Huge Benefits, Tiny Particles: the Extraordinary Benefits of Nanotechnology in Medicine

Nearly 550 million people are exposed to Leishmaniasis disease, known in Israel as Rose of Jericho. Current treatments require hospitalization and have severe side effects. A new therapeutic nano-drug developed by Prof. Shulamit Michaeli Vice President of Research at Bar-Ilan University and Prof. Jean-Paul (Moshe) Lellouche, both from BINA center, provides a non-intrusive alternative that truly works.

Leishmania is a unicellular parasite transmitted via sandfly bites and multiplies in macrophages, the cells of our immune system. The disease presents in two ways: internally, in the spleen and liver, fatal if untreated, common mainly in Asia, South-America, southern Europe and the Middle East, with some cases reported in Israel; and externally, by skin ulcers that leave unseemly scars that can only be removed by plastic surgery.  

"Incidence of leishmaniasis in Israel have increased in recent years to the point of an epidemic," says Prof. Shulamit Michaeli of the Mina and Everard Goodman Faculty of Life Sciences, "previously confined to the Negev and the Dead Sea, leishmaniasis has now spread to Judea and Samaria and the Lower Galilee."

Some interesting trivia:

• The parasite’s host is the rock hyrax.
• Urban development in Judea and Samaria created a multitude of residual rock, which was used as rockery and provide a cozy new habitat for the rock hyrax.
• Leishmaniasis is spread through the bite of female sandflies, which looks like a mosquito.
• Female sandflies require blood to nourish her eggs.
• Through her bite, the female sandfly transfers the parasite from its host, the rock hyrax, to rodents, dogs and humans, infecting them with the disease.
• About 4-12 million people worldwide are infected with lieshmanaisis, and 2 million are added every year; approximately 20-50 thousand deaths occur each year.
• The first written reference to leishmaniasis dates back to the 7th century BC.

Both African trypanosomiasis and Chagas’ disease, common in South-America, belong to the same family of infectious diseases, caused by parasites from the kinetoplastida family.

"These ancient parasites are not only painful, but also fatal to humans, there is no vaccine and the parasites quickly develop resistance to the treatments currently available; they are simply defeating us. Leishmania is a very important model to our understanding of those parasites' progression within our body. Therefore, the World Health Organization prioritizes the development of a treatment to leishmaniasis," says Prof. Michaeli. 

Prof. Michaeli was working on an entirely different cancer research on gene silencing by RNA manipulation, when she suddenly had an epiphany: she realized she might be on to a new form of Leishmania treatment. In this research, thanks to an innovative collaboration with Prof. Jean-Paul (Moshe) Lellouche of the Chemistry Department, Prof. Michaeli uses hybrid nanoparticles to deliver drugs directly into cancerous cells. "In our experiments we saw that the nanoparticles are being linked to one another, forming bacteria-sized particles that are identified as hostile and as a result being directed to the spleen and liver as well as to the tumor cells." This was her eureka moment: Leishmania parasites proliferate in the spleen and the liver – and here we have an effective way to reach and eliminate them.

"Our nanoparticles are based on iron compounds, and their surface is linked to Polyethylenimine. In vitro, we saw these particles enter the parasite's lysosome; in less than 20 minutes, all parasites had burst and died. We tested these particles on infected macrophages cells, still in vitro, and saw them penetrate the cell and progress to the parasite, killing it without harming the macrophage cell. We proceeded to a pre-clinical in vivo model where we injected infected animals with the particles and saw 90 percent drop in parasitic burden, with blood tests revealing no evidence of toxicity.  

"At this stage I've decided to develop a treatment for the Rose of Jericho; first of all, because this leishmaniasis is common in Israel, and second, because topical drugs are much easier to commercialize than ingested or injected drugs, in terms of FDA demands. Using sonochemistry, we’ve integrated the particles into an ointment available in every drugstore. Once Hadassah Medical Center provided us with a species of Leishmania common in Israel, we infected our animal models and started treatment immediately after the infection, in order to examine the preventative qualities of the ointment; a second course of treatment was administered after ten days from infection, in order to examine its efficacy after the formation of an ulcer. Our ointment has proven to be effective in both cases, showed no evidence of toxicity, but sadly, it did not prevent scarring.   

With these promising results, Prof. Michaeli has contacted Israeli pharmaceutical companies. "We had learned that drug development processes require clean pharma conditions (GMP), which means shutting down the company's entire experimental developing operation for the development of a single product; it’s an insanely costly process. Therefore, we are now negotiating with South-American, Indian, and South-European pharmaceutical groups. At the same time and thanks to the generous KAMIN grant awarded to us by the Israel Innovation Authority, and the Applebaum Foundation we are continuing in-lab development. We aim to cut down on some of the production stages, economizing ROI for the company that will eventually take on the production. The moment we'll have our therapeutic ointment authorized to clinical trials, Israeli patients will have the opportunity to try it, thanks to our established collaborations with Prof. Sprecher, of the Tel Aviv Sourasky Medical Center, and Dr. Shoshana Greenberger, of the Sheba Medical Center, Tel Hashomer.   

"We also established the drug as an effective treatment for African trypanosomiasis and Chagas disease, which makes it even more commercially appealing," stresses Prof. Michaeli and adds, "entire herds in Africa are infected with trypanosomiasis, resulting in malnourished cows with poor milk production, with devastating effects to the local food industry. Hence, in the next five years, the EU will allocate major funds to eliminate infectious diseases in the third world, for sake of its residents as well as local productivity potential and sustainability. A broad team of students and researches is involved in this project, and we are all very proud to be taking part in this important global effort. 

"We would also like to thank BIRAD Research & Development Company and its biomedicine department for helping us find prospective pharmaceutical companies for drug production, as well as potential funds throughout international pharma industry. A special thanks goes to the devoted team at the animal house in the Mina and Everard Goodman Faculty of Life Sciences, who help us conduct meticulous experiments involving contagious disease factor."