may contribute to its lower accumulation in renal proximal tubules.

Structure

Like most Platinum-based anti cancer drugs, nedaplatin is a square planar platinum(II) complex. It contains two leaving groups in the form of the glycolate and two mutually cis amines.^[13]

Reactivity

Activation of platinum drugs occurs through displacement of the leaving groups by water molecules. In nedaplatin, the glycolate ligand leaves the complex through two consecutive aquation reactions, in which water hydrolyses the ligand and sequentially replaces it. In this activated state, nedaplatin becomes highly electrophilic and readily forms stable complexes with soft nucleophiles.^[3][14][15] The active species reacts with nucleobases within DNA, preferentially at guanine and, less frequently, adenine. It primarily forms intrastrand crosslinks, including 1,2-adducts between adjacent guanines and 1,3-adducts between guanines separated by a single nucleotide residue, bending the DNA helix and disrupting its structure.^[15] Formation of the active species depends on the rate of hydrolysis, which is influenced by the identity of the leaving ligand. The glycolate ligand hydrolyses relatively readily under physiological conditions, producing the active species at a comparatively uniform rate throughout the body. This differs from cisplatin, whose chloride leaving groups hydrolyse more rapidly in low-chloride environments.^[15] Although nedaplatin has a high affinity for nucleobases, it can also bind other soft nucleophiles, including purine alkaloids and sulfur-containing proteins. Binding to these non-target biomolecules can reduce its interaction with DNA, thereby diminishing its anti-cancer activity.^[15]

Synthesis

Nedaplatin is synthesized from platinum(II) tetraiodide [PtI₄]²⁻ by treatment with silver nitrate, followed by reaction with a glycolate salt to form the final complex.^[16]