Internorional Journal/or Parasirology Vol. 23, No. 3, pp. 427429, 1993 Printed in Grear Britain 002&7519/93 16.M) + 0.M) Pergamon Press Lrd 0 1993 Ausmlinn Sociery for Parasifology zyxwvuts RESEARCH NOTE EXPERIENCE WITH DOXORUBICIN-BOUND POLYISOHEXYLCYANOACRYLATE NANOPARTICLES ON MURINE ALVEOLAR ECHINOCOCCOSIS OF THE LIVER M. LIANCE,* F. NEMATI,t C. BoRIEst and P. CoUVREURt *Laboratoire de Parasitologie, Faculte de Midecine, 8 rue du GBn&ral Sarrail, 94000 Cr&teil, France TLaboratoire de Pharmacie galenique et Biopharmacie, URA CNRS 1218, Facultt de Pharmacie, 92296 Chatenay- Malabry, France (Received 16 December 1992; accepted 24 January 1993) Abstract-FIANCE M., NEMATI F., BORIES C. and COUVREUR P. 1993. Experience with doxorubicin-bound polyisohexylcyanoacrylate nanoparticles on murine alveolar echinococcosis of the liver. Znrernational Journalfor Parasitology 23: 427-429. The parasiticidal properties of doxorubicin against the metacestode of Echinococcus multiloculuris were investigated after binding of that drug to polyisohexylcyanoacrylate nanoparticles, a colloidal biodegradable drug carrier. A reduction of the hepatic parasite development and a reduced viability of the metacestode were observed in mice injected with 5 mg kg-’ body weight-‘, but 7.5 mg kg-’ body weight-’ did not appear more efficient. Free doxorubicin or unbound nanoparticles had no antiparasitic activity. INDEX KEY WORDS: Echinococcus multiloculuris; murine model; hepatic alveolar echinococcosis; nanoparticles; doxorubicin. THE potentially unlimited proliferation of Echino- coccus multilocularis metacestodes is responsible for alveolar echinococcosis, a neoplastic-like hepatic disease. Chemotherapy of human patients with benzimidazoles is still not yet satisfactory (Eckert, 1991). To date only two experimental therapeutic approaches have been shown partially effective in a rodent model with an induced peritoneal infection. The first, Mitomycin C, is used in the treatment of human cancers (Novak, 1990). It has been suggested that the second one, Isoprinosine, inhibited the larval growth by inducing damages in the nucleic acids synthesis (Sarciron, Al-Nahhas, Walbaum, Raynaud & Petavy, 1991). Following these studies and taking into account the primary localization of the parasite in the liver, we have tested the efficacy of doxorubicin loaded onto polyisohexylcyanoacrylate nanoparticles. In fact, it has been shown previously that this binding resulted in a preferential tissue distribution of the drug to the liver (Verdun, Brasseur, Vranckx, Couvreur & Roland, 1990), with a subsequent re- duced toxicity and an increased antitumoral activity (Chiannilkulchai, Driouich, Benoit, Parodi & Couvreur, 1989). * To whom all correspondence should be addressed. Free doxorubicin was obtained from Farmitalia Carlo Erba (Rueil-Malmaison, France), and iso- hexylcyanoacrylate (IHCA) monomer from Sopar (Start-Dames-Avelynes, Belgium). Doxorubicin-bound nanoparticles were prepared by polymerization of IHCA, according to Couvreur, Roland & Speiser (1982). Unbound PIHCA nanoparticles were pre- pared in the same way. For doxorubicin-bound nanoparticles 0.1 ml of the suspensions used for animal treatment contained 1.6 mg of nanoparticles, expressed in polymeric compound, and 0.075 mg of entrapped doxorubicin. The size of the nanoparticles ranged from 250 to300 nm, and their number was 1.9 X lOI* ml-‘. Groups of 10 AKR female mice (C.N.R.S- C.S.A.L., OrlCans, France), 6 weeks old, received an intrahepatic inoculum of an E. multilocularis meta- cestode suspension, as previously described (Liance, Vuitton, Guerret-Stocker, Carbillet, Grimaud & Houin, 1984). Treatments were performed by inject- ing via the tail vein 0.1 ml of the nanoparticle suspensions, or free doxorubicin solution (same dose of doxorubicin). Three administration schedules of bound doxorubicin were established for 30 g in- fected-mice. Mice of group 1 received a single dose of 2.5 mg kg-’ body weight-’ at day 70 p.i. Those of groups 2 and 3 received additional injections of the 427