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Researchers
  • Prof.  Simon Benita
Prof. Simon Benita
 
Research Interest 
Improving Drug Performance using Nanodelivery Systems
 
The search to design efficient nanodelivery systems is leading to refined drug targeting and enhanced oral, topical or ocular bioavailability of poorly absorbed lipophilic drugs which will improve the treatment of severe diseases such as cancers, ophthalmological, metabolic and immunological disorders. We are focusing our efforts in the following areas:
 
Enhanced oral delivery of P-gp substrate drugs or peptides using double-coated trojan nanocapsules
Targeted delivery of chemotherapeutic drugs to specific cancerous cells using nanoparticles conjugated to monoclonal antibodies for decreased toxicity, enhanced drug-cell penetration and performance
Delivery of macromolecules to intracellular sites of action
Nanoemulsions and nanoparticles for drug delivery in opthalmology
 
  
Keywords: nanocapsules, nanoemulsions, nanoparticles, P-gp, cationic, lympha, docetaxel, lopinavir, bioavailability, oral, ocular, skin, nanotransporter, macromolecules, linkers, monoclonal antibody, controlled release
 
Targeted drug nanocarriers as potential therapeutic innovations in oncology 
 
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Fig.1: (A) Transmission electron microscopy microphotography of trastuzumab following incubation of 1 h, using goat anti-human IgG secondary antibody conjugated to 12 nm gold particle at different magnifications. (B) upper row: Detection of tumor size in live mice by luciferase assay using CCCD following 3 consecutive treatment injections of different pcpl formulations. Mice pictures were taken at day 95. Lower row: Effect of paclitaxel-palmitate-loaded formulations on the tumor progression over time. It can be seen that immunoNPs inhibit the tumor growth much more than the pcpl solution and pcpl NPs. N=8, values are mean±SE
 
Cancer is becoming the leading cause of death in the world today. At present, about 50% of cancer patients can be cured, with chemotherapy contributing to 17% of this number. These figures would be improved if more efficient chemotherapeutic regimens could be identified. Unfortunately, increased doses of chemotherapy are problematic due to the indiscriminate distribution of chemicals into the body and the toxic effects caused by them. In order to improve the therapeutic index of chemotherapeutic drugs while greatly reducing their side effects, efforts are being concentrated on designing targeted drug delivery systems using biodegradable and biocompatible nanoparticles (NPs) conjugated to monoclonal antibodies (mAbs), resulting in the formation of immunonanoparticles (INPs). Our work has lead us to the design of advanced effective NP delivery systems which will improve the chemotherapeutic drug performance in oncology
 
Enhanced bioavailability of P-gp Substrate Drugs using an oral Trojan nanotransporter

Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-gp and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA nanocapsules (NCs) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, at a 5mg/kg dose as depicted in Figure 2 . Two batches of the same NC formulation elicited Cmax values that were 1735 and 2254% respectively; higher than the Cmax value of the oral docetaxel solution combined with blank microparticles, at a 10mg/kg dose. No significant difference in AUC was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery and represents a potential opportunity to transport through the intestinal barrier macromolecules and sensitive lipophilic P-gp substrate molecules. 
 
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Figure 2: (A) SEM micrograph of the microsphere formulation consisting of docetaxel (2%), labrafil M 1944 (3.6%), tributyrine (18%), Eudragit blend L:RS, 3:1 (36%) hydroxypropylmethylcellulose (36%) cut with a scapel. (B) Mean plasma docetaxel concentration–time profiles following iv (jugular) administration of Taxotere (red) and docetaxel loaded nanocapsules (green) or oral administration of docetaxel-loaded nanocapsules embedded in microparticles (blue) at the same dose of 5 mg/kg in fasted rats.
 
 
 
 
 
Lab Members
 
Present Lab Members
Graduates (since 2008)
Dr. Taher Nassar
Danny Goldstein, Ph.D.
Dr. Marina Zlotkin
Nir Debotton, Ph.D.
Oren Giladi (Ph.D)
Oshrat Harush-Frenkel, Ph.D.
Amit Badihi (Ph.D)
Tal Hagigit, Ph.D.
Aiman Abuammar (Ph.D)
Suha Attili, Ph.D
Orit Amsallem (Ph.D. in collaboration with Prof. Lazarovici and Dr. E. Yavin)
Nour Karra, Ph.D
​Liat Kochavi (Ph.D) Muhammed Abdulrazik, Ph.D
Eve Bohbot (M.Sc.)
Shimon Farber, Post. Doc.
Yoav Hamdi (M.Sc.)
Ayala Rohald, M.Sc.
Ouri Schwob
Eva Rozentur, M.Sc.
Natalia Nayarkin
Polina Rozentur, M.Sc.
Eleanora Boyarkin
Alona Rom, M.Sc.
 
 
 
 
 
 
 
 
 
Publications
O. Harush-Frenkel, E. Rozentur, S. Benita and Y. Altschuler, Surface charge of nanoparticles determines their endocytic and  transcytotic pathway in polarized MDCK cells. Biomacromolecules, 9, pp 435-443 (2008)
 
N. Debotton, M. Parnes, J. Kadouche and S. Benita, Overcoming the formulation obstacles towards targeted chemotherapy: in vitro  and in vivo evaluation of cytotoxic drug loaded immunonanoparticles. J. Control. Rel.,127, pp 219-230 (2008)
 
T. Hagigit, T. Nassar, F. Behar-Cohen, G. Lambert and S Benita, The influence of cationic lipid type on in-vitro release kinetic profiles of antisense oligonucleotide from cationic nanoemulsions. Eur. J. Pharm. Biopharm., 70, pp 248-259 (2008)
 
T. Nassar, A. Rom, A. Niska and S. Benita, A novel nanocapsule delivery system to overcome intestinal degradation and drug transport limited absorption of P-glycoprotein substrate drugs. Pharm. Res., 25, pp 2019-2029 (2008)
 
O. Harush-Frenkel, Y. Altschuler and S.  Benita, Nanoparticle-cell interactions-drug delivery implications. Critical Reviews in Therapeutic Drug Carrier Systems, 25, pp 485-544 (2008)
 
T. Nassar, A. Rom, A. Niska and S. Benita, Novel double coated nanocapsules for intestinal delivery and enhanced oral bioavailability of Tacrolimus, a P-gp substrate drug. J. Control. Rel., 133, pp 77-84 (2009)
 
D. Goldstein and S. Benita, Paclitaxel-palmitate loaded anti-HER2 cationic immunoemulsion: pharmacokinetic and biodistribution study in healthy mice. J. Drug Del. Sci. Technol.,19,  pp 269-275 (2009)
 
N. Debotton, O. Giladi, M. Parnes and S. Benita, Novel high content paclitaxel palmitate nanospheres for improved cancer treatment. J. Drug Del. Sci. Technol., 19, pp 275-282 (2009)
 
N. Debotton, H. Zer, M. Parnes, O. Harush-Frenkel, J. Kadouche and S.Benita, A quantitative evaluation of the molecular binding affinity between a monoclonal antibody conjugated to a nanoparticle and an antigen by surface plasmon resonance.,  Eur. J. Pharm. Biopharm., 74, pp 148-56 (2010)
 
T. Hagigit, M. Abdulrazik, F. Orucov, F. Valamanesh, M. Hagedorn, G. Lambert, F.  Behar-Cohen and S. Benita, Topical and intravitreous administration of cationic nanoemulsions to deliver antisense oligonucleotides directed towards VEGF KDR receptors to the eye. J. Control. Rel., 145, pp 297-305 (2010)
 
O. Harush-Frenkel, M. Bivas Benita, T. Nassar, C. Springer, Y. Sherman, A. Avital, Y. Altschuler, J. Borlak  and S. Benita, A safety and tolerability study of differently charged nanoparticles for local pulmonary drug delivery. Toxicology and Applied Pharmacology, 246, pp 83-90 (2010)
 
T. Nassar, SA. Qadri, OH. Frenkel, S. Farber, S. Lecht, P. Lazarovici, and S. Benita, High plasma levels and effective lymphatic uptake of docetaxel in an orally-available  nanotransporter formulation. Cancer Res., 71, pp 3018-28 (2011)
 
N. Karra and S. Benita, The ligand nanoparticle conjugation approach for targeted cancer therapy., Curr. Drug Metab., (2011), In Press
 
T. Hagigit, M. Abdulrazik, F. Valamanesh, F. Behar-Cohen and S. Benita, Ocular antisense oligonucleotide delivery by cationic nanoemulsion for improved treatment of ocular neovascularization: An in-vivo study in rats and mice. J. Control. Rel., (2011), In Press
 
F. Lallemand, P. Daull, S. Benita, R. Buggage and J.-S. Garrigue, Successfully improving ocular drug delivery using the cationic nanoemulsion, Novasorb. Journal of Drug Delivery, Received 2011, Volume 2012, In Press
 
G. Cohen, S. Lecht, H. Arien-Zakay, K. Ettinger, O. Amsalem, M. Oron-Herman, E. Yavin, D. Prus, S. Benita, A. Nissan and P. Lazarovici, Bio-imaging of Colorectal Cancer Models Using Near Infrared Labeled Epidermal Growth Factor. PLoS One, 2012;7(11):e48803. doi: 10.1371/journal.pone.0048803. Epub  2012 Nov 8.
 
N. Karra, T. Nassar, F. Laenger, S. Benita* and J. Borlak*. Safety and Proof-of-Concept Efficacy of Inhaled Drug Loaded Nano- and Immunonanoparticles in a c-Raf Transgenic Lung Cancer Model. Curr. Cancer Drug Targets, 13, pp11-29 (2013).
 
N. Karra, T. Nassar, A. Nemirovski Ripin, O. Schwob, J. Borlak and S. Benita. Antibody Conjugated PLGA Nanoparticles for Targeted Delivery of Paclitaxel Palmitate: Efficacy and Biofate in a Lung Cancer Mouse Model. Small, 2013. DOI 10.1002/smll.201301417.
 
S. Attili-Qadri, N. Karra, A. Nemirovski, O. Schwob , Y. Talmon, T. Nassar, S. Benita. Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption. Proc. Natl. Acad. Sci. USA. 2013 Oct 22;110(43):17498-503. Doi 10.1073/pnas.  1313839110. Epub 2013 Oct 7              

 
 
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