Bioinspired soft nanovesicles for site-selective cancer imaging and targeted therapies

Funding Information: European Research Council, ERC Starting Grant, Grant/Award Number: ERC‐StG‐2019‐848325 Funding information Funding Information: This work is supported by the European Research Council, ERC Starting Grant ‐ ERC‐StG‐2019‐848325. The authors would like to thank Dr. N. K. Jain, Dr. S. Meena, and Dr. Gorain for glancing at this article. We would like to dedicate this article to the memory of late Prof. Sanjiv Sam Gambhir, a molecular imaging and early cancer detection scientist. We have cited all reproduced images and figures in this review. Publisher Copyright: © 2022 Wiley Periodicals LLC.Cell-to-cell communication within the heterogeneous solid tumor environment plays a significant role in the uncontrolled metastasis of cancer. To inhibit the metastasis and growth of cancer cells, various chemically designed and biologically derived nanosized biomaterials have been applied for targeted cancer therapeutics applications. Over the years, bioinspired soft nanovesicles have gained tremendous attention for targeted cancer therapeutics due to their easy binding with tumor microenvironment, natural targeting ability, bio-responsive nature, better biocompatibility, high cargo capacity for multiple therapeutics agents, and long circulation time. These cell-derived nanovesicles guard their loaded cargo molecules from immune clearance and make them site-selective to cancer cells due to their natural binding and delivery abilities. Furthermore, bioinspired soft nanovesicles prevent cell-to-cell communication and secretion of cancer cell markers by delivering the therapeutics agents predominantly. Cell-derived vesicles, namely, exosomes, extracellular vesicles, and so forth have been recognized as versatile carriers for therapeutic biomolecules. However, low product yield, poor reproducibility, and uncontrolled particle size distribution have remained as major challenges of these soft nanovesicles. Furthermore, the surface biomarkers and molecular contents of these vesicles change with respect to the stage of disease and types. Here in this review, we have discussed numerous examples of bioinspired soft vesicles for targeted imaging and cancer therapeutic applications with their advantages and limitations. Importance of bioengineered soft nanovesicles for localized therapies with their clinical relevance has also been addressed in this article. Overall, cell-derived nanovesicles could be considered as clinically relevant platforms for cancer therapeutics. This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.publishersversionpublishe

Using gold nanobeacons as a theranostic technique to recognize, detect, and inhibit specific nucleic acids

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mRNA therapy at the convergence of genetics and nanomedicine

OKJ.C. acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325).publishersversionpublishe

Cancer theranostics: multifunctional gold nanoparticles for diagnostics and therapy

Doctorate in Biology, Specialty in BiotechnologyThe use of gold nanoparticles (AuNPs) has been gaining momentum in molecular diagnostics due to their unique physico-chemical properties these systems present huge advantages, such as increased sensitivity, reduced cost and potential for single-molecule characterisation. Because of their versatility and easy of functionalisation, multifunctional AuNPs have also been proposed as optimal delivery systems for therapy (nanovectors). Being able to produce such systems would mean the dawn of a new age in theranostics (diagnostics and therapy)driven by nanotechnology vehicles. Nanotechnology can be exploit for cancer theranostics via the development of diagnostics systems such as colorimetric and imunoassays, and in therapy approaches through gene therapy, drug delivery and tumour targeting systems. The unique characteristics of nanoparticles in the nanometre range, such as high surface-tovolume ratio or shape/size-dependent optical properties, are drastically different from those of their bulk materials and hold pledge in the clinical field for disease therapeutics This PhD project intends to optimise a gold-nanoparticle based technique for the detection of oncogenes’ transcripts (c-Myc and BCR-ABL) that can be used for the evaluation of the expression profile in cancer cells, while simultaneously developing an innovative platform of multifunctional gold nanoparticles (tumour markers, cell penetrating peptides, fluorescent dyes) loaded with siRNA capable of silencing the selected proto-oncogenes, which can be used to evaluate the level of expression and determine the efficiency of silencing. This work is a part of an ongoing collaboration between Research Centre for Human Molecular Genetics, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal and Biofunctional Nanoparticles and Surfaces Group, Instituto de Nanociencia de Aragón, Spain within a European project [NanoScieE+ - NANOTRUCK]. In order to achieve this goal we developed effective conjugation strategies to combine, in a highly controlled way, biomolecules to the surface of AuNPs with specific functions such as: ssDNA oligos to detect specific sequences and for mRNA quantification; Biofunctional spacers: Poly(ethylene glycol) (PEG) spacers used to increase solubility and biocompatibility and confer chemical functionality; Cell penetrating peptides: to overcome the lipophilic barrier of the cellular membranes and deliver molecules into cells using TAT peptide to achieve cytoplasm and nucleus; Quaternary ammonium: to introduce stable positively charged in gold nanoparticles surface; and RNA interference: siRNA complementary to a master regulator gene, the proto-oncogene c-Myc, that is implicated in cell growth, proliferation, loss of differentiation, and cell death. In order to establish that they are viable alternatives to the available methods, these innovative nanoparticles were extensively characterized on their chemical functionalization, ease of uptake, cellular toxicity and inflammation, and knockdown of MYC protein expression in several cancer cell lines and in in vivo models.Fundação para a Ciência e Tecnologia - (SFRH/BD/62957/2009); PTDC/BIO/66514/2006; NANOLIGHT-PTDC/QUI-QUI/112597/2009; Silencing the silencers via multifunctional gold nanoconjugates towards cancer therapy - PTDC/BBB-NAN/1812/201

Nanomedicine-based strategies to target and modulate the tumor microenvironment

Funding Information: The authors acknowledge financial support from Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia, e Ensino Superior in the framework of PhD grant 2020.06638.BD (to D.P.S.), and from the European Research Council grant agreement No 848325 (J.C. for the ERC Starting Grant). Funding Information: The authors acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia/ Minist?rio da Ci?ncia, Tecnologia, e Ensino Superior in the framework of PhD grant 2020.06638.BD (to D.P.S.), and from the European Research Council grant agreement No 848325 (J.C. for the ERC Starting Grant). None declared by authors. Publisher Copyright: © 2021 Elsevier Inc.The interest in nanomedicine for cancer theranostics has grown significantly over the past few decades. However, these nanomedicines need to overcome several physiological barriers intrinsic to the tumor microenvironment (TME) before reaching their target. Intrinsic tumor genetic/phenotypic variations, along with intratumor heterogeneity, provide different cues to each cancer type, making each patient with cancer unique. This brings additional challenges in translating nanotechnology-based systems into clinically reliable therapies. To develop efficient therapeutic strategies, it is important to understand the dynamic interactions between TME players and the complex mechanisms involved, because they constitute invaluable targets to dismantle tumor progression. In this review, we discuss the latest nanotechnology-based strategies for cancer diagnosis and therapy as well as the potential targets for the design of future anticancer nanomedicines.publishersversionpublishe

Edificação de Capacidades Operacionais no Sistema de Armas EH-101

Este trabalho de investigação individual tem como objetivo avaliar a possibilidade de potenciar as capacidades operacionais do Sistema de Armas (SA) EH-101 por forma a participar em missões de âmbito internacional. Analisaram-se as missões ao serviço da Organização do Tratado do Atlântico Norte (OTAN) e da União Europeia (UE) executadas por outras nações, que o EH-101 da Força Aérea Portuguesa poderia realizar. Foram igualmente estudadas as necessidades de adaptação das capacidades operacionais do SA por forma a ser empenhado internacionalmente. Concluiu-se que o SA EH-101 tem potencial para participar em missões de Joint Personnel Recovery (JPR) no âmbito da OTAN, e que ao nível da UE, numa perspetiva de Segurança Cooperativa, poderia participar no apoio à agência FRONTEX, não fosse a elevada relação custo/benefício identificada por esta entidade. Apurou-se que existem várias lacunas nomeadamente as que dizem respeito ao número de tripulações, ao treino dos tripulantes e a material essencial em falta. Foi possível concluir que o SA EH-101 tem condições para participar em missões internacionais de JPR no âmbito da OTAN mas para que isto se efetive na realidade, é necessário desenvolver a capacidade operacional do Sistema de Armas nas dimensões do pessoal, treino e material. Abstract: This individual research work aims to evaluate the possibility of enhancing the operational capabilities of EH-101 Weapons System (WS) in order to participate in international missions. The North Atlantic Treaty Organization (NATO) and European Union (EU) missions carried out by other nations which the EH-101 of the Portuguese Air Force could carry out were analyzed. The need to adapt the WS operational capabities to engage internationally has also been studied. It was concluded that the EH-101 WS has the potential to participate in Joint Personnel Recovery (JPR) missions under NATO, and that at EU level, in a Cooperative Security perspective, it could participate in supporting the FRONTEX agency, not feasible due to the non-compensatory cost / benefit ratio identified by this entity. It has been found that there are several shortcomings, namely those concerning staff number, crew training and lack of essential equipment. It was therefore possible to conclude that EH-101 WS is able to participate in JPR international NATO missions, but for this to be effective, it is necessary to develop the operational capability of the Weapons System on dimensions like personnel, training and equipment.N/

Maintenance Resource Management MRM

Dado o acréscimo considerável de acidentes aeronáuticos que têm na sua génese o erro humano em ambiente de manutenção aeronáutica, surge a necessidade de conhecer os fatores que contribuem para as falhas de manutenção, supervisão e inspeção e encontrar soluções adequadas à respetiva resolução. Neste trabalho, demonstrou-se que os programas de Maintenance Resource Management (MRM) visam, através de um maior esclarecimento do indivíduo sobre Fatores Humanos, garantir a mutação das suas atitudes e comportamentos. Em função dos dados obtidos e respetiva análise à luz dos conceitos teóricos e melhores práticas, concluiu-se do impacto positivo que esta iniciativa poderá ter na Segurança de Voo da Força Aérea Portuguesa e da pertinência da sua implementação. Quanto à melhor forma de endereçar o treino inicial e recorrente de Fatores Humanos em ambiente de manutenção aeronáutica, recomenda-se a estruturação de um programa integrado de MRM de raiz, que beneficie da experiência de outras Organizações na implementação de programas desta natureza e que seja passível de acomodar as necessidades específicas de cada Unidade da Força Aérea Portuguesa. Como resultado deste trabalho de investigação foram identificadas algumas das áreas de intervenção mais críticas na Força Aérea Portuguesa, a endereçar no programa, e estabelecidas as linhas de orientação a seguir, ao nível da cultura de segurança, dos fatores organizacionais, individuais e ambientais, da norma, da comunicação e trabalho em equipa e da liderança e planeamento. Por último, teceram-se um conjunto de recomendações condicionantes do sucesso do programa, que se prendem com o envolvimento de toda a organização e o apoio do topo da hierarquia, com a definição de mecanismos de comunicação específicos do programa e com a importância da definição dos parâmetros de avaliação e métodos corretivos. Abstract: Given the considerable increase of aviation accidents caused by maintenance human error, there is a clear need of better knowing the factors that contribute to maintenance, supervision and inspection failure and find the appropriate solutions to their resolution. In this essay it was evidenced that Maintenance Resource Management (MRM) programs aim to guarantee attitude and behaviour changes, through each individual Human Factors better awareness. The collected data and its respective analysis based on the theoretical concepts and best practices, made it possible to draw the conclusion towards the positive impact of these programs in the improvement of Portuguese Air Force Flight Safety and the relevance of its implementation. As regards to the best approach for initial and continuation Human Factors training in aeronautical maintenance environment, the recommendation goes to structuring an integrated Maintenance Resource Management program, benefiting from other organizations previous implementation experience and however flexible to accommodate the specific requirements of each Air Base. As a result of this research, the most critical maintenance areas to be addressed in the Maintenance Resource Management program were identified and guidelines were established as regards to safety culture, organizational, individual and environmental factors, procedures, communication and team work, leadership and planning perspectives. Finally, several recommendations were put together as the program critical success factors, encompassing global organization participation, hierarchy commitment to the program, establishing the appropriate communication channels and demystifying the importance of defining evaluation parameters and corrective procedures