Liposomes as drug carrier system for cis-diamminedichloroplatinum (II)

Abstract

In this study we have investigated the use of liposomes as a drug carrier system for cis-diamminedichloroplatinum(II) (cis-DDP) in order to reduce the nephrotoxicity with preservation of antitumor activity. Liposomes (PC/PS/Chol 10:1:4) were prepared using hydration media containing no or a relatively low concentration of NaCl. It was found that cis-DDP containing liposomes (lip cis-DDP) injected i.v. to IgM immunocytoma-bearing LOU/M rats at a dose of 1 mg cis-DDP/kg (cumulative dose 7 mg cis-DDP/kg) showed less antitumor activity than the free drug. The optimal cumulative dose of free cis-DDP for induction of antitumor activity in this tumor system is 7 mg/kg (7 X 1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)]. cis-DDP incorporated in DPPC/DPPG/Chol liposomes showed a similar antitumor activity to cis-DDP incorporated in PC/PS/Chol liposomes. After an i.v. dose of 2 mg lip cis-DDP/kg (PC/PS/Chol) kidney damage was less compared to the treatment with free cis-DDP (1 mg/kg). However, after a single dose of 2 mg cis-DDP/kg or a cumulative dose of 8 or 16 mg cis-DDP/kg, kidneys of rats treated with lip cis-DDP contained twice as much Pt as after treatment with free cis-DDP. Moreover, after treatment with lip cis-DDP, a twofold increase of the amount of Pt in tumor tissue was measured. In vitro studies with Pt recovered from spleens obtained from rats treated with lip cis-DDP i.v. showed that based on the equal amounts of Pt recovered the antitumor activity of the recovered Pt was reduced, indicating inactivation of cis-DDP in vivo. As during treatment with free cis-DDP, recurrence of the tumor was observed during the continued treatment with lip cis-DDP. It was found that these recurrent tumors were resistant to further therapy with cis-DDP. In conclusion, cis-DDP encapsulation into liposomes decreased the nephrotoxicity. The antitumor activity of cis-DDP is preserved by liposome encapsulation when it was used at a dose of 2 mg/kg, but it was reduced in terms of earlier onset of regrowth.

Confluence‐dependent resistance in human colon cancer cells: Role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells

“…Intracellular accumulation of VCR and DXR was assayed using radiolabeled compounds; ''C-doxorubicin (1.85 GBq/mmol) and 'H-vincristine (74 GBq/mmol) were obtained from Amersham (Les Ulis, France); cells were lysed with 1N sodium hydroxide and radioactivity was measured in a liquid scintillation counter. CDDP cellular content was measured using graphite furnace atomic absorption spectroscopy (Steerenberg et al, 1987); cells were lysed with 1N sodium hydroxide and aliquots of cell lysate were injected into a Hitachi 27000 Atomic Absorption Spectrophotometer. 'To whom correspondence and reprint requests should be addressed.…”

Tissue distribution evaluation of stealth pH-sensitive liposomal cisplatin versus free cisplatin in Ehrlich tumor-bearing mice

“…This fact can allow for a reduction in or elimination of toxicity and an increase in therapeutic efficacy. Non-long-circulating liposomes composed of phosphatidylcholine/phosphatidylserine/cholesterol were evaluated by Steerenberg et al (1988) as CDDP carriers. This liposome formulation induced a lower incidence and severity of renal lesions on IgM immunocytoma-bearing LOU/M rats when compared to the free CDDP formulation.…”

What Drives Innovation: The Canadian Touch on Liposomal Therapeutics

“…Initial attempts include the work by Steerenberg et al demonstrating that the nephrotoxicity of cisplatin (CDDP) was decreased when the compound was encapsulated in liposomes. However, not only did antitumor activity decrease upon encapsulation, the tumors recurred and resistance to CDDP developed [17]. In contrast, the work by Sharma et al showed a drastic increase in potency against models of ovarian cancer when N -(phosphonoacetyl)- l -aspartate was encapsulated in liposomes [18].…”