Therapy of leishmaniasis: Superior efficacies of liposome-encapsulated drugs

Abstract

Liposomes containing antimonial compounds trapped in the aqueous phase were tested in the treatment of experimental leishmaniasis. The rationale of this approach was based on the hypothesis that the liposomes and the parasite are taken up by the same cell, the reticuloendothelial cell, and we present electron microscopic evidence that supports this hypothesis. Suppression of leishmaniasis was quantified by determining the total number of parasites per liver from impression smears. When two antimonials, meglumine antimoniate and sodium stibogluconate, were encapsulated within lipo somes, each was more than 700 times more active compared to either of the free (unencapsulated) drugs. After infection, if untreated, all of the hamsters eventually would die from the disease. Liposome-encapsulated meglumine antimoniate was about 330-640 times more effective in causing a drop in the death rate than was the free antimonial. The efficacy of treatment was influenced by the lipid composition and charge of the liposomes. For example, positively charged liposomes containing egg phosphatidylcholine were much less effective than negatively charged ones. In contrast, positively and negatively charged sphingomyelin liposomes were equally effective. Liposomes containing phosphatidylserine (which were negatively charged, but also had a much higher charge density) were among the less-effective preparations. Among those tested, the most consistently efficacious liposomes contained highly saturated long-chain phospholipids (eg., dipalmitoyl phosphatidylcholine), cholesterol, and a negative charge.We conclude that liposomes may be useful as carriers of drugs to treat infectious diseases involving the reticuloendothelial system. The toxicities of antimony are very similar to those of arsenic. Encapsulation of antimonial drugs and reduction of the dose required for effective therapy should minimize such systemic toxicities as acute cardiomyopathy and toxic nephritis.

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

“…Liver, spleen, and bone marrow are particularly rich in sinusoidal and resident macrophages capable of phagocytizing circulating material; thus, encapsulation or carrier vehicles facilitate rapid, high-level tissue uptake and favor intracellular drug accumulation. The remarkable clinical efficacy and good tolerability of the lipid formulations of amphotericin B certainly attest to this approach, and well illustrate interdigitating benefits suggested by early experimental studies of targeted agents (7,20,32,44,136), including (i) use of lower total drug doses with comparable or greater efficacy, (ii) selective tissue uptake and reduced systemic toxicity, (iii) improved tolerability permitting higher daily doses and, in turn, short-course therapy, and (iv) likely persistence of drug in targeted tissues and/or within parasitized macrophages themselves.…”

“…As demonstrated Ͼ20 years ago (7,136) and without any experimental doubt, encapsulating drug is effective in delivering treatment to parasitized macrophages within Leishmania-targeted organs. Liver, spleen, and bone marrow are particularly rich in sinusoidal and resident macrophages capable of phagocytizing circulating material; thus, encapsulation or carrier vehicles facilitate rapid, high-level tissue uptake and favor intracellular drug accumulation.…”

Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis

“…9,10 Over the past decades, liposomes have demonstrated an increase in the therapeutic efficacy of several drugs. [11][12][13][14][15][16][17][18] Depending upon their physical properties, liposomes are recognized as foreign particles after in vivo administration and are easily cleared by the reticuloendothelial system that harbors Leishmania parasites. [19][20][21] Thus, the association or incorporation of chemotherapeutic agents in liposomes has immense therapeutic benefits against the intracellular infection of Leishmania.…”

Antimonial drugs entrapped into phosphatidylserine liposomes: physicochemical evaluation and antileishmanial activity

“…In contrast, positively and negatively charged sphingomyelin liposomes were equally effective. Liposomes containing phosphatidylserine were among the less effective preparations, due to the fact that they had a much higher surface charge density (22) . To our knowledge, PS liposomes containing MA were preferentially taken up by infected rather than by uninfected macrophages, probably due to changes in phagocytic behavior after infection (12) .…”