Capacity of a cis-diammineplatinum[II]-polyglutamic acid complex to cure Trypanosoma congolense infections in mice

Abstract

A cis-diammineplatinum(II)-polyglutamic acid complex proved to have marked trypanocidal activity in vivo. When 5 mg of platinum per kg was administered daily for 5 days or when 20 mg of platinum per kg was administered on days 1, 3, and 6, five of five treated Trypanosoma congolense-infected mice were cured. In contrast, cis-platin was ineffective at all doses tested. We believe that the complex has a much higher therapeutic ratio than does uncomplexed drug because it is less toxic.Cis-platin (CDDP) is an anticancer drug with demonstrable activity against a broad spectrum of human tumors (7). It also effects significant increases in survival of mice infected with Trypanosoma rhodesiense when administered at maximum tolerated doses (4). Recently, Wysor and co-workers were able to cure T. rhodesiense-infected mice with CDDP. They accomplished this by reducing the toxicity of CDDP with hydration and coadministration of the chelator diethyldithiocarbamate and were thus able to administer doses of the drug which would have ordinarily been lethal (9).In this report we have taken a different approach and followed the lead of Williamson and Scott-Finnigan who treated T. rhodesiense-infected mice with daunorubicin complexed to macromolecules to reduce the toxicity of daunorubicin (8). Accordingly, we prepared a macromolecular derivative of CDDP in which cis-diammineplatinum(II) (DP) was bound to polyglutamic acid (PGA). We report here that this complex effected cures of T. congolense-infected mice at tolerated doses.T. congolense TREU 1183 (6) was maintained by serial passage in Rockefeller NCS mice. For evaluation of antitrypanosomal activity, freshly obtained infected blood was diluted with minimal essential medium and counted by phase-contrast microscopy with a Petroff-Hauser cell counter. Mice utilized in assessments of therapeutic activity were inoculated with 105 organisms intraperitoneally. They were then randomized into treatment groups of five mice each and a control group of at least 10 mice. Compounds were dissolved in normal saline except for CDDP, which was not soluble. This latter compound was suspended in normal saline and then sonicated. All drugs were administered intraperitoneally.DP-PGA was synthesized by a two-step process. A solution of cis-Pt(NH3)2(NO3)2 was prepared by reacting AgNO3 (14.34 g) with CDDP (12.0 g) in 100 ml of distilled water at room temperature for 16 h and filtered. Two milliliters of the filtrate was then added to 0.5 g of PGA (sodium salt; weight average molecular weight, 50,000; Sigma Chemical Co., St. Louis, Mo.) in 210 ml of distilled water at room temperature. The reaction mixture was stirred for 20 h and then dialyzed for 6 h (dialysis tubing molecular weight cutoff, 5,000 to 6,000) to remove NaNO3 and unreacted cis-Pt(NH3)2(NO2)2. * Corresponding author.The resulting reaction product contained 0.61% bound platinum as determined by atomic absorption. Infrared spectroscopy of the lyophilized compound confirmed the presence of platinum-carboxyl moiety bonds (unpublished data)....

Cysteine proteases as targets for metal-based drugs

“…97,98 However there still remains a major need for new drugs for both Chagas' disease and leishmaniasis. Several metal complexes including platinum(II) and (IV) complexes [99][100][101][102] and organometallic complexes of iridium, rhodium, palladium and osmium [102][103][104] have been reported to have antiparasitic activity against a variety of trypanosomatids. Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast, [100][101][102][103][104] the molecular target of these compounds has not been defined.…”

Metal compounds for the treatment of parasitic diseases

“…Metal compounds have been shown to have anti-parasitic properties in models of parasitic disease [23][24][25][26][27][28][29][30][31], and the antimonial drugs are still first line treatment for leishmaniasis [2]. However the molecular mechanism of these metal compounds is undefined.…”

“…Several metal complexes have been reported to have anti-parasitic activity such as gold(I) phosphine and chloroquine complexes [23][24][25], platinum(II) and (IV) complexes [26][27][28][29] and organometallic complexes of iridium, rhodium, palladium and osmium [29][30][31] against a variety of trypanosomatids. Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast [27][28][29][30][31], the molecular target of these compounds has not been defined.…”

Pharmacological Approaches to Antitrypanosomal Chemotherapy

“…Unloaded nanoparticles were shown to have some antitrypanosomal activity (Lherm et al 1987, Golightly et al 1988. In another approach involving a molecular carrier, the anticancer drug cisplatin was more effective against T. congolense in mice when complexed with polyglutamic acid than when administered free, probably due to both a longer plasma half-life and improved uptake (Meshnick et al 1984). The applicability of these approaches to the treatment of T. brucei infections always appeared to be limited especially in view of the CNS stage of trypanosomiasis.…”