Indocyanine green (ICG) is a Food and Drug Administration–approved near-infrared fluorescent dye, employed as an imaging agent for different clinical applications due to its attractive ...physicochemical properties, high sensitivity, and safety. However, free ICG suffers from some drawbacks, such as relatively short circulation half-life, concentration-dependent aggregation, and rapid clearance from the body, which would confine its feasible application in oncology. Here, we aim to discuss encapsulation of ICG within a nanoparticle formulation as a strategy to overcome some of its current limitations and to enlarge its possible applications in cancer diagnosis and treatment. Our purpose is to provide a short but exhaustive overview of clinical outcomes that these nanocomposites would provide, discussing opportunities, limitations, and possible impacts with regard to the main clinical needs in oncology.
Protein nanocages represent an emerging candidate among nanoscaled delivery systems. Indeed, they display unique features that proved to be very interesting from the nanotechnological point of view ...such as uniform structure, stability in biological fluids, suitability for surface modification to insert targeting moieties and loading with different drugs and dyes. However, one of the main concerns regards the production as recombinant proteins in
, which leads to a product with high endotoxin contamination, resulting in nanocage immunogenicity and pyrogenicity. Indeed, a main challenge in the development of protein-based nanoparticles is finding effective procedures to remove endotoxins without affecting protein stability, since every intravenous injectable formulation that should be assessed in preclinical and clinical phase studies should display endotoxins concentration below the admitted limit of 5 EU/kg. Different strategies could be employed to achieve such a result, either by using affinity chromatography or detergents. However, these strategies are not applicable to protein nanocages as such and require implementations. Here we propose a combined protocol to remove bacterial endotoxins from nanocages of human H-ferritin, which is one of the most studied and most promising protein-based drug delivery systems. This protocol couples the affinity purification with the Endotrap HD resin to a treatment with Triton X-114. Exploiting this protocol, we were able to obtain excellent levels of purity maintaining good protein recovery rates, without affecting nanocage interactions with target cells. Indeed, binding assay and confocal microscopy experiments confirm that purified H-ferritin retains its capability to specifically recognize cancer cells. This procedure allowed to obtain injectable formulations, which is preliminary to move to a clinical trial.
Cancer-associated fibroblasts (CAFs) are key actors in regulating cancer progression. They promote tumor growth, metastasis formation, and induce drug resistance. For these reasons, they are emerging ...as potential therapeutic targets. Here, with the aim of developing CAF-targeted drug delivery agents, we functionalized H-ferritin (HFn) nanocages with fibroblast activation protein (FAP) antibody fragments. Functionalized nanocages (HFn-FAP) have significantly higher binding with FAP
CAFs than with FAP
cancer cells. We loaded HFn-FAP with navitoclax (Nav), an experimental Bcl-2 inhibitor pro-apoptotic drug, whose clinical development is limited by its strong hydrophobicity and toxicity. We showed that Nav is efficiently loaded into HFn (HNav), maintaining its mechanism of action. Incubating Nav-loaded functionalized nanocages (HNav-FAP) with FAP
cells, we found significantly higher cytotoxicity as compared to non-functionalized HNav. This was correlated with a significantly higher drug release only in FAP
cells, confirming the specific targeting ability of functionalized HFn. Finally, we showed that HFn-FAP is able to reach the tumor and to target CAFs in a mouse syngeneic model of triple negative breast cancer after intravenous administration. Our data show that HNav-FAP could be a promising tool to enhance specific drug delivery into CAFs, thus opening new therapeutic possibilities focused on tumor microenvironment.
O objetivo deste artigo é o de esboçar a prova da existência de Deus traçada por Agostinho de Hipona no segundo livro do De libero arbitrio. Tendo em vista tal fim, na primeira parte desta pesquisa, ...examinar-se-á o critério indicado pelo Hiponense para provar que Deus existe. Em seguida, isto é, na segunda etapa deste estudo, analisar-se-á a reflexão agostiniana sobre a Verdade como objeto comum e imutável do conhecimento da razão humana. Por fim, na terceira parte desta pesquisa, examinar-se-á por que a Verdade é superior à razão e assim mostrar-se-á por que, para Agostinho, Deus existe.
O objetivo deste artigo é examinar o conceito agostiniano de futuro tal como aparece em "Confissões", XI. Buscaremos mostrar que a noção de futuro é tanto uma parte constitutiva quanto uma expressão ...própria do conceito agostiniano de tempo. Vamos analisar inicialmente a reflexão agostiniana concernente à criação do mundo e à pergunta acerca do ser do tempo. Em seguida, vamos examinar o conceito de instante e sua natureza cinética. A terceira parte tratará da reflexão agostiniana sobre a medida do tempo, isto é, sobre o tempo como objeto de quantificação. Finalmente, voltaremos à noção agostiniana de futuro e sua ligação com o conceito de movimento.
The aim of this paper is to examine the emergence of the Augustinian concept of future in "Confessions" XI. We will argue that the notion of future is both an essential element and a specific expression of Augustine's concept of time. Firstly, we will focus on the Augustinian reflections about the creation of the world and the question whether time is a being or not. The notion of instant and its kinetic nature will be the center of our concerns in the second part of the paper. In the third part, we will examine Augustine's reflections about the measurement of time, that is, about time as object of quantification. Finally, we will be back to the notion of future and its connection with the concept of movement.
O objetivo deste artigo é o de examinar as análises do De Ordine para esclarecer por que, para Agostinho, o estudo das disciplinas liberais é necessário para reconhecer que Deus governa o mundo. ...Tendo em vista tal fim, na primeira fase desta pesquisa examinar-se-á o diálogo entre Agostinho, Licêncio, Trigécio e Mônica sobre o mal e a ordem das coisas (De Ord., I, 3.7- II, 7.23). Em seguida, analisar-se-ão as reflexões do Hiponense sobre a disciplina ética (De Ord., II, 8.25) e sobre a relação entre auctoritas e ratio (De Ord., II, 9.26-9.27). Por fim, examinar-se-ão as análises de Agostinho relativas às disciplinas liberais (De Ord., II, 12.35-16.44). Assim, ao esboçar a reflexão agostiniana sobre a natureza e as funções das disciplinas liberais, será possível esclarecer por que o estudo delas é necessário para poder enxergar que nada está fora da ordem (De Ord., I, 1.2).
O objetivo deste artigo é o de delinear o conceito agostiniano de matéria assim como aparece no âmbito da hermenêutica de Gn. 1,1 do livro XII das Confessiones. Tendo em vista tal fim, na primeira ...fase deste estudo examinar-se-á o problema do estatuto ontológico da hyle, segundo a interpretação agostiniana das palavras céu e terra do primeiro versículo do Gênesis. Em seguida, isto é, no segundo momento, o intuito será o de esboçar a relação entre a matéria e o tempo, à luz da análise agostiniana da falta de indicações concernentes ao dia da criação do céu e da terra em Gn. 1,1. Depois, na terceira fase deste estudo, analisar-se-á o tema da anterioridade da matéria informe à matéria formada na criação divina, segundo a hermenêutica agostiniana da narração genesiaca. Por fim, nas conclusões, analisar-se-á se e como as caracteristicas da hyle exprimem o limite da compreensão humana da Sagrada Escritura (Confessiones, VI).
The aim of this paper is to examine whether and, if so, how far, the Augustinian notion of malum is related to Plotinus' concept of evil, as it appears in Ennead I. 8 51. The Augustinian notion of ...evil will be analyzed by focusing on the De natura boni, considering plurality and unity in Augustine's identification of malum and nihil, both in their ontological and axiological dimensions. Topics selected for special consideration will be, first, evil as lack of modus, species and ordo naturalis (De nat. b., 4), and, secondly, corruptio as cause of defectio boni (De nat. b., 6). The second part will analyze Plotinus' notion of evil, as spelled out in Ennead I, 8 51, considering the Plotinian identity of to kakon and me on. Topics selected for analysis will be, first, the concept of evil as lack of measure, form and order (Enn. I. 8. 3), and secondly, the notion of to kakon as lack of good (Enn. I. 8. 5) simpliciter. The third part of this paper will consider the differences between Augustine's and Plotinus' identity of evil and non-being, as related to the notion of matter. Topics selected for analysis will be, firstly, Plotinus' identity of matter and evil (Enn. I. 8. 10), and, secondly, Augustine's concept of matter as capacitas formarum (De nat. b., 18). The conclusion will bring out how Plotinus' concept of steresis suggests both a different relation between evil and non-being while being closely resembling Augustine's pattern of malum and nihil. Keywords: Augustine, Plotinus, matter, evil, non-being.
O objetivo deste artigo é o de esboçar as aporias concernentes à relação entre tempo e movimento assim como aparecem nos livros XI e XII das Confessiones de Agostinho. Tendo em vista tal fim, na ...primeira fase desta pesquisa, analisar-se-á o problema da relação entre tempo e moto com base na interpretação agostiniana das palavras In principio fecit Deus, do primeiro versículo da Gênese. Em seguida, no segundo momento, verificar-se-á o problema de se a matéria ou a forma é a condição da existência do tempo e do movimento, segundo a interpretação agostiniana das palavras caelum et terram de Gênese 1,1. Por fim, nas conclusões, examinar-se-á se as questões mencionadas são autênticas aporias ou se elas exprimem os limites da compreensão humana da autoridade divina (Confessiones, VI).
PDF
