Yes / The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable Combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC-MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery. / The work was funded by the Medical Research Council (grant number: MR/L01629X MRC Medical Bioinformatics Centre) and the EPSRC (grant number EP/P023266/1 Health Impact Partnership). EPSRC (EP/I000623/1, EP/K023845/1). Laura E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

L'angiogénèse est un phénomène vital dans de nombreux processus physiologiques tels que le développement embryonnaire ou la cicatrisation. Mais c'est aussi un processus pathologique impliqué dans la croissance des tumeurs malignes, dans le développement des métastases et dans des maladies telles que l'endométriose, la dégénérescence Maculaire liée à l'âge (DMLA) et l'arthrose. La néovascularisation pathologique est dense et désordonnée contrairement à la néovascularisation physiologique, ce qui en fait une cible thérapeutique attrayante. Les agents perturbateurs vasculaires (VDA) sont une nouvelle classe de molécules bioactives qui détruisent sélectivement la néovascularisation tumorale et arrêtent l'apport sanguin aux tumeurs solides, provoquant une nécrose tumorale étendue. Parmi les VDA, les agents se liant à la tubuline sont principalement représentés. Le processus d'angiogénèse au sein de l'arthrose ainsi que le mode d'action des VDA nous amène a envisager l'utilisation de ses derniers en tant que nouveau traitement anti-arthrosique. Dans la recherche de nouveaux scaffolds VDA, nous avons d'abord comparé les activités biologiques de plusieurs VDA. Une classe en particulier a attiré notre attention sur laquelle seules quelques études avaient été menées. Cela nous a permis de sélectionner des pistes avec un espace chimique exploitable pour concevoir des scaffolds originaux. Cette thèse présentera les analogues qui ont été synthétisés, leur viabilité cellulaire sur les HUVEC (cellules endothéliales de la veine ombilical humaine) et leur activité sur l'inhibition de la polymérisation de la tubuline (ITP). / Angiogenesis is a vital phenomenon in many physiological processes such as embryonic development or wound healing. But it is also a pathological process involved in the growth of malignant tumors, in the development of metastases and in diseases such as endometriosis or age-related macular degeneration (AMD) and osteoarthritis. Pathological neovasculature is dense and disordered in contrast to physiological neovasculature, which makes it an attractive therapeutic target. Vascular Disrupting Agents (VDA) are a new class of bioactive molecules that selectively destroy tumour neovasculature and shut down blood supply to solid tumours, causing extensive tumour cell necrosis.1 Among small molecule VDAs, tubulin-binding agents are mostly represented. The process of angiogenesis within osteoarthritis as well as the mode of action of VDA leads us to consider the use of its last as a new anti-osteoarthritis treatment. In the search for novel VDA scaffolds, we first compared the biological activities of several VDA. One class in particular attracted our attention on which only a few studies had been conducted. This allowed us to select leads with exploitable chemical space to design original scaffolds. These thesis will present analogs which were synthesized, their cell viability on HUVEC (human umbilical vein endothelial cells) and their activity on tubulin polymerization inhibition (ITP).

Orientador: Prof. Dr. Fabio Furlan Ferreira / Tese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Nanociências e Materiais Avançados, 2017. / Atualmente, o câncer é um dos problemas de saúde pública mais complexos que o sistema de saúde brasileiro enfrenta, dada a sua magnitude epidemiológica, social e econômica. É bem sabido que a combretastatina A4 (CA-4), que é isolada a partir das cascas da árvore sul-africana, cujo nome científico é Combrettum caffrum, é utilizada para inibir a angiogênese, que consiste no crescimento de novos vasos sanguíneos a partir dos já existentes. No entanto, dependendo da dose administrada ao paciente, a CA-4 pode causar alguns efeitos colaterais. Aqui, será apresentada a caracterização físico-química de um novo derivado N-acilidrazônico - LASSBio-1735 - um análogo da CA-4. O LASSBio-1735 foi avaliado quanto a seus efeitos citotóxicos, por ensaios de MTT, frente às linhagens tumorais HL-60 (leucemia humana), SF-295 (glioblastoma humano), MDA-MB435 (melanoma) e HCT-8 (carcinoma ileocecal ¿ cólon), apresentando resultados promissores. Pudemos determinar com êxito as estruturas cristalinas - utilizando dados de difração de raios X por policristais e um procedimento de simulated annealing - das formas anidra e di-hidratada do composto sintetizado. Foi observado que os compostos cristalizaram em sistemas cristalinos ortorrômbicos, porém em distintos grupos espaciais. A forma anidra cristalizou no grupo espacial Pna21 e a forma hidratada no grupo espacial P212121. Os efeitos sobre a viabilidade celular das formas anidra e di-hidratada do LASSBio-1735 foram comparativamente avaliados em diferentes linhagens tumorais e a forma di-hidratada exibiu maior citotoxicidade frente a linhagem tumoral K562 (leucemia mieloide crônica). Os resultados de velocidade de dissolução intrínseca levaram-nos a classificar o LASSBio-1735 em suas diferentes formas como um fármaco de baixa solubilidade, tendo sido observado um ligeiro aumento da solubilidade da forma anidra quando comparada a forma di-hidratada. / Currently, cancer is one of the most complex public health problems faced by the Brazilian health system, given its epidemiological, social and economic magnitudes. It is well known that combretastatin A4 (CA-4), which is isolated from Combretum caffrum, is used to inhibit angiogenesis, which is related to the growth of new blood vessels from the existing ones. However, depending on the dose administered to the patient, it can cause some side-effects. Herein, we present the physicochemical characterization of a novel N-acylhydrazone derivative ¿ LASSBio-1735 ¿ a CA-4 analogue. LASSBio-1735 was evaluated for its cytotoxic effects, using MTT assays, against HL-60 (human leukemia), SF-295 (human glioblastoma), MDA-MB435 (melanoma) and HCT-8 (ileocecal adenocarcinoma) tumor cells, showing promising results. We could successfully determine the crystal structures ¿ by using X-ray powder diffraction data and a simulated annealing procedure ¿ of the anhydrous and hydrated forms of the as-synthesized compound. Both compounds crystallized in orthorhombic crystal systems but under different space groups. The anhydrous form crystallized in the Pna21 while the hydrated one in the P212121 space groups. The effects on cell viability of anhydrous and dihydrated forms of LASSBio-1735 were comparatively evaluated in different tumor cell lines, and the dihydrated form exhibited higher cytotoxicity against the K562 (human chronic myeloid leukemia) tumor cell line. The results of intrinsic dissolution rate lead us to classify LASSBio-1735 in its different forms as a pharmaceutical candidate with low solubility; however, a slight solubility increase of the anhydrous form when compared to the dihydrated one was found.