Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH2), dextran T10-polyethylene glycol (DT10-PEG), dextran T10-sulfobetaine (DT10-SB) and poly(acrylic acid) (PAA), and compared to uncoated. 89Zr was incorporated into CONPs for positron emission tomography (PET) imaging and ex vivo tissue analysis in tumor bearing mice. Compared to uncoated [89Zr]CONPs, coated [89Zr]CONPs showed improved biodistribution, including significantly enhanced renal clearance of PAA- [89Zr]CONPs. The toxicity of CONPs was evaluated in vitro and in vivo, with low toxicity at therapeutic doses. After clinically mimetic radiation therapy, pre-treatment of mice with coated and uncoated CONPs showed greater than 50% reduction of cell death in normal colon tissue, comparable to the clinically available radioprotective drug amifostine. Tumor control after irradiation of spontaneous colon tumors was unchanged with PAA-CONP pre-treatment, while citrate, DT10-PEG, and uncoated CONP pre-treatment had slightly less tumor control. Xenograft tumors were irradiated after pH normalizing treatment with sodium bicarbonate and PAA-CONP pre-treatment. Treatment of these tumors showed slightly less tumor control than irradiation alone or PAA-CONP plus irradiation, demonstrating that the acidic pH of the tumor microenvironment may be the basis of preventing CONPs’ radioprotective properties in tumor. These studies show that, among the variations of CONPs tested, PAA-CONP shows the most promise for its good biodistribution and quick clearance, low toxicity, ability to protect normal tissue, and lack of protection of tumor, meeting all the criteria set forth for an ideal radioprotective drug. Further studies on the effects of pH on CONPs actions may further elucidate their mechanisms of action, advancing them as a candidate for use as a radioprotective drug during radiation therapy.

La radiothérapie basée sur l'utilisation des photons de haute énergie (rayons X) est l'approche la plus courante dans le traitement du cancer. Toutefois, elle est limitée par la tolérance des tissus sains. Par conséquent, il est d'un intérêt majeur de développer de nouvelles techniques et protocoles pour améliorer le ciblage dans les tumeurs. Dans cette perspective, la hadronthérapie (irradiation de la tumeur par des protons ou des ions carbone) est considérée comme l'une des techniques les plus prometteuses car le dépôt d'énergie est maximum en fin de parcours, ce qui permet de cibler la tumeur. Pourtant, l’utilisation de cette modalité reste limitée du fait de la dose reçue par les tissus sains situés à l'entrée du faisceau.Pour améliorer les performances des thérapies par radiation, une nouvelle stratégie basée sur la combinaison de nanoparticules métalliques (nano-médecine) avec des rayonnements ionisants a été développée par le groupe. En effet, les nanoparticules ont une chimie de surface remarquable qui permet de les fonctionnaliser avec des ligands qui les rendent plus futiles et moins reconnus des macrophages afin de les concentrer dans les tumeurs.Le but de mon travail a été de développer des nanoparticules à base de platine (NPs de platine pelylée et des nanoparticules bimétalliques) visant à améliorer l’effet des rayonnements ionisants (photons et ions carbone) dans les cellules.Une méthode originale de synthèse en une seule étape combinant la radiolyse et la PEGylation in situ a été optimisée. Cette méthode a permis d’obtenir des NPs stables, de taille homogène (cœur métallique proche de 3 nm).L'impact biologique de ces nouvelles NPs a été évalué sur deux lignées de cellules cancéreuses humaines. Il a été observé que les NPs, non-toxiques, ont un mode d’internalisation qui dépend de la lignée cellulaire. Celles-ci sont, dans tous les cas, localisées exclusivement dans le cytoplasme. Les NPs de platine développées dans ce travail permettent d’amplifier significativement la destruction des cellules cancéreuses, en particulier lorsqu’un faisceau médical d’ions carbone est utilisé comme rayonnement. Les mécanismes moléculaires à l’origine de cet effet ont été étudiés grâce à l’utilisation d’une nanosonde biologique. Ces expériences ont montré que les NPs sont responsables de l’augmentation de dommages nanométriques, qui peuvent être létaux pour les cellules. Cet effet est attribué à des processus électroniques d’activation et de reneutralisation de la NP qui engendre une forte perturbation dans le volume nanométrique qui l’entoure tel que la production groupée de radicaux fortement réactifs et toxiques.En conclusion, ce travail à l’interface de la physique, chimie et biologie montre les capacités des NPs à base de platine à améliorer l’éradication par radiation des cellules cancéreuses. / Radiotherapy based on the use of high energy photons (X-rays) is the most common approach in cancer treatment. However, its implementation is limited by the tolerance of healthy tissue. Therefore, it is of major interest the development of new techniques and protocols to improve the selectivity of radiation effects within the tumor. In this perspective, the hadrontherapy (tumor irradiation by protons or carbon ions) is considered as one of the most promising techniques due to the energy deposition of ions in depth which is maximum at the end of the track. However, the use of this modality remains restricted by the lower but significant damage induced to the normal tissue located at the entrance of the ion beam.To improve the performance of radiation therapies, a new strategy based on the combination of metallic nanoparticles (nanomedicine) with ionizing radiations was studied. These treatments have been developed by the group. Indeed, the nanoparticles present a remarkable surface chemistry that allows their functionalization with ligands which make them less recognized by macrophages allowing an important accumulation of these nano-agents selectively into the tumors.The goal of my work was thus to develop platinum based nanoparticles (mono- and bimetallic Pt NPs) to enhance the effect of radiations (photons and carbon ions) into the cells.A novel one-step method of synthesis combining radiolysis and in situ PEGylation has been optimized. This method enabled to obtain stable NPs with a uniform size (metallic core diameter close to 3 nm) and shape. The biological impact of these new Pt NPs was evaluated in two human cancer cell lines.It has been observed that non-toxic Pt NPs have an internalization pathway that strongly depends on the cell line. These are, in all cases, exclusively localized in the cytoplasm. The Pt NPs developed in this work significantly enhanced cancer cell killing, particularly when medical carbon ions are used to irradiate.The molecular mechanisms underlying this effect were investigated through the use of a bio-nanoprobe. These experiments showed that NPs are responsible for the increase of nanometric damage, lesions that can be lethal to cells. This effect is attributed to an electronic activation processes and to the reneutralisation of NPs, which generates a strong perturbation in the surrounding nanometer volume producing highly reactive and toxic free radical clusters.In conclusion, this work at the interface of physics, chemistry and biology shows the potential of platinum NPs to improve the eradication of cancer cells by radiation.

Silica nanoparticles are effective fluorophore carriers with high potential in imaging, diagnostics, and therapy. The particles are resistant to drastic change of environmental conditions (pH, temperature etc.) and insulate the dyes so as to protect them from photobleaching. Silica chemistry is also versatile and affords an easy modification of the particle composition and surface to integrate targeting ligands or to integrate other nanoparticles. Regardless of their advantages, there exists a lack of dye diversity in the literature that is connected to a low affinity for potential tools for biology and medicineThis thesis describes the development of an alternative method for the synthesis of fluorescent silica nanoparticles and their modification to incorporate iron oxide and gold. cont/d.

Master of Science / Department of Chemistry / Santosh Aryal / Nanomedicine-based therapeutics have exhibited clear benefits when compared to unmodified drugs, which include improved pharmacokinetics, drug retention, targeting efficiency, and minimizes toxicity. Every year thousands of bone cancer cases are diagnosed in the United States. Moreover, development of bone metastasis occurs in over 80% to 90% of various cancers that metastasize and signals the entry of the disease into an incurable phase. Cancer in bones can cause pain, fractures, hypercalcemia, and compression of the spinal cord, due to deposits that can erode into the bone using bone-absorbing cells. Bisphosphonates are drugs that reduce the activity of bone-absorbing cells and targets overexpressed calcium. They are characterized pharmacologically to inhibit bone resorption, skeletal distribution, and renal elimination. In addition, they can target bone microenvironment and bind strongly with calcium. The goal of this thesis is to engineer targeted nanomedicine drug with the ability to spatiotemporally control therapeutics delivery to the bone. Herein we synthesized biopolymers with functional end group moieties as alendronate (a molecular member of bisphosphate), which can target overexpressed calcium ions at the vicinity of the bone lesion where bone resorption takes place. In order to achieve our goal, a ring opening polymerization of cyclic L-lactide initiated by ALE in the presence of catalytic amount of stannous octoate was conducted in an inert environment. Thus, formed polymers are characterized for their chemistry and physicochemical properties using various analytical tools. These polymers were characterized by nuclear magnetic resonance (¹H-NMR) and Fourier Transfer Infrared Spectrometer (FT-IR), which shows monomer conversion and the presence of amide and phosphate moiety. Thereafter we engineered bone-homing polymeric nanoparticles of 80nm diameter by nanoprecipitation for controlled delivery of Dox, a first line anticancer drug used in clinics. The in-vitro results show that the nanoparticles have the ability to accumulate and internalized into the bone cancer cells, deliver drugs efficiently, and are least toxic. Therefore, innovative and efficient bisphosphonate functionalized Poly-l-lactide polymers were synthesized to target bone microenvironment.

<p>Many anti-cancer drugs are poorly water-soluble and show undesirable pharmacokinetics and low bioavailability. Nanoparticles (NP) are used as delivery vehicles to improve bioavailability and biodistribution of such drugs. For clinical translation of an NP product, it is critical that the NP carry a large amount of drug and maintain good stability during circulation. A typical drug loading capacity of current NP formulations is less than 20% of the total mass, which is concerning from the standpoint of safety and administration convenience. Current NP formulations are also limited in retaining a drug during circulation and release the drug prematurely before they reach target tissues. These challenges are responsible at least partly for recent failure of leading NP products in clinical trials. </p> Given these challenges, I have focused on developing a stable NP formulation with high drug loading capacity, drug-rich nanocores stabilized by interfacial assemblies of iron-tannic acid (pTA) and albumin. Tannic acid is a polyphenol of natural origin and can form coordination complexes with Fe³⁺ ions that stabilize the interface between drug rich core droplets and aqueous solution. The underlying hypotheses are that (i) NP core formed solely of drug will offer a high drug loading capacity and (ii) the strong interaction of TA with drug molecules will maintain the nanocore stability and avoid premature drug release. Carfilzomib (CFZ), an epoxyketone peptide and a second-generation proteasome inhibitor, the use of which is limited to multiple myeloma due to the low stability, was chosen as a model drug to encapsulate in the new NP formulation. The NP surface was further functionalized with albumin, quinic acid derivative and plasmid DNA based on their affinity for TA complex. With an additional albumin coating, CFZ nanocore (CFZ-pTA-alb) showed sustained drug release and metabolic stability. In murine syngeneic model of B16F10 melanoma, systemically administered CFZ-pTA-alb showed enhanced biodistribution and anti-tumor effect than commercial cyclodextrin-based CFZ (CFZ-CD). With localized intratumoral administration, CFZ-pTA-alb also outperformed CFZ-CD in antitumor efficacy, potentially by prolonged drug retention, reduced damage to tumor-infiltrating lymphocytes, and enhanced delivery of tumor antigens to DCs.

Os nanomateriais, nanopartículas e nanocompósitos apresentam novas propriedades físicas e químicas, que combinam as do mundo clássico com as do mundo quântico, e despontam de maneira surpreendente na ciência e na vida cotidiana impulsionando a era da nanotecnologia. Os avanços tecnológicos nessa nova ciência estão atrelados à descoberta de materiais com características inovadoras e as moléculas atualmente são peças chaves de sistemas mais elaborados e projetados para maior desempenho. A presente dissertação teve como principal proposta levantar o estado da arte da utilização da nanotecnologia em diagnóstico e terapia no panorama nacional. O trabalho abordou pesquisa bibliográfica em bases de dados e pesquisa de campo com entrevistas semi estruturadas a profissionais locais atuantes na área biomédica. A coleta de dados evidenciou o progresso da nanotecnologia em função do tempo de acordo ao crescimento do número de publicações desde os primeiros artigos publicados até o presente e mostrou que ainda é incipiente o número de referências da nanotecnologia dentro da área nuclear: IAEA/INIS 25.948, frente a MEDLINE 90.627, PubMed 102.738 e Scopus 268.299 em maio 2015. A revisão bibliográfica contextualizou e embasou os conceitos, como interação da nanotecnologia nos sistemas biológicos e também a utilização e problemática da fiscalização e regulamentação nacional. Chegou-se à conclusão que a nanomedicina no Brasil está em processo de evolução e desenvolvimento tecnológico. O País se encontra atualmente em fase de testes pré clínicos de nanomedicamentos e ainda não possui produção em escala industrial, e está na criação e implantação legislativa. O conhecimento e a tecnologia estão sediados em pólos já desenvolvidos, fundamentalmente na região sudeste, e que mesmo nesta, a nanotecnologia encontram-se numa etapa muito inicial de aplicação no setor terapêutico e diagnóstico. / Nanomaterials, nanoparticles and nanocomposites exhibit new physical and chemical properties, matching those from the classic world with the ones from the quantum world: they emerge, surprisingly, in science and everyday life, boosting the era of nanotechnology. Technological advances in this new science are linked to the discovery of materials with innovative characteristics and molecules are, nowadays, key pieces of more complex systems designed for higher performance. This work was, mainly, proposed to improve the state of the art nanotechnology use for both diagnosis and therapy, in the national scene. This work covered bibliographic research in databases and field survey with semi-structured interviews with local professionals working in the biomedical field. Data collection showed the progress of nanotechnology, as a function of time, in agreement with the growing number of publications since the first articles published to date, demonstrating that the number of nanotechnology references is still deficient, within the nuclear area: IAEA / INIS 25 948 , compared to 90,627 MEDLINE, PubMed and Scopus 268 299 102 738, in May 2015. The literature review contextualized and comprised some concepts, such as the nanotechnology interaction with biological systems and, also, its use and problems concerning supervision and national regulation. We came to the conclusion that nanomedicine, in Brazil, is under an evolution process and technological development. The country is, currently, in a preclinical testing phase of nanodrugs, which are not produced in industrial scale yet. Also, we are working for creating and establishing a legislative policy. Our knowledge and technology are based on a geographical distribution already developed, mainly, in the southeastern region. Nevertheless, even there, nanotechnology is at an early stage as to its application for therapeutic and diagnostic purposes.

The field of nanomedicine has witnessed an incredible expansion, from a total market value in 2003 of $500 million expected to rise to $160 billion by 2015 (Global Industry Analysts, Inc.). The nanomedicine industry is forecasted to grow and have a significant impact on the economy, with sectors such as biomaterials, diagnostics and drug delivery expected to play a major role. This thesis gives a detailed account of the synthesis and characterisation of molecularly imprinted nanogels for drug delivery. Their toxicity and potential use as a targeted carrier to cancerous cells is evaluated. Initially an overview of nanomaterials and their uses in many areas such as agriculture, energy storage and technology are discussed. The impact of nanomaterials on the life sciences is examined; in particular their application in drug delivery is focussed upon. Chapters 2, 3 and 4 make up the results and discussion of this work. Chapter 2 focuses on developing the synthesis of the acrylamide based nanogels and, vitally, incorporating a suitable fluorescent tag in order to track the nanogels in vitro and in vivo. Fundamentally toxicity studies carried out on the nanogels, both in vitro and in vivo in Danio rerio (zebrafish) are reported in Chapter 3 to ensure the nanogels are biocompatible. Chapter 4 introduces an innovative approach, molecular imprinting, to incorporating a drug into the nanogels. The upload and release of Tamoxifen (a drug used to treat breast cancer) at reduced pH, was also analysed. Finally future development of the carrier is discussed and key issues that need to be addressed.

Doctor of Philosophy / Department of Chemistry / Santosh Aryal / Nanotechnology offers exciting options for the site-selective delivery of chemotherapeutics and diagnostic agents using nanoparticles. Varieties of organic and inorganic nanomaterials have been explored extensively as a delivery system either in the form of drug carriers or imaging agents. Successful stories include the clinical translation of anticancer nanomedicines such as PEGylated liposomal doxorubicin (DOXIL®), albumin-bound paclitaxel (Abraxane®), and polymeric micelle loaded paclitaxel (Genexol®), which are currently used in the clinic as one of the first lines for cancer chemotherapies. These conventional nanomedicines rely on passive-drug targeting taking advantage of leaky tumor vasculature, called the Enhanced Permeability and Retention (EPR) effect. However, delivering biologically active components selectively to the diseased cell, for example, cancer, is highly challenging due to the biological barriers in the body including blood pool cells/proteins, heterogeneous microenvironment, and intracellular degradation. Therefore, the goal of this dissertation is to develop nanoplatforms that can deliver the agents of interest in targeted fashion to cancer while bypassing or collaborating with the biological barriers. The design consideration of these nanoplatforms centralizes on using simple chemical reactions and cell biology to engineer nanoparticles. The presented nanoparticles were extensively studied and evaluated for their biological functions using in vitro and in vivo models. These nanoconstructs described herein address current limitations of conventional nanomedicine such as (1) the lack of understanding of the interaction of nanoparticle and biological system, and (2) the lack of an effective targeting strategy to deliver drugs to the cancer cell in the tumors. The significant findings of each system will be highlighted and discussed throughout this dissertation. Results obtained highlight key findings such as NP intracellular fate, maximized tumor accumulation, and unique pharmacokinetics could open the avenues for systemic investigations for personalized medicine and lay the foundation for nanomedicine design to accelerate clinical translation.

Nanomedicine has emerged in the past decades, and a variety of designs for drug/gene delivery have been reported since the concept of nanomedicine was first demonstrated. However, with the exception of a few notable successes, the clinical translation of nanomedicine has been slow. Specificity and delivery efficiency are the major obstacles; only a few nanomedicine systems can effectively reach and release the therapeutic payload at the target site, thereby limiting the therapeutic efficacy. To tackle these issues, this work aims to design new strategies to improve nanomedicine systems at the gene-, protein- and tissue- levels. We applied CRISPR/Cas9 technology for gene targeting. Delivering CRISPR/Cas9 elements, including Cas9 endonuclease and a corresponding guide RNA, allows for specific gene mutagenesis. A conventional gene delivery carrier often has a highly positive charge density for higher transgene expression, but this may result in unfavorable effects on the Cas9 plasmid transfection. As a large plasmid, strong interaction between the Cas9 plasmid and the polycation with high charge density may hinder the plasmid’s intracellular release. Moreover, high Cas9 expression usually leads to undesirable off-target effects. We addressed these two major obstacles by designing a low-charged density micelle, composed of quaternary ammonium‐terminated poly(propylene oxide) and amphiphilic Pluronic F127. We tested this design on a human papillomavirus (HPV)-induced cervical cancer model to target the HPV oncogene, E7. Our micellar carrier enabled effective Cas9 transfection with a transient Cas9 expression, which offered enhanced Cas9 on-target specificity. This nonviral Cas9‐mediated E7 mutagenesis resulted in significant inhibition of HPV‐induced cancerous activity both in vitro and in vivo. Although CRISPR/Cas9 technology is a powerful toolkit for gene manipulation, gene editing might not be practical for therapeutics in the cancers that develop from endogenous mutations, which may vary among patients and disease stages. Protein-targeting, therefore, may be a more efficient approach. Aptamer and its selection technology, namely SELEX, offer direct evolution to obtain a nucleic acid ligand that specifically recognizes the protein target. Yet, aptamer screening remains unsatisfactory, and the success rate of SELEX is limited. We designed two approaches to improve the aptamer screening. We first employed a microarray platform to deconvolute the aptamer sequence and identified the aptamer functional motif. The resulted protein-targeting motif with an optimal length and showed enhanced structural and functional characteristics compared with its parental sequence. In addition to sequence optimization, conjunction of two distinct aptamers that recognize different epitopes of the protein target is another approach to improve the aptamer’s affinity. In looking for a rapid way to screen this bivalent aptamer pair, we designed a quantum dot (QD)/ Förster resonance energy transfer (FRET) sensor. Using a thrombin aptamer as a model system, we conjugated an anti-thrombin aptamer with QD and stained the other one with the intercalation dye, YOYO-3. If the two aptamers recognized different epitopes of thrombin, the conformational change of the two aptamers would take place when interacting with thrombin, and this would induce YOYO-3 dye’s translocation. YOYO-3 would be transferred from the aptamer to QD surface, resulting in a strong FRET signal. In contrast, if they recognized the same epitope, binding competition between two aptamers would inhibit dye translocation, thereby giving a minimal FRET signal. By measuring the FRET signal, we can verify if the two aptamers may form a bivalent pair. Lastly, we integrated mesenchymal stem cell (MSC) with a nanomedicine system to achieve active tissue-targeting. MSC is known to migrate toward certain types of cancer cells by chasing the chemotaxis release from the cancer cells, but the therapeutic payload that MSC can carry is limited. Forming an MSC spheroid allowed the loading of the nanomedicine system with another type of anti-cancer drug. We therefore designed a hybrid MSC/nanomedicine spheroid, which functioned as an active tumor-targeting platform, enabling effective delivery for both cytotoxic protein and chemotherapeutic drugs. In a heterotopic glioblastoma model, the hybrid spheroid significantly improved the retention of the nanomedicine system at the tumor site, leading to enhanced tumor inhibition in vivo. Collectively, this work demonstrated the effective approaches for gene, protein and tissue targeting by addressing the issues of low specificity and limited delivery efficiency that many current nanomedicine systems face. Particularly, the results may add to the armamentarium of cancer therapeutics, which remains largely challenging and intractable.

L'imagerie par résonance magnétique (IRM) est largement utilisée dans le milieu médical pour l'imagerie des tissus mous. Afin d'obtenir des images de meilleures qualité, les hôpitaux s'équipent d'IRM avec des champs de plus en plus intenses. Les agents de contraste à base de nanoparticules de fer sont très prometteurs pour l'imagerie à haut champ. En effet, au contraire des agents de contraste à base de gadolinium, ils ne perdent pas leur efficacité à haut champ. Plusieurs paramètres sont à prendre en compte afin d'obtenir des agents de contrastes plus efficaces en IRM : tout d'abord, les propriétés magnétiques des nanoparticules d'oxydes de fer. Celles-ci doivent avoir des aimantations importantes. Ensuite, les nanoparticules agrégées sont plus efficaces que les nanoparticules individuelles. Pour finir, la présence d'une couche plus ou moins imperméable à l'eau ainsi que son épaisseur vont influencer l'efficacité de l'agent de contraste. Ce mémoire de thèse présente la conception de nouveaux agents de contraste à base de nanoparticules d'oxyde de fer, depuis l'optimisation de la synthèse afin d'obtenir les nanoparticules ayant les propriétés magnétiques les plus intéressantes pour l'IRM, jusqu'à l'assemblage de ces nanoparticules afin d'améliorer leur efficacité en IRM. La première partie de ce travail est donc consacrée à la synthèse de nanoparticules d'oxyde de fer. Une approche organométallique a été choisit car elle permet d'obtenir des nanoparticules de taille contrôlée. Nous montrons dans cette partie que les conditions de synthèse ont une grande influence sur la structure cristalline des nanoparticules synthétisées ainsi que sur leurs propriétés magnétiques. La deuxième partie de ce travail est consacrée à la réalisation d'agrégats de nanoparticules de taille contrôlée. L'agrégation des nanoparticules est réalisée par effet solvophobe en ajoutant de l'eau sur une solution de nanoparticules hydrophobes dans le THF. Nous montrons dans cette partie que la cinétique d'agrégation dépend de la quantité d'eau ajoutée. Les agrégats sont ensuite stabilisés par l'ajout d'un polymère et nous montrons que la morphologie et la taille des agrégats après leur transfert dans l'eau dépendent de la masse molaire et de la nature du polymère utilisé. La troisième partie de ce travail est consacrée à l'évaluation de l'efficacité des agrégats de nanoparticules en tant qu'agent de contraste. Les agrégats testés se sont révélés prometteurs, et des efficacités supérieures à celles d'agents de contraste commerciaux ont été obtenues. / The magnetic resonance imaging (MRI) is widely used in the medical field for soft tissue imaging. In order to obtain images of better quality, hospitals equip themselves with MRI of higher fields. Iron-based nanoparticle contrast agents are very promising for imaging at high field. Indeed, unlike the gadolinium contrast agents, they do not lose their effeciency at high field. Several parameters must be taken into account to achieve more effective contrast agents in MRI: first, the magnetic properties of iron oxide nanoparticles. They must have significant magnetization. Then, aggregated nanoparticles are more effective than individual nanoparticles. Finally, the presence of a more or less hydrophylic layer and its thickness will influence the effeciencys of the contrast agent.This thesis presents the design of new contrast agents based on iron oxide nanoparticles assembly, since the optimization of the synthesis to obtain nanoparticles with the most interesting magnetic properties for MRI up assembly of nanoparticles to improve their effectiveness in MRI.The first part of this work is devoted to the synthesis of iron oxide nanoparticles. An organometallic approach was chosen because it allows to obtain nanoparticles of controlled size. We show in this part of the synthesis conditions have a great influence on the crystal structure of the synthesized nanoparticles and their magnetic properties.The second part of this work is dedicated to the production of controlled size aggregates of nanoparticles. The aggregation of nanoparticles is performed by solvophobic effect by adding water to a solution of hydrophobic nanoparticles in THF. We show in this section that the kinetics of aggregation depends on the amount of water added. The aggregates are then stabilized by the addition of a polymer and show that the morphology and size of the aggregates after transfer into the water depend on the molecular weight and nature of the polymer used.The third part of this work is devoted to the evaluation of the efficiency of nanoparticle aggregates as a contrast agent. The aggregates tested have shown promise, and efficiencies higher than commercial contrast agents were obtained.