Toxicity and anti-tumor activity of hydrophobic diammine and diaminocyclohexane platinum complexes entrapped in multilamellar vesicles

The toxicity and anti-tumor activity of a lipophilic diaminocyclohexane (DACH) platinum complex entrapped in liposomes (liposomal-cis-bis-neodecanoate-trans-R, R-1, 2-DACH platinum IL-L-NDDP) were compared with those of the liposomal preparation of the same compound without the DACH group (liposomal-cis-bis-neodecanoato-(diammine) platinum II-L-CNDP). Both liposomal preparations had the same liposome size distribution, drug entrapment efficientcy (> 95%), and liposome stability (> 95%). Although no differences were observed in the mouse LD₅₀ (60.2 mg/kg for L-NDDP vs 67.8 mg/kg for L-CNDP), the liposome entrapped non-DACH compound (L-CNDP) was more nephrotoxic than the liposome entrapped DACH compound (L-NDDP), but much less than cisplatin (CDDP) (mean BUN elevation 4 days after the administration of the LD₅₀ dose 67 mg% for L-CNDP vs 30 mg% for L-NDDP vs 255 mg% for CDDP). L-NDDP was not cross-resistant with CDDP against L1210/CDDP leukemia while L-CNDP was cross-resistant (%T/C 200 for L-NDDP, 112 for CDDP, and 100 for L-CNDP). In addition, L-NDDP was slightly more active than L-CNDP against i.p. L1210/0 leukemia and i.v. M5076 reticulosarcoma. These studies suggest that the attachment of a cyclohexane group to the amino functions of lipophilic platinum complexes results in a decrease of the nephrotoxicity and a lack of cross-resistance with CDDP. The lack of cross-resistance is preserved when the compounds are entrapped and delivered in a liposomal carrier but not when they are delivered in a micellar suspension.