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Simon Benita

Department of Pharmaceutics
The School of Pharmacy, Faculy of Medicine
The Hebrew University, Jerusalem 91120, Israel
Tel:+972-2-6758668, FAX:+972-2-6757140
E-mail: benita@cc.huji.ac.il
Website:http://pharmacy.huji.ac.il/eng/staff_win.asp?id=34&type=2


Improving Drug Performance by Means of Nanodelivery Systems

Research interests

The search to design efficient nanodelivery systems is leading to refined drug targeting and enhanced oral and ocular bioavailability of poorly absorbed lipophilic drugs which will improve the treatment of severe diseases such as cancers and ophthalmological and immunological disorders. We are focusing our efforts in the following areas:

  1. Enhanced oral delivery of P-gp substrate drugs using double-coated trojan nanocapsules
  2. Targeted delivery of chemotherapeutic drugs to specific cancerous cells using nanoparticles conjugated to monoclonal antibodies for decreased toxicity, enhanced drug-cell penetration and performance
  3. Delivery of large macromolecules to intracellular sites of action

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.

Safety and Proof-of-Concept Efficacy of Inhaled Drug Loaded Nano- and Immuno-nanoparticles in a c-Raf Transgenic Lung Cancer Model

Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. We reported the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-of- concept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively.

Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment.

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 1. 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.

Figure 1:(Left) 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. (Right) 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.

Specific Research Topics related to Nanoscience and Nanotechnology

  • 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 ophthalmology

List of publications in Nanoscience and Nanotechnology (2010-2012)

  • N. Karra and S. Benita. The Ligand Nanoparticle Conjugation Approach for Targeted Cancer Therapy. Curr. Drug Metab.,13:2-41 (2012).
  • N. Debotton, H. Zer, M. Parnes, O. Harush-Frenkel, J. Kadouche and  S.Benita, "A quantitative evaluation of the molecular binding affinity between a monoclonalantibody conjugated to a nanoparticle and an antigen by surface plasmon resonance", Eur. J. Pharm. Biopharm., 74,pp148-56 (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, S. Attili-Qadri, O. Harush-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 Research, 71; 3018-28 (2011)
  • N. Karra and S. Benita "The ligand nanoparticle conjugation approach for targeted cancer therapy", Curr. Drug Metab., Epub Sept., 2011, (Epub ahead of print)

Published articles resulting from cooperation between the universities:

  • 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.,160:225-31(2012).
  • F. Lallemand, P. Daull, S. Benita, R. Buggage and J-S Garrigue. Successfully Improving Ocular Drug Delivery Using the Cationic Nanoemulsion, Novasorb. J. Drug Del., 2012; 2012:604204. Epub 2012 Feb 27.
  • 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, In Press.

Significant publications in the last years

  • Novel double coated nanocapsules for intestinal delivery and enhanced oral bioavailability of tacrolimus, a P-gp substrate drug. Nassar T, Rom A, Nyska A, Benita S. J Control Release. 2009 Jan 5;133(1):77-84. Epub 2008 Sep 9. 20
  • Overcoming the formulation obstacles towards targeted chemotherapy: in vitro and in vivo evaluation of cytotoxic drug loaded immunonanoparticles. Debotton N, Parnes M, Kadouche J, Benita S. J Control Release. 2008 May 8;127(3):219-30. Epub 2008 Feb 8. 17
  • Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells. Harush-Frenkel O, Rozentur E, Benita S, Altschuler Y. Biomacromolecules. 2008 Feb;9(2):435-43. Epub 2008 Jan 12. 64
  • Anti-HER2 cationic immunoemulsion as a potential targeted drug delivery system for the treatment of prostate cancer. Goldstein D, Gofrit O, Nyska A, Benita S. Cancer Res. 2007 Jan 1;67(1):269-75. 16
  • In vitro adsorption of plasma proteins onto the surface (charges) modified-submicron emulsions for intravenous administration. Tamilvanan S, Schmidt S, M?ller RH, Benita S. Eur J Pharm Biopharm. 2005 Jan;59(1):1-7.

New patents and patents utilization (2011-2012):

Applied patents:
  • NANOPARTICLES FOR COSMETIC APPLICATIONS (Use of biodegradable lactic and glycolic acid nanoparticles as cosmetic agents) 24/1/2012 PCT/IL2012/050019
  • Nano Delivery Systems 20/9/2012 PCT/IL2012/050382
Approved patents:
  • A. Badihi, N. Karra, T.Nasser, and S. Benita Prolonged delivery of lactic and glycolic acid into skin by means of biodegradable polyester nanoparticles US 61/435,640 & 61/435,674 (Jan 2011). Great Britain 1101122.8 (Jan 2011)
  • S.Benita and G. Lambert Emulsion for dry-eye treatment France, no. 153269-6 (Feb 2011) accepted with publication in Patents and Designs Journal No. 02/2011

Success stories:

Founder of Novagali Pharma that received in 2009 the ?91 d?or? Award from the French Business Confederation and the Siemens ?Health Award?. Frost & Sullivan recognizes Novagali Pharma for Innovation in Ophthalmic Therapies and in 2009 was awarded Best Practices Award. Novagali was listed in the Euronext in 2010 and acquired by Santen Japan in 2012.

Cooperation with other researchers/universities in Israel:

With other universities:
  • Prof Borlak, Hannover University, Germany
  • Prof Francine Behar Cohen, Universit? Paris Descartes, Paris, France

Distinctions and awards:

  • Hebrew University Kaye Innovation Award in 2000 and again in 2005.
  • Knight of the National Order of Merit (France) 2012.
  • Israel Controlled Release Society Chapter Prize for Outstanding Achievements in Controlled Release, September 2012.

Students, postdocs and researchers :

Staff senior scientist :  Dr. Taher Nassar
Research scientist:Dr Yoram Soroka, Dr. Marina Zlotkinfrusic and Ouri Schwob
Technician: Natalia Nayarkin
Post Doc: Dr. Nir Debotton
Ph.D students: NOUR KARRA, SUHA ATTILI, OREN GILADI, AMIT BADIHI, AIMAN ABU-AMAR, ORIT AMSALLEM
M.Sc. students: LIAT KOCHAVI, EVE BOHBOT

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