ARAÚJO, Christianne Evaristo de. Movimento dos atingidos por barragens (MAB), a questão ambiental e a participação política. 2006. 145 f. : Dissertação (mestrado) - Universidade Federal do Ceará, Pró-Reitoria de Pesquisa e Pós-Graduação, Programa Regional de Pós-Graduação em Desenvolvimento e Meio Ambiente - PRODEMA, Fortaleza-CE, 2006. / Submitted by demia Maia (demiamlm@gmail.com) on 2016-04-26T13:46:43Z No. of bitstreams: 1 2006_dis_cearaujo.pdf: 2565575 bytes, checksum: a2fd04672f92462df3cca5a50030c7f0 (MD5) / Approved for entry into archive by demia Maia (demiamlm@gmail.com) on 2016-04-26T13:48:05Z (GMT) No. of bitstreams: 1 2006_dis_cearaujo.pdf: 2565575 bytes, checksum: a2fd04672f92462df3cca5a50030c7f0 (MD5) / Made available in DSpace on 2016-04-26T13:48:05Z (GMT). No. of bitstreams: 1 2006_dis_cearaujo.pdf: 2565575 bytes, checksum: a2fd04672f92462df3cca5a50030c7f0 (MD5) Previous issue date: 2006 / During the previous years, but above all starting in the 90’s, researchers have been calling the attention for an emerging field of studies composed by the confluence of environmentalism and social movements, a quite promising political trend since it integrates universalistic demands instead of particularistic ones, as it is the case of the majority of the most contemporary social movements. As this is an emerging field, and therefore a challenging one, I have found it pertinent to propose as an investigation object the relationships between the environmental issue and an specific social movement – the Affected by Dams Movement (MAB), based on the hypothesis that environmental issues should receive a prominent place in the pedagogy and methodology of this movement due to its own political nature. However, considering the research and analysis of the documents produced by the MAB, I have decided to verify through a case study – and using the participating observation as a method – how the relationship between the environmental issue and the political participation was configured in the daily routine of the residents affected by dams. To carry out this verification I have chosen the Castanhão Dam, located in the Middle Jaguaribe, Ceará, and the Novo Alagamar rural resettling, which at the time of the research (2004-2005) had already obtained considerable political results through the support and militancy in the MAB. The data presented and discussed in this work, with the support of current theoretical texts, have confirmed that the environmental theme is very integrated in the ideology of the MAB – either in the identification of problems or in the emergent ways of solving them, this movement has already achieved, in dialogues with similar international movements, to produce a critical reflection on the model of energy and water policies in the current historical moment of the capitalist production way, commonly denominated globalization. This research has also verified that the residents of the Novo Alagamar resettling have an understanding of the environment meaning and environmental education, although they do not use those terminologies produced by the Brazilian institutional culture. All the data obtained through the participating observation – considered as the most appropriate method for the registration of implicit conceptions – have revealed that for the residents of the resettling, the atmosphere is conceived as historicized, that is, inseparable from the human being and social universe. / Durante os anos anteriores, mas sobretudo a partir da década de 1990, pesquisadores têm chamado a atenção para um campo emergente de estudos formados pela confluência de ambientalismo e movimentos sociais, vertente política bastante promissora já que integra demandas universalistas ao invés de particularistas, como é o caso da maioria dos movimentos sociais mais contemporâneos. Como este campo é emergente e, portanto desafiador, pareceu-me pertinente propor como objeto de investigação as relações entre a questão ambiental e um movimento social específico – o Movimento dos Atingidos por Barragens (MAB), partindo da hipótese de que a as questões relativas ao meio ambiente deveriam receber um lugar de destaque na pedagogia e na metodologia deste movimento em razão de sua própria natureza política. Porém, a partir da pesquisa e análise dos documentos produzidos pelo MAB decidi verificar, através de um estudo de caso – e utilizando a observação participante como método – como a relação entre a questão ambiental e a participação política se configurava no cotidiano de moradores atingidos por barragens. Para proceder a esta verificação escolhi a barragem do Castanhão, localizada no Médio Jaguaribe, Ceará, e o reassentamento rural Novo Alagamar que à época da pesquisa (2004-2005) já obtivera resultados políticos consideráveis através do apoio e da militância no MAB. Os dados apresentados e discutidos neste trabalho, com apoio de textos teóricos atuais, confirmam que a temática ambiental é tão integrada na ideologia do MAB – seja na identificação de problemas ou nas formas emergenciais de solucioná-los, que este movimento já conseguiu, em diálogo com movimentos internacionais similares, produzir uma reflexão crítica sobre o modelo de políticas energéticas e hídricas no momento histórico atual do modo de produção capitalista, comumente denominado globalização. Esta pesquisa também constatou que os moradores do reassentamento Novo Alagamar possuem uma compreensão do significado de meio ambiente e educação ambiental, embora não utilizem essas terminologias produzidas pela cultura institucional brasileira. Todos os dados obtidos por meio da observação participante – o método considerado como o mais adequado para registro de concepções implícitas – revelaram que, para os moradores do reassentamento, o ambiente é concebido como historicizado, isto, é inseparável do ser humano e do universo social.

Les impacts environnementaux sont un défi global. Le programme sur l’Homme et la Biosphère de l’UNESCO (MAB) peut donner un appui international à un de ces défis que l’humanité doit relever : comment arriver à promouvoir un développement économique, social et politique tout en conservant les ressources naturelles limitées dont nous disposons. Cette thèse propose une vision historique du programme afin de comprendre son évolution et de mettre en avant la relation entre les sphères politique et scientifique qui l´ont dirigé. Les cas d´étude du Mexique, du Chili et de la République d´Haïti, mettront en lumière les défis que ces pays doivent relever et la manière dont le Programme a été adapté au niveau national. Deux groupes d´acteurs, scientifiques et instances politiques, ont façonné le programme tout au long de son histoire et maintenu le dialogue pour adapter les principes du Programme MAB dans les Réserves de Biosphère. Par ailleurs, la toute récente création d´une Réserve de Biosphère transfrontalière entre la République d´Haïti et la République Dominicaine est un exemple de la collaboration et du rôle qu´ont joué d´autres instances de l´UNESCO telles que les Commissions Nationales et les Délégations Permanentes. / Environmental challenges have a significant impact. The Man and the Biosphere (MAB) Programme of UNESCO provides international support to one of the challenges facing humanity; that is how to achieve economic, social and political development and to promote the conservation of limited natural resources at the same time.This thesis takes into account a historical vision of the programme at the global level to understand its evolution and to highlight the relationship between the political and scientific spheres of the programme.On the other hand, it presents three study cases in different countries: Mexico, Chile and the Republic of Haiti to demonstrate how the programme has been adapted on the national level and the challenges they face. Two groups of actors have shaped the programme throughout its history, scientists and political bodies. They have maintained dialogues to adopt the principles of the MAB Programme in the Biosphere Reserves. Moreover, the recent creation of a Transboundary Biosphere Reserve between the Republic of Haiti and the Dominican Republic is an example of collaboration, but also it highlights the importance of other bodies of UNESCO such as the National Commissions and Permanent Delegations in policy-making.

La mise en place de la lignée germinale au cours du développement constitue une des étapes fondamentales conditionnant la fertilité de l’individu adulte. Au cours des dernières décennies, le nombre croissant de couples consultant pour une aide médicale à la procréation a fait émerger l’hypothèse d’une altération des fonctions de reproduction chez l’Homme qui pourrait trouver son origine dans la perturbation du développement précoce. Dans l’ovaire fœtal, les cellules germinales s’orienteront vers la voie de l’ovogénèse, caractérisée entre autres par l’entrée en méiose de ces cellules. La majorité des données actuelles relatives à ces évènements sont issues du modèle murin alors que le développement de l’ovaire humain est significativement diffèrent de celui de la souris. Il est donc nécessaire d’approfondir nos connaissances du développement ovarien humain et d’identifier ses éventuelles perturbations. L’objectif de mon travail a été de mettre au point un outil d’étude du développement ovarien et d’identifier de nouvelles voies impliquées dans la régulation de l’entrée en méiose des cellules germinales fœtales humaines et leurs perturbations éventuelles.Nous avons mis au point un nouveau modèle de xénogreffe d’ovaires fœtaux humains du premier trimestre de gestation (au moment de l’apparition des premières cellules méiotiques). Ce modèle nous a permis d’observer un développement de l’organe et une différenciation des cellules germinales similaires à ceux observés in vivo. Ce modèle permettra des travaux à des âges auxquels le matériel d’étude est peu accessible. En couplant ce modèle de xénogreffe à une stratégie d’ARN-interférence, il nous a été possible d’inhiber l’expression d’un gène spécifiquement exprimé dans les cellules germinales ovariennes, DMRTA2, et de mettre en évidence un potentiel rôle de ce gène dans leur différenciation pré-méiotique. Nous avons observé une diminution du nombre de cellules ayant initié la méiose après inhibition de l’expression de ce gène. Par ailleurs, nous avons également identifié la présence dans l’ovaire fœtal de nombreux marqueurs décrits comme testiculaires chez la souris (PLZF, DNMT3L, FGF9, NANOS2 ou CYP26B1). L’expression de ces marqueurs pourrait expliquer la présence de cellules mitotiques tardives dans l’ovaire fœtal humain que nous avons pu observer jusqu’à 30 semaines de gestation. En parallèle de ces travaux, nous avons testé la sensibilité des cellules germinales à la dexaméthasone, glucocorticoïde pouvant être administré au cours de la grossesse. Il a été observé une augmentation de l’expression de PLZF, gène cible de l’activation des récepteurs aux glucocorticoïdes, pouvant expliquer la diminution du nombre de cellules germinales.En conclusion, ce travail de thèse a permis d’identifier un nouveau gène potentiellement régulateur de la transition mitose/méiose dans l’ovaire humain, et d’affiner nos connaissances sur le développement de l’ovaire humain et l’entrée en méiose des cellules germinales. Toutefois, de nombreuses questions restent posées ainsi de futures études devront clarifier si les cellules germinales mitotiques observées à des stades tardifs sont capables de se différencier en ovocytes compétents. / Woman fertility is partially dictated by the set up of the human female germ line. During the last ten years, which saw an increased number of couples consulting for assisted reproductive cares, the hypothesis of an early alteration in reproduction functions has emerged.In the fetal ovary, germ cells enter the path of oogenesis differentiation characterized by meiotic initiation. On this subject, vast majority of the scientific data are obtained from the mouse model, even if differences with human ovarian physiology are widely acknowledged. Therefore it is necessary to extend our knowledge on human ovarian development and identify its perturbations. The objective of my work was to assess a new model to study ovarian growth, studying regulation of meiotic entry and perturbation of germ line differentiation.We sat up a new xenograft model of early human fetal ovaries, when very early meiotic germ cells appear. Organ growth and germ cells differentiation were comparable with in vivo observations. Using this model with an RNA-interference strategy, we inhibited the expression of an oogonia germ cell gene, DMRTA2. This inhibition conducted to a significantly reduced number of germ cells gene that initiated meiosis and DMRTA2 seemed to be required for mitotic-meiotic transition. In another hand, we identified, in the ovary, the expression of germ cells markers described as specifically male in rodent (PLZF, DNMT3L, FGF9, NANOS2 ou CYP26B1). The expression of these markers in the human ovary could explain the observation of mitotic germ cells in late fetal ovaries (30 wpf).In parallel, we tested germ cells sensibility to a synthetic glucocorticoid, dexamethasone, administrated during pregnancy in some justified pathologies. We observed an increased expression of PLZF that could explain the decreased number of germ cells observed in treated ovaries.In conclusion, we identified a new gene expressed in human fetal ovaries, potentially involved in the meiotic entry, and we extended our knowledge to characterized human germ line development. However, many points have to be clarified, as the possible competence of late mitotic germ cells to form oocytes.

Type II Ribosome Inactivating Proteins (RIPs), commonly known as A/B toxins are heterodimers comprising of a catalytically active A chain, an RNA N-glycosidase which inhibits protein synthesis and a lectin-like B chain required for the binding of the toxin to the cell surface and internalization of the same. Abrin is a type II RIP obtained from the mature seeds of Abrus precatorius plant that is extremely toxic and has been shown to be 75 times more potent than its well studied sister toxin, ricin. The LD50 dose for abrin is only 2.8 µg/kg body weight of mice and its potential use in bio-warfare is a cause of major concern. Abrin has been classified as a select agent by the Centre for Disease Control and Prevention, U.S.A., because it is stable, effective at very low concentrations and easy to purify and disseminate in large amounts. In spite of abrin being a potential bio-warfare agent, there is no antidote or vaccine available against this toxin till date. The first and only neutralizing monoclonal antibody (mAb) against abrin, namely D6F10, was reported from our laboratory and has been shown to rescue toxicity of abrin in cells as well as in mice. The study reported in the thesis focuses on understanding the mechanism of neutralization of abrin by the mAb D6F10 and development of a potential vaccine candidate against the toxin. In order to map the epitope corresponding to the antibody, first, overlapping gene deletion constructs spanning the entire length, 251 amino acids, of ABA were generated and checked for binding to the mAb. Fragments shorter than 1-175 did not show immuoreactivity. Analysis of the crystal structure of abrin A chain revealed that a helix spanning the amino acids 148-167 was present at the core of the protein structure and truncation in this region of the protein possibly results in loss of conformation leading to abrogation of antibody binding. Therefore, a novel strategy of epitope mapping was adopted. Abrus precatorius agglutinin (APA) is a homologue of abrin obtained from the same plant source. The A chains of abrin and APA share 67% sequence identity and their crystal structures superimpose very well but unlike abrin the APA A chain does not bind the mAb D6F10. Chimeric constructs were generated within the region 1-175 of A chains of both ABA and APA and deletions and mutations of the ABA was then made on the APA as scaffold. It could be concluded that the amino acids of the region 75¬123 are involved in the formation of the epitope. Further, based on sequence alignment of ABA and APA A chain 13 residues in the chimera ABA1-123APA124-175 were mutated and it was found that the mutation of the residues Thr 112, Gly 114 and Arg 118 resulted in loss of binding to the antibody. Furthermore, the mAb D6F10 rescues inhibition of protein synthesis by abrin in HeLa cells by internalizing in cells along with abrin and possibly occluding the active site cleft of ABA. The antibody prevents cell attachment of abrin at higher concentrations. The observations provide novel insights into mechanisms of many known neutralizing antibodies against A/B toxins. The study also highlights that chimeric protein constructs could possibly be developed as potential vaccine candidates for neutralization of abrin intoxication.

Le CD154 est une glycoprotéine transmembranaire de type II, appartenant à la famille des facteurs de nécrose tumorale (TNF) et s’exprime d’une façon transitoire à la surface des lymphocytes T activés et des plaquettes. Notre laboratoire a démontré que la forme membranaire devient soluble suite à un clivage enzymatique par les métalloprotéinases (ADAM-10 et ADAM-17). De plus, il a été montré que le CD154 soluble (sCD154) peut aussi être relâché du milieu intracellulaire sans qu’il soit exprimé à la surface cellulaire suite à un clivage enzymatique intracellulaire entre les résidus acide Glutamique 112 (E112) et Méthionine 113 (M113). Les deux formes du CD154, soluble et membranaire, possèdent une structure trimérique nécessaire pour son activité biologique. Son récepteur principal, le CD40, est une glycoprotéine de type I appartenant à la famille des récepteurs des TNFs. Il est exprimé constitutivement à la surface des cellules B, des cellules dendritiques, des macrophages, des basophiles, des plaquettes, ainsi qu’à la surface de certaines cellules non hématopoïétiques telles que les cellules endothéliales, les fibroblastes et les cellules du muscle lisse vasculaire. Outre le CD40, quatre autres récepteurs appartenant à la famille des intégrines, ont été identifiés: l’αIIbβ3, l’α5β1, l’αMβ2, l’αvβ3 et l’α4β1. Les études de notre laboratoire ont démontré que l’interaction du CD154 avec ses récepteurs induit une activation bidirectionnelle, cependant, on a observé que le clivage du CD154 de la membrane cellulaire reste une propriété privilège au CD40. Le travail illustré dans cette thèse consiste à étudier l’inhibition du clivage enzymatique du CD154 et son effet dans la régulation de la réponse immune. Les résultats générés ci-dessous montrent que le CD154 résistant au clivage est un stimulant plus important que sa forme clivable. En effet, la double mutation des résidus E112 et M113 du CD154 abolit sa libération spontanée du milieu intracellulaire ainsi que son clivage de la membrane médié par le CD40 sans affecter sa liaison à ce dernier. Ce mutant s'est avéré capable d'induire une réponse apoptotique plus importante des cellules B, des réponses prolifératives plus prononcées et déclenche la différenciation des cellules B humaines d’une manière plus significative que le CD154-WT. De plus, notre étude met en évidence le développement et la caractérisation d'un anticorps monoclonal (mAb), le Clone 8, capable d'inhiber la libération/le clivage du CD154 à partir des cellules et ainsi de le maintenir à la surface cellulaire et d'augmenter sa puissance en tant qu'activateur des réponses induites par le CD40. Le Clone 8 est capable de lier le CD154 murin et d’inhiber son clivage de la surface cellulaire de la même façon que celle étudiée dans les cellules humaines. Ces travaux vont permettre le passage de cet anticorps bloquant le clivage du CD154 au stade des essais cliniques afin de mettre en place un nouveau traitement efficace pour les maladies auto-immunes et le cancer. / CD154 is a type II transmembrane glycoprotein belonging to the tumor necrosis factor superfamily (TNF), that is transiently expressed on the surface of activated T cells and platelets. We have demonstrated that this membrane form becomes soluble following an enzymatic cleavage by metalloproteinases (ADAM-10 and ADAM-17). CD154 also exists in a soluble form originating from a direct release of an intracellular processing without being expressed on the cell surface. This fragment is the result of an intracellular enzymatic cleavage between the residues Glutamic acid at position 112 (E112) and Methionine at position 113 (M113). Both soluble and membrane-bound forms of CD154 occur as non-covalently-linked homotrimers a property conveying to CD154 its biological activity. Its main receptor, CD40, is a type I glycoprotein belonging to the TNF receptor family. It is constitutively expressed on the surface of immune and non-immune cells including B cells, dendritic cells, macrophages, basophils, endothelial cells, fibroblasts, and vascular smooth muscle cells. CD154 was also shown to bind other receptors: αIIbβ3, α5β1, αMβ2, αvβ3 and α4β1 integrin. We have shown that the interaction of CD154 with its receptors induces bidirectional activation, however, only CD40 was capable of inducing the cleavage of CD154 from T cell surface. Our results here consist in studying the inhibition of the enzymatic cleavage of CD154 and its effect in the regulation of the immune response. Our data show that the cleavage resistant CD154 is a more potent stimulant than its cleavable form. Indeed, the double mutation of residues E112 and M113 of CD154 abolishes its spontaneous release from the intracellular milieu as well as its cleavage from the membrane. This mutant was found to be able to induce a stronger apoptotic response from B cells, induce more pronounced proliferative responses and trigger human B cell differentiation in a more significant way than CD154-WT. In addition, our study highlights the development and characterization of a monoclonal antibody (mAb), Clone 8, capable of inhibiting the release/cleavage of CD154 from cells and thus maintain it on the cell surface and increase its potency as an activator of CD40-induced responses. Clone 8 binds murine CD154 and inhibit its cell surface cleavage in the same way that in human cells. This study will allow the passage of this antibody blocking the cleavage of CD154 to the stage of clinical trials to develop a novel tool to treat diseases in which CD154 is implicated.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

La recherche sur le cancer s'oriente vers le développement de « stratégies ciblées » comme la vectorisation de composés actifs permettant d'augmenter l'efficacité thérapeutique et de réduire la toxicité du traitement. Dans ce contexte, ces travaux ont été consacrés à la conception de vecteurs peptidiques pour des applications anticancéreuses. Ces systèmes ont été élaborés à partir d'un châssis moléculaire cyclodécapeptidique présentant des propriétés conformationnelles particulières. Deux approches différentes ont été envisagées. La première a consisté à rechercher de nouveaux ligands de récepteurs tumoraux en s'inspirant du domaine de reconnaissance d'un anticorps monoclonal thérapeutique. Dans ce contexte, nous proposons la conception de mime du Rituximab ciblant l'antigène CD20 utilisé dans le traitement des lymphomes Non-Hodkinien. Dans la seconde approche, nous avons développé des vecteurs destinés à des applications d'imagerie tumorale. Pour cela, des châssis multivalents présentant des ligands peptidiques RGD ciblant l'intégrine alpha-v-beta-3 ont été conjugués avec différents agents de détection puis évalués par techniques d'imagerie TEP, IRM et imagerie optique. Dans ces deux stratégies, les systèmes de vecteurs sont constitués d'un domaine de reconnaissance présentant un ou plusieurs ligands, et d'un module effecteur composé d'un élément de détection, le tout assemblé sur le châssis moléculaire. Nous nous sommes donc intéressés à développer des procédures d'assemblages biomoléculaires permettant de moduler les sites d'accrochages du châssis. Pour cela, nous avons mis au point des méthodologies de synthèse originales combinant plusieurs ligations chimiosélectives orthogonales. On démontrera que cette stratégie offre de multiples avantages et permet un assemblage macromoléculaire en une seule étape sans déprotection ni purification intermédiaire.

Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.

This project describes and evaluates a method of assessing the suitability of 161 farms for inclusion in a biosphere reserve. Farms were chosen as a basic study unit over more ecologically based units because the decision to participate in the biosphere reserve rests with the landowner. The study area is located in northern KwaZulu-Natal, between Hlobane, near Vryheid, and the Itala Nature Reserve where local landowners are exploring the possibility of establishing a biosphere reserve. A brief review of the natural, social and economic contexts is given in order to identify local dynamics relevant to the establishment of a biosphere reserve. Farm suitability for inclusion was assessed with respect to its capability to fulfil the three main roles of a biosphere reserve as defined by the Man and Biosphere Programme of UNESCO. These are conservation, sustainable development and research. Ten factors were identified to determine farm suitability: vegetation, fauna and soil conservation, present land use, agricultural potential, tourism potential, education, settlement density and location. These were prioritised using the Analytical Hierarchy Process according to their impact on the main roles of the biosphere reserve.Each farm was given a factor score according to the expression of that factor on that farm. Overall farm suitability was taken as the sum of the weighted factor scores. The final scores for each farm were grouped into suitability classes and these were mapped. This map was then used to make recommendations on which farms should be considered for inclusion in the reserve. This method of assessing farm suitability for inclusion in a biosphere reserve, involving scoring the factors determining suitability and prioritising these factors was evaluated with respect-to its efficiency in identifying suitable properties. This was achieved by comparing the results of the assessment with the suitability class of farms with known suitability. The conceptual approach to the assessment was reviewed against published guidelines for integrated regional planning and rational resource planning. The accuracy of the project method in correctly identifying suitable farms was assessed against two other simplified methods of assessment, involving no weighting between factors, and a limited number of factors. Based on these analyses, conclusions have been drawn as to the strengths and weaknesses of both the method of farm assessment and the method of evaluation itself Recommendations were made for further research into and development of methods of assessing farm suitability for biosphere reserves. A procedure for the establishment of the proposed Itala Biosphere Reserve was suggested. / Thesis (M.Env.Dev.)-University of Natal, Pietermaritzburg, 1997.

Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.