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Liposome-Encapsulated Anthraquinone improves efficacy and safety in Triple Negative Breast Cancer

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Background:Breast cancer is the most diagnosed cancer and a leading cause of cancer mortality in women worldwide. Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is highly heterogeneous, with high rates of relapse and distant metastasis, especially to the brain a

nd lung. Treatment of TNBC is a challenge because it lacks druggable targets and gene profiling shows six different subtypes which have distinct responses to different therapies.This shows that the ideal treatment strategy is the use of multi-targeting agents or a combination of agents.Drugs contain

ing anthraquinone scaffolds have shown to have enormous potential in cancer treatment and previous studies have shown that combining thiadiazole-fused anthraquinone scaffolds with other side chains expands the range of activities of the synthesized molecules, increasing its potency against several c

ancer cell lines.Small molecules are often limited by poor targeting and retention at tumor sites, as well as having poor pharmacokinetics. This leads to increased toxicity and rapid clearance from the bloodstream. Drug delivery carriers, such as liposomal formulations, can overcome these limitation

s, resulting in enhanced targeting, better efficacy, and reduced toxicity.Aim:The aim of this study is to develop a novel agent for TNBC therapy by screening a series of nitrogen-substituted anthra[1,2-c][1,2,5] thiadiazole-6,11-dione anthraquinone derivative small molecules. Upon selection of a sui

tably potent molecule, a drug delivery system will be formulated and characterized, aiming to improve drug therapeutic index and efficacy and, reduce toxicity.Materials and Methods:Eight in-house synthesized molecules were screened against two TNBC cell lines. Todetermine selectivity for breast canc

er cells one non-tumourigenic cell line was also used. Viability and cytotoxicity assays were performed, and “RV-59” was identified as the most suitable molecule. However, this molecule was poorly soluble in aqueous buffers and was relatively toxic to non-cancer cells. To overcome this, a liposome w

as developed which could encapsulate RV-59 with high efficiency and improve its activity. The liposome was formed using thin film hydration of lipids and cholesterol then sized by extrusion. The final liposomal formulation, LipoRV, was characterized by cryo-electron microscopy, dynamic light scatter

ing and dialysis to measure drug release. In-vitro assays were performed to compare LipoRV with the free molecule RV-59 and in-vivo studies were used to determine the therapeutic potential of LipoRV, as well as gather toxicity and safety data. RNA sequencing was used to examine the RV-59 mechanism o

f action and key differentially expressed proteins were confirmed by antibody array.Results:RV-59 was found to be one of the most potent molecules against both TNBC cell lines based on the in vitro screening. It was found to inhibit the cell cycle and induced necrosis and apoptosis. After liposome f

ormation, dynamic light scattering confirmed a single population of 91.02 ± 42.46 nm, PDI 0.081. Cryo-EM confirmed spherical uni-lamellar liposomes. LipoRV showed improved cell uptake and a four-fold increase in selectivity for cancer cells. It induced apoptosis and inhibited cell cycle readily and

demonstrated efficient inhibition of cell growth.In a TNBC xenograft mouse model, tumour volume was significantly reduced by LipoRVcompared to the free drug, clearing tumours in 85 % of animals. LipoRV also demonstrated an increased half-life and good safety profile compared to RV-59, without detrim

ental offtarget effects on organs or serum biochemical markers. Biodistribution analysis showed a higher drug serum concentration and reduced urinary output for LipoRV compared to RV-59.RNA sequencing of treated cells showed strong upregulation of cytokine and TNF-alphasignaling pathway and down reg

ulations genes related to extra cellular matrix components. A membrane-based antibody array confirmed the differential expression of multiple cytokines following LipoRV treatment.Conclusion:This study showed that encapsulating a thiadiazole-fused anthraquinone scaffold-basedmolecule into liposome gr

eatly improves its efficacy, reducing toxicity. This molecule shows immense potential for future use in TNBC therapy.