EXPRESSION OF INTEREST FOR HOSTING MARIE S. CURIE FELLOWS IN SPANISH INSTITUTIONS (CALL MSCA IF 2015)

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1 1. Interested institution: Universidad Complutense de Madrid Departamento de Química Física II (Fisicoquímica Farmacéutica) Research Group: Materiales Nanoestructurados Bioactivos (MATNABIO, Grupo UCM ) DIRECCION POSTAL DEL GRUPO: Departamento de Química Física II, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain WEB site: 2. Brief Description of the Institution 1. Introduction Universidad Complutense de Madrid (UCM) is one of the largest Universities in Spain and all around Europe. With a tradition beyond 5 centuries, UCM has become a very important institution in terms of higher education and research activities. UCM is home of research groups which are in the cutting edge of research in many areas. UCM technological scientific infrastructure (with an annual budget almost reaching 600M ), together with the quality of its researchers (more than 6000), has established some of its laboratories among the best all around Europe. 2. Research and Education The UCM is a broad-scoped university in which almost every field of knowledge is envisaged. From the 2012 research annual report (the last consolidated figures), there has been a total income of almost 40M for research activities: 6% of this income has been obtained through EU funded programmes and 21% through R&D service contracts with the private sector. The research at UCM is developed through its 21 faculties, 5 university schools, 9 associated centres, 40 university research institutes, 8 schools for professional specialization, 4 university hospitals, and 17 research assistance centres. Due to its broad-scoped nature UCM is able to offer 170 official degrees of which 65 correspond to bachelor degrees and 105 to master degrees. For these degrees UCM counts on more than students distributed among the faculties, university schools and associated centres. Both students and researchers benefit from a vast collection of volumes in the UCM library (more than 2,7 million of volumes), as well periodic publications exceeding The historic collection of at the UCM s library reaches volumes and there are substantial historic and artistic funds all over the 12 museums and the 11 art, entomological, palaeontological, etc. collections.

2 More detailed information on R&D and Higher Education activities of the UCM can be found on and 3. UCM: Campus of International Excellence UCM is located in the Campus de Moncloa at Ciudad Universitaria of Madrid. This location is a large space devoted to Science and Higher Education. With over 10,000 researchers and 10% of the national scientific production of Spain the Campus de Moncloa, which houses two universities and several research centres is a unique environment, fostering synergies in higher education, research, innovation and social and cultural projection. This uniqueness has favoured the awarding of the Campus of International Excellence label to the institutions joining this Campus de Moncloa. The UCM through the Campus of International Excellence is committed to specialization in five thematic clusters to achieve scientific and teaching excellence: Global Change and New Energies, Materials for the Future, Agri-Food Industry and Health, Innovative Medicine and Heritage. The distinctive strengths of each cluster will converge to create unique configurations marked by their innovative and interdisciplinary character, highly competitive at the European level, and producing significant progress in knowledge transfer. More information on the Moncloa Campus of Excellence can be found in 4. UCM: support to researchers in mobility programmes The UCM provides advice to foreign researchers moving to the institution to develop R&D projects on how to process residence permits, visas or other related documents through the personnel department of its Fundación General ( On the other hand, by means of the Oficina de Alojamiento and the Casa del Estudiante (Centro Internacional de Visitantes y Acogida, CIVA), the UCM provides to the visiting researchers the possibility to get accommodation though different options like residences or apartments. Regarding the aspects related to the management of international Fellowships and Grants, the UCM, through the European Office for R&D ( provides advice and support throughout the preparation process of the Contracts and Agreements and the following management of the projects. A smooth financial management of the grants will be guaranteed by the Economic Management Unit of the FGUCM which deals at the time of submitting this EOI with more than 100 active international grants. 3. Please tick the areas of research (as established in Marie Sklodowska Curie Actions) Chemistry (CHE) Environmental Sciences and Geology (ENV) Social Sciences and Humanities (SOC) X Life Sciences (LIF) Economic Sciences (ECO) Mathematics (MAT) Information Science and Engineering (ENG) Physics (PHY)

3 4. Research / Project Description Bone mainly consists of inorganic hydroxyapatite (HAP) limiting most of these therapeutic agents that are not specific for bone hampering their clinical application to bone disease. Developing a specific system for bone-targeted drug delivery could impart osteotropicity to a variety of bone drugs and improve their therapeutic potential.[1] Biodegradable polymer nanoparticles based on poly-esters have been studied with promising results concerning the encapsulation and activity of hydrophobic drugs.[2] Polymeric nanoparticles (NPs) have found remarkable applications in biomedicine due to their uniques features like large payloads, stability, multiple and simultaneous applications [3]. The targeting profile depends mainly on the nanoparticle surface-chemistry, which is typically achieved by the introduction of targeting groups at the nanoparticle surface,[2] such as bisphosphonates and derivatives that can specifically target bone.[4] Due to the high affinity to the bone mineral hydroxyapatite, bisphosphonates have emerged as a great option for bone targeted therapy and have been studied intensively.[5] However, side effects have been reported for bisphosphonates as osteonecrosis of the jaw, atrial fibrillation, and renal insufficiency.[6] Thus, there is a need to provide a new way for targeting drug delivery to the bone reducing the side effects of present drug delivery systems and improve the efficiency of the drug to treat bone diseases. HYPOTHESIS Nanoparticles based on modified polymers biomimetic system could improve efficacy of target bone delivery systems and drugs currently available for bone targeted drug delivery reducing their side effects. Objective The aim of this study is: 1) To develop a new vehicle for bone targeted drug delivery; 2) In vitro assessment of their binding to HAP and kinetic study of the controlled drug release; Objective 1: Different biopolymers such as alginate, chitosan, and dextran will be modified by introducing carboxylate or phosphate groups in to the backbone of the biopolymer to increase its affinity to hydroxyapatite and the capacity of target bone. First, the biopolymer will be functionalized by introduction of poly-ethylene-glycol (PEG) to increase the hydrophilicity and the stealth capacity to avoid antibody opsonization and NPs RES uptake.[7] The PEGylation will be done using two different strategies: 1) by coupling of PEG-COOH using EDC and DMAP activated ester bonding, and 2) using an activated PEG-succinate N-hydroxysuccinimide.[8] The optimal degree of PEGylation will be assessed since its dependent by the biopolymer used. After PEGylation, the biopolymer will be functionalized by insertion of phosphate group using phosphoryl trichloride (PO3Cl) that will react with the OH groups present on the biopolymer.[9] Another approach will be done by reductive amination of adenosine triphosphate. In order to follow the in vitro binding of the modified-biopolymer to hydroxyapatite, the biopolymer will be labeled with the fluorescent tag fluorescein isothiocynate.[8] The modified biopolymer will be purified by extensive dialysis against water and characterized using 31P NMR, UV-Vis spectroscopy, fluorescence spectroscopy, and by Fourier transform infrared spectroscopy. (The applicant has extensive experience on all these techniques) Objective 2: The phosphate biopolymer will be used to encapsulate different kinds of drugs and

4 their in vitro release will be studied. NPs with the encapsulated drug will be prepared using two different methods: 1) Ionotropic gelation method using calcium ions or polyions, and 2) by the emulsion evaporation method. The ionic-ionic interactions between the modified biopolymer and the drug will permit to encapsulate the drug. The polymeric NPs will be characterized by Scanning Electron Microscopy and Dynamic Light Scattering. One of the drugs taken into account will be Vitamin D that plays an important role on osteoporosis treatment. We will investigate the controlled release of different compounds like cholecalciferol D3, ergocalciferol D2, and calcitonin by assessing several concentrations. The binding of the modified biopolymer to hydroxyapatite will be study by UV-Vis following the absorbance of the fluorescent tag attached to the biopolymer. The drug loading efficiency will be estimated by calculating the concentration of the free drug in solution by UV-Vis, while the drug release will be studied in vitro using the dialysis-diffusion method performed in buffer solution at ph The released drug concentration will be determined by UV-Vis monitoring the peak maximum absorbance of each drug. Data Analysis Plan The functional groups and the amount of released drug obtained by spectroscopy techniques will be quantified (objective 1 and 2). Descriptive outcomes (mean, median and standard deviation) will be evaluated for the proportion of each functional group and amount of drug released of the NPs phosphate biopolymers and the drug loaded nanoparticles (objective 1 and 2). Unpaired Student s T test will be used to assess the difference in chemical composition between the functionalized polymers and their respective controls (objective 1). In vitro (drug release) will be evaluated using unpaired Students t test and ANOVA test (objective 2). Values will be considered statistically significant at p < Feasibility and Pertinence The applicant will be working under the supervision of Dr. Enrique Lopez-Cabarcos. The applicant should have expertise in nanoparticles synthesis, surface modification od nanoparticles, and application as drug-delivery vehicle. References [1] Bioconjugate Chem. 2003, 14, p [2] Adv. Drug Delivery Rev., 2004, 56, p [3] Acc. Chem. Res. 2008, 41, p [4] Int. J. Nanomed., 2012, 7, p [5] Expert Opin. Invest. Drugs, 2008, 17, p [6] Mayo. Clin. Proc. 2009, 84, p [7] Pharm. Res. 2007, 24(8), p [8] Biomacromolecules 2011, 12, p [9] Langmuir 2010, 26(2), p [10] Clin. Oral Impl. Res. 2012, 23, p Who can apply? At the deadline for the submission of proposals (10/09/2015), researchers (*): shall be in possession of a doctoral degree or have at least four years of full-time equivalent research experience. must not have resided or carried out their main activities in the country of Spain for more than 12 months in the 3 years immediately prior to the abovementioned deadline.

5 6. Contact person Prof. Enrique Lopez Cabarcos Departamento de Química Física II, Facultad de Farmacia Universidad Complutense de Madrid, Madrid, Spain Phone: Applications: documents to be submitted and deadlines Please note that: Deadline of the next call for proposals for Marie Sklodowska Curie Individual Fellowships is September, 10 th Oficina Europea is only responsible for the display of the expressions of interests received by the institutions; further contact and information requests will take place directly between the host institutions and the interested researchers. (*) Further details on the Call and additional eligibility criteria can be found at the Participants Portal