A expansão do desenvolvimento de radionuclídeos para uso em terapia de tumores, permite que técnicas de tratamento de tumores sejam mais seletivas e adequadas. Novos agentes têm como finalidade reduzir o tempo de tratamento e acelerar o tempo de recuperação de muitos pacientes. O principal objetivo deste trabalho é o desenvolvimento de microesferas de ácido lático e resina marcadas com Hólmio-166, para que se obtenha um radiofármaco que possa oferecer um tratamento localizado do tumor e, portanto para que se tenha a máxima irradiação do tumor e a diminuição dos efeitos de toxicidade nos tecidos adjacentes saudáveis. A metástase hepática é a principal causa de morte de pacientes com câncer de colo retal, para estes pacientes a resposta da quimioterapia e da radioterapia é baixa. Uma alternativa é a radioterapia interna seletiva utilizando microesferas marcadas com Hólmio-166, um emissor b (Emax=1,84 MeV), com um alcance máximo no tecido de 8,4mm e emissor de fótons (81 keV, 6,2%), apropriado para a aquisição de imagens. A produção de Hólmio-166 é possível no reator nuclear IEA-R1 (IPEN-CNEN/SP), um reator de pesquisa com baixo fluxo de nêutrons. O Hólmio tem uma abundância de 100% na natureza e seção de choque de 64 barns. Isso permite produzir uma atividade de 344mCi (~12GBq) (reator IEA-R1, 60 horas, 4,0x 1013n .s-1.cm-2), o suficiente para produção de doses terapêuticas. As resinas de troca catiônica, AG50W-X2, AG50W-X8, Amberlite, Sephadex e Sepharose, foram marcadas com 166Ho. Todas elas apresentaram um ótimo resultado de marcação. As resinas AG50W-X2, AG50W-X8, Amberlite e Sephadex não têm o tamanho de partícula ideal para terapia de tumores hepáticos, porém foi proposto que partículas com tamanho entre 100-450 m podem ser usadas no tratamento de tumores de cabeça e pescoço. A resina Sepharose tem as características essenciais para terapia de tumores hepáticos. Entretanto, estudos in vivo devem ser realizados para comprovar a sua eficácia. O preparo das microesferas de ácido lático não foi bem sucedido, mas a primeira fase da preparação apresentou bons resultados. / A surge in research activity is expanding the applications for therapeutic radiopharmaceuticals, which are employing more sophisticated targeting methodologies and more appropriate therapeutic isotopes for the tumors being treated. These new agents will reduce treatment time and accelerate recovery for many patients. The aim of this work is the development of resin-based and acid lacticbased microspheres labeled with 166Ho, in order to obtain selective delivery of radioisotopes to the tumor, thus maximizing the irradiation effect while sparing toxicity to the surrounding healthy liver. Liver metastases cause the majority of deaths from colorectal cancer, and response to chemotherapy and external radiotheraphy is poor. An alternative is an internal radionuclide therapy using microspheres labeled with 166Ho, a beta minus emitter (Emax=1.84 MeV), with maximum tissue range 8.4 mm, that also emits photons (81keV, 6.2%) suitable for imaging. The production of 166Ho is feasible in the IEA-R1 Reactor at IPEN-CNEN/SP, a low power reactor with low neutron fluxes. The nuclear reaction has a cross section of 64 barns and 165Ho has a natural abundance of 100%. It is possible to produce 344 mCi (~12GBq) (IEA-R1 Reactor, 60 hours, 4,0x 1013n .s-1.cm-2) a sufficient therapeutic dose, depending on the demand of doses. The cation exchange resins, AG50W-X2, AG50W-X8, Amberlite, Sephadex and Sepharose, were labeled with 166Ho. All the resins showed a very good retention. Although AG50W-X2, AG50W-X8, Amberlite and Sephadex did not have the right particle size, it is suggested that particles of 100-450 m could be used in the treatment of head-and-neck tumours. Sepharose labeled with 166Ho has essential characteristics for treatment liver therapy. However, further in vivo studies should be performed to prove its effectiveness. The preparation of acid lactic-based microspheres was not successful, but the first step of the preparation was very effective.

Hollow glass microspheres have been used extensively in the automotive and marine industries as an additive for reducing weight and saving material costs. They are also added to paints and other materials for their reflective properties. They have shown promise for weight critical applications, but have thus far resulted in materials with low fracture toughness and impact resistance when combined with thermosetting resins in syntactic foam. The advent of commercially available microspheres with a wide range of crushing strengths, densities and adhesive properties has given new impetus to research into syntactic foam with better fracture behaviour. Current research suggests that the beneficial effects on fracture and impact resistance gained by the addition of solid reinforcements such as rubber and ceramic particles are not seen with the addition of hollow glass microspheres. The research presented in this paper has examined the mechanisms for fracture resistance in glass microsphere filled epoxy (GMFE) syntactic foams, as well as determined the effect microsphere crushing strength and adhesion strength has on the material???s fracture toughness. The flexural properties of various GMFE have also been determined. GMFE were manufactured with varying microsphere volume fraction up to 50%, and with variances in microsphere crushing strength and adhesion. The specimens were tested for Mode I fracture toughness in a three point single edge notched bending setup as described in ASTM D5045 as well as a three point flexural setup as described in ASTM D790-3. Fracture surfaces were inspected using scanning electron microscope imaging to identify the fracture mechanisms in the presence of microspheres. Results indicate a positive effect on fracture toughness resulting from new fracture areas created as tails in the wake of the microspheres in the fracture plane. Results also indicate a negative effect on fracture toughness resulting from weak microspheres or from interfacial disbonding at the fracture plane. These two effects combine to show an increase in GMFE fracture toughness as the volume fraction of microspheres is increased to between 10 ??? 20% volume fraction (where the positive effect dominates), with a reduction in fracture toughness as microspheres are added further (where the negative effect dominates).

A magnetic target drug delivery system consisting of biodegradable polymeric microspheres (poly D, L-lactic acid) loaded with magnetite nanoparticles (10-100 nm) and anticancer drug (paclitaxel) was studied. The magnetite nanoparticles were synthesized by chemical precipitation. The as-synthesized magnetite nanoparticles were subsequently introduced into a mixture of polymer magnetic polymeric composite particles were investigated and further correlated with the reaction parameters. It was found that the size and characteristics of the polymeric composite particles depended on the viscosity of the polymer solution. Preliminary drug release experiments showed that the loaded drug was released with the degradation of the polymer. The release rates could be enhanced by an oscillating external magnetic field. / Singapore-MIT Alliance (SMA)

Thesis (Ph.D.)--McMaster University, 2004. / Supervisor: Harald D. H. Stöver.

Lanthanide-encoded polystyrene-co-methacrylic acid (P(S-MAA)) microspheres with narrow size distributions were synthesized by two-stage dispersion polymerization. I examined how the amounts of methacrylic acid (MAA) and lanthanide (Ln) salts affect the composition of the particles formed in the reaction. Also, I performed a systematic study of Ln ion release into different aqueous solutions. In normal buffers, these particles were stable against ion leakage, even upon prolonged storage and stirring. When strong chelating agent ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were present in buffer, the loss of Ln ions increased to 15 % after 8 weeks. A preliminary kinetic study of Ln ion incorporation was performed to help understand the particle formation mechanism.

Lanthanide-encoded polystyrene-co-methacrylic acid (P(S-MAA)) microspheres with narrow size distributions were synthesized by two-stage dispersion polymerization. I examined how the amounts of methacrylic acid (MAA) and lanthanide (Ln) salts affect the composition of the particles formed in the reaction. Also, I performed a systematic study of Ln ion release into different aqueous solutions. In normal buffers, these particles were stable against ion leakage, even upon prolonged storage and stirring. When strong chelating agent ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were present in buffer, the loss of Ln ions increased to 15 % after 8 weeks. A preliminary kinetic study of Ln ion incorporation was performed to help understand the particle formation mechanism.

Using protein design, a series of metal binding proteins have been designed, allowing the local factors that contribute to metal affinity and thermostability to be studied. Those proteins with the highest metal binding affinities had the lowest apo-form Tm and the largest ÄTm upon metal binding. In this thesis, major steps have been taken toward applying the engineered protein to MR imaging. The progress of magnetic resonance imaging is hindered by low specificity and rapid elimination of FDA-approved MRI contrast agents. The engineered protein contrast agent has been conjugated to a cancer-specific targeting peptide and encapsulated in albumin microspheres to provide tandem passive and active tumor targeting. Also, a simple, high-yield purification method has been developed.

Controlled drug delivery systems deliver drugs at predetermined rates for extended periods. Although there are various types such as capsules, tablets etc, micro and nano spheres are the most commonly used systems. In this study, a set of chitosan-polyvinylpyrrolidone (CH-PVP) microspheres containing different amounts of polyvinylpyrrolidone as semi inter penetrating networks (semi-IPN) were prepared as controlled release systems. Emulsification method was applied for the preparation of microspheres and some of them were conjugated with a monoclonal antibody which is immunoglobulin G (IgG). CH-PVP films were also prepared by solvent casting method with the same composition as in the microspheres and, mechanical and surface properties of the films were examined. Prepared microspheres were characterized by SEM, stereo and confocal microscopes. Some microspheres were loaded with a model chemotherapeutic drug, 5-Fluorouracil (5-FU), and in-vitro release of 5-FU were examined in phosphate buffer solutions (pH 7.4, 0.01 M.) It was shown that for semi-IPN samples release was faster compared to pure CH samples and the total release was achived 30 days for CH:PVP-2:1, CH:PVP-3:1 semi-IPNs and CH microspheres and 27 days for CH:PVP-1:1 semi-IPN microspheres. The antibody conjugated microspheres were targeted to MDA-MB (human causasian breast carcinoma cancer cells and coculture cells in culture medium. For the CH-PVP films, it was obtained that as the amount of PVP increased, hydrophobicity as well as mechanical strength of the system was decreased.

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