DLM-GelMA/tumor slice sandwich structured tumor on a chip for drug efficacy testing.

The in vitro recapitulation of tumor microenvironment is of great interest to preclinical screening of drugs. Compared with culture of cell lines, tumor organ slices can better preserve the complex tumor architecture and phenotypic activity of native cells, but are limited by their exposure to fluid shear and gradual degradation under perfusion culture. Here, we established a decellularized liver matrix (DLM)-GelMA "sandwich" structure and a perfusion-based microfluidic platform to support long-term culture of tumor slices with excellent structural integrity and cell viability over 7 days. The DLM-GelMA was able to secrete cytokines and growth factors while providing shear protection to the tumor slice via the sandwich structure, leading to the preservation of the tumor microenvironment where immune cells (CD3, CD8, CD68), tumor-associated fibroblasts (α-SMA), and extracellular matrix components (collagen I, fibronectin) were well maintained. Furthermore, this chip presented anti-tumor efficacy at cisplatin (20 µM) on tumor patients, demonstrating our platform's efficacy to design patient-specific treatment regimens. Taken together, the successful development of this DLM-GelMA sandwich structure on the chip could faithfully reflect the tumor microenvironment and immune response, accelerating the screening process of drug molecules and providing insights for practical medicine.

A versatile dilution-treatment-detection microfluidic chip platform for rapid In vitro lung cancer drug combination sensitivity evaluation.

Combination drug therapy represents an effective strategy for treating certain drug-resistant and intractable cancer cases. However, determining the optimal combination of drugs and dosages is challenging due to clonal diversity in patients' tumors and the lack of rapid drug sensitivity evaluation methods. Microfluidic technology offers promising solutions to this issue. In this study, we propose a versatile microfluidic chip platform capable of integrating all processes, including dilution, treatment, and detection, for in vitro drug sensitivity assays. This platform innovatively incorporates several modules, including automated discrete drug logarithmic concentration generation, on-chip cell perfusion culture, and parallel drug treatments of cancer cell models. Moreover, it is compatible with microplate readers or high-content imaging systems for swift detection and automated monitoring, simplifying on-chip drug evaluation. Proof of concept is demonstrated by assessing the in vitro potency of two drugs, cisplatin, and etoposide, against the lung adenocarcinoma A549 cell line, under both single-drug and combination treatment conditions. The findings reveal that, compared to conventional microplate approaches with static cultivation, this on-chip automated perfusion bioassays yield comparable IC50 values with lower variation and a 50 % reduction in drug preparation time. This versatile dilution-treatment-detection microfluidic platform offers a promising tool for rapid and precise drug assessments, facilitating in vitro drug sensitivity evaluation in personalized cancer chemotherapy.

Deep learning unlocks label-free viability assessment of cancer spheroids in microfluidics.

Despite recent advances in cancer treatment, refining therapeutic agents remains a critical task for oncologists. Precise evaluation of drug effectiveness necessitates the use of 3D cell culture instead of traditional 2D monolayers. Microfluidic platforms have enabled high-throughput drug screening with 3D models, but current viability assays for 3D cancer spheroids have limitations in reliability and cytotoxicity. This study introduces a deep learning model for non-destructive, label-free viability estimation based on phase-contrast images, providing a cost-effective, high-throughput solution for continuous spheroid monitoring in microfluidics. Microfluidic technology facilitated the creation of a high-throughput cancer spheroid platform with approximately 12 000 spheroids per chip for drug screening. Validation involved tests with eight conventional chemotherapeutic drugs, revealing a strong correlation between viability assessed via LIVE/DEAD staining and phase-contrast morphology. Extending the model's application to novel compounds and cell lines not in the training dataset yielded promising results, implying the potential for a universal viability estimation model. Experiments with an alternative microscopy setup supported the model's transferability across different laboratories. Using this method, we also tracked the dynamic changes in spheroid viability during the course of drug administration. In summary, this research integrates a robust platform with high-throughput microfluidic cancer spheroid assays and deep learning-based viability estimation, with broad applicability to various cell lines, compounds, and research settings.

Drug testing of monodisperse arrays of live microdissected tumors using a valved multiwell microfluidic platform.

Cancer drug testing in animals is an extremely poor predictor of the drug's safety and efficacy observed in humans. Hence there is a pressing need for functional testing platforms that better predict traditional and immunotherapy responses in human, live tumor tissue or tissue constructs, and at the same time are compatible with the use of mouse tumor tissue to facilitate building more accurate disease models. Since many cancer drug actions rely on mechanisms that depend on the tumor microenvironment (TME), such platforms should also retain as much of the native TME as possible. Additionally, platforms based on miniaturization technologies are desirable to reduce animal use and sensitivity to human tissue scarcity. Present high-throughput testing platforms that have some of these features, e.g. based on patient-derived tumor organoids, require a growth step that alters the TME. On the other hand, microdissected tumors (µDTs) or "spheroids" that retain an intact TME have shown promising responses to immunomodulators acting on native immune cells. However, difficult tissue handling after microdissection has reduced the throughput of drug testing on µDTs, thereby constraining the inherent advantages of producing numerous TME-preserving units of tissue for drug testing. Here we demonstrate a microfluidic 96-well platform designed for drug treatment of hundreds of similarly-sized, cuboidal µDTs ("cuboids") produced from a single tumor sample. The platform organizes a monodisperse array of four cuboids per well in 384 hydrodynamic traps. The microfluidic device, entirely fabricated in thermoplastics, features 96 microvalves that fluidically isolate each well after the cuboid loading step for straightforward multi-drug testing. Since our platform makes the most of scarce tumor tissue, it can potentially be applied to human biopsies that preserve the human TME while minimizing animal testing.

Synthesis and evaluation of platinum complexes with potential antitumor activity

Abstract A novel series of platinum (II) complexes was synthesized and the complexes were evaluated for their in vitro cytotoxicity against four human cancer cells lines. Five platinum complexes showed activity against at least one tumor cell line. Complexes 3 and 6 were promising, being active, at micromolar concentrations, against all the assayed tumor cell lines. Compound 3 was selected for further studies in mice with Ehrlich solid tumors and it was able to reduce the rate of tumor growth significantly during the first seven days. However, at the end of the experiments, there was no significant difference between the group of animals treated with 3 and the control group. The low solubility of the compound in the assay conditions can explain, at least in part, these results.

Exclusión endovascular de aneurisma poplíteo roto / Endovascular exclusion of a ruptured politeal aneurysm

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Síntesis de nuevos antitumorales por manipulación de modelos naturales de origen marino / Synthesis of new antitumour agents through structure manipulation of

Se están estudiando diversas series de compuestos con estructura de pirazino[2,1-b]isoquinolina y 6,15-iminoisoquino[3,2-b]-3-benzazocina tomando comomodelos productos naturales de origen marino con actividad antitumoral. Hasta elmomento se han desarrollado diversas estrategias de síntesis, y se ha evaluado lacitotoxicidad in vitro de estos compuestos frente a tres líneas celulares de cáncerhumano. El paso clave para su obtención se basa fundamentalmente en la síntesisde pirazinoisoquinolina-1,4-dionas por un procedimiento «one-pot» N-alquilaciónciclaciónde 3-arilmetilpiperazina-2,5-dioxosilillactimas con dimetil acetales de diversosaldehídos, utilizándose también otras reacciones de α-amidoalquilación yciclación intramolecular tipo Pictet-Spengler. Se han obtenido diversas pirazino[2,1-b]isoquinolinas, pirazino[2,1,6-bc]isoquinolinas, 6,15-iminoisoquino[3,2-b]-3-benzazocinas y otros compuestos octacíclicos más complejos, y se están derivandoen algunos casos a precursores de especies iminio alquilantes. La actividadcitotóxica micromolar y submicromolar que se ha encontrado hasta el momentoparece no depender de su capacidad para generar intermedios que permitan elenlace covalente con el ADN

Several series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to marine antitumour natural products are beingsynthesized and their in vitro cytotoxic activities are being evaluated against threehuman cancer cell lines. The key synthetic step is based on the synthesis of pyrazinoisoquinoline-1,4-diones by the one-pot N-alkylation-cyclization of 3-arylmethylpiperazine-2,5-dioxosilyllactims with aldehyde dimethyl acetals or throughdifferent alpha-amidoalkylation reactions and intramolecular cyclizations of Pictet-Spengler type. Pyrazino[2,1-b]isoquinolines, pyrazino[2,1,6-bc]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines and other more complex octacyclic compoundshave been obtained and derived in some cases to precursors of alkylatingiminium ion species. The micromolar an submicromolar cytotoxic activity foundup to date is apparently uninfluenced by the ability to generate intermediateswhich would permit covalent bonding to DNA