Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS


2.1. General and specific goals and achievements. NANOTAR aims to build up and consolidate a research program in Pharmaceutical Nanomaterials Science based on the design, synthesis and chemical characterization of novel self-assembly polymeric nano-biomaterials, namely polymeric micelles, and the investigation of the relationship between the nano/microstructure and the properties and the exploration of new processing methods for the improvement of the biopharmaceutical performance of drugs for the therapy of diseases with high socioeconomic impact. The proposal was initially oriented to make a substantial contribution to improve the treatment of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and tuberculosis (TB). Since we are devoted to investigate robust and versatile nanotechnology platforms that are optimizable for a broad spectrum of active molecules, our vision is to also establish new and strategic scientific collaborations that expand the applicability of these novel platforms, the socio-economic impact of our research, and the additional funding that we will achieve in the future to consolidate my new research group. In this framework, some of the new polymeric micelles developed in the present project are being investigated for the administration of anticancer drugs in pediatric tumors. This new research avenue has emerged due to the establishment of a new collaboration at the Hospital Sant Joan de Déu (Barcelona, Spain). In advance, the specific aims of the proposal and the progresses made in each one are summarized:

Specific aim 1-Development of alkoxysilane-grafted polymeric amphiphiles. This goal was undertaken by the MSc student Julia Talal and the undergraduate student Vladi Kushnirov-Melnitzer. The concept was to use of inorganic sol-gel chemistry to physically stabilize the micelles and to produce a superficial release-controlling membrane with fine-tuned porosity and diffusion properties. For this, different amphiphilic copolymers that form micelles were chemically modified to enable the formation of a siloxane surface. Then, the self-aggregation of the modified copolymers was compared to the one shown by the unmodified counterparts. After the characterization of the copolymers and the micelles, the work focused on the production of the inorganic crosslinked surface for which a drying stage was required. Two methods were studies: freeze- and spray-drying. Freeze drying led to massive crosslinking of the material and generated a macroscopic porous matrix. Conversely, spray-drying with the Nano Spray-Dryer B-90 produced a structured powder that upon resuspension in water resulted in nanoparticles of spherical morphology. Then, the encapsulation the anti-HIV protease inhibitor tipranavir was assessed. We are currently investigating its release kinetics from unmodified and modified micelles.

Specific aim 2-Development of polymeric amphiphiles conjugated with mono- and oligosaccharide residues. The first work in this goal was conducted during my transition period at Technion by a postdoc fellow under my supervison at the University of Buenos Aires, Dr. Romina Glisoni. In October 2014, the MSc student Alexandra Bukchin undertook this part of the project. The hypothesis was that conjugation of oligosaccharides to the surface of polymeric micelles will increase their physical stability, the uptake of the micelle by sugar-avid cells and the inhibition of efflux pumps that remove drugs against a concentration gradient with respect to pristine micelles and micelles modified with monosaccharide groups. For this, we also used amphiphilic copolymers that form polymeric micelles and tried to modify them with monosaccharides and oligosaccharides. We investigated three synthetic pathways to obtain polymeric micelles that present one, two and three sugar units in each terminal block. The chemical modification was characterized by complementary techniques. Then, we explored the formation of the micelles and compare this to the copolymers without modification. Modification with sugars increased the aggregation trend of the copolymers and their physical stability. The capacity of the sugar-modified micelles to bind sugar receptors was demonstrated in vitro using a vegetal sugar receptor. The first evaluation of the encapsulation capacity of the sugar-modified micelles was conducted with the first-line anti-HIV drug darunavir. Sugar modified PEO-PPOs displayed better encapsulation. Two anticancer drugs used in the treatment of sugar avid tumors are also being encapsulated. Next stages will comprise study of cell compatibility and active targeting in vitro and in vivo.

Specific aim 3. Development of mucoadhesive polymeric micelles. This goal was undertaken by the MSc students Maya Menaker Raskin and Inbar Schlachet. In addition, the five undergraduate students also participated in it. We also collaborated with researchers in Argentina, Mexico and Germany. The concept in this aim was that the grafting of hydrophobic blocks of different chemical nature to mucoadhesive polysaccharides confers them self-assembly properties, improve the encapsulation capacity of model drugs and prolong the residence time of the nanocarrier in different mucosal tissues. We initially worked with chitosan as mucoadhesive template and modified its side-chain with different hydrophobic blocks. After characterizing the produced copolymers and demonstrating the formation of nanometric polymeric micelles, we investigated encapsulation of the anti-TB drug rifampicin and the anti-HIV agents, indinavir and efavirenz. We confirmed good cell compatibility in different cell types and the mucoadhesion in vitro with mucin in solution. A new idea that emerged was to physically stabilize the polymeric micelles using mild chemistries. Following this concept, these polymeric micelles were crosslinked in a controlled manner to form amphiphilic nanogels that were stable for several weeks. We are now dedicating efforts to extend this technology to other multifunctional templates and hydrophobic modifications and to study the release kinetics of different cargos.
Finally, the investigation of a new kind of polymeric micelle, namely core-anchored polymeric micelles, has been incorporated to the research plan as new Specific aim 4. This work is being conducted by the MSc student Doaa Abu Saleh.

2.2. Incorporation of human resources. The training of human resources is very relevant and critical to build a fully functioning laboratory. NANOTAR was fundamental to incorporate the first five MSc students to my new group and five undergraduate students. I prioritize a balanced gender and minority participation; the female/male balance in the project is 80%/20%, 20% of the graduate students belonging to Israeli minorities.

2.3. Impact on reintegration. The MCR fully funded the first 20 months of my research work upon reintegration. Due to the progresses made, my tenure has been recommended by my Department and it is currently being evaluated by Technion. Moreover, it became the basis of additional applications for competitive funding.

2.4. Dissemination. The progresses in project are updated in my personal website During this period, the results of the project were presented in nine regular congress presentations and nine invited congress conferences. We published nine original and review articles in indexed journals. Specific aim 3 led to one US provisional patent application in 2015.

2.5. Scientific collaborations. The results of the different aims resulted in four new scientific collaborations with Spanish (1), German (2) and Australian (1) groups.

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