Cisplatin

Example 17

50 μmol (Gd³⁺) of AGuIX® were redispersed in 125 μl of ultrapure water in order to obtain a solution at 400 mM [Gd³⁺]. 2.8 mg of cisplatin are placed in a 2.5 ml flask. 1.1 ml of ultrapure water are added to the flask, which is stirred. Since cisplatin is not very soluble at ambient temperature, it is necessary to heat to 40° C. until it is completely dissolved. A solution containing 2.5 g/l of cisplatin is then obtained, and is protected from the light with aluminium. 229 μl of this solution are then added to the solution of AGuIX®, as are 146 μl of ultrapure water. The flask is stirred for 30 minutes in the dark. A solution containing 100 mM of gadolinium and 1160 mg/l of cisplatin is thus obtained.

This solution is placed in a 3 kDa Vivaspin®, and a tangential filtration cycle is carried out so as to obtain a supernatant of 160 μl. The subnatant is analysed by UV-visible analysis. The cisplatin is detectable by UV/VIS absorption at a wavelength of 706 nm after reaction with ODPA. For the reaction with cisplatin, a solution of ODPA at 1.4 mg/ml and a phosphate buffer (pH 6.8) are prepared. The subnatant is diluted 5-fold. 140 μl of this solution are added to 200 μl of buffer and 100 μl of ODPA. The resulting solution is heated at 100° C. for 15 min.

Once the reaction is finished and the temperature has returned to ambient temperature, 560 μl of DMF are added. The final solution is filtered and then analysed by UV-visible analysis.

Example 6

For the synthesis of platinum based anti cancer prodrugs, two approaches may be followed. The first approach (FIG. 10) may involve the preparation of an amine terminated cis platin (9) followed by conjugation with oxidized lipids. The coupling intermediate produced from the amidation reaction of compound 8 with mono Boc-ethylenediamine in presence of HATU/DIPEA, may be subjected to deprotection to produce compound 9. Compound 9 may undergo reductive amination with ALDO PC in methanol to generate cis platin prodrug-1 (10).

A second approach (FIG. 11) may involve the synthesis of an analogue bearing hydrophobically modified chelating diamines. Cis-platin intermediate 16 may be obtained in three steps from compound 13. Intermediate 16 may be subjected to complexation with K₂PtCl₄ by maintaining the pH of the resulting solution at pH 6-7. Finally, compound 13 may undergo reductive amination with ALDO (PC) or (PE) to produce cis platin prodrug-2 (18).

Example 3

A female patient with cervical carcinoma is treated with combined radiation therapy and chemotherapy+NVX-108. Radiation dosage is 45 Gray (Gy) in 20 fractions followed by low dose-rate intracavitary application of 30 Gy to the cervical region. Chemotherapy consists of intravenous cisplatin 40 mg/m2 every week for up to 6 weekly cycles. The patient is administered a bolus IV dose of 0.2 cc/kg NVX-108 (2% w/vol DDFPe) 60 minutes prior to each dose of radiation. Follow-up shows complete response to treatment.