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

為了解決Vincristine的問題，作者GEORGE, THOMASHIRE ANITA 這樣論述：

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.

改善原發性腦瘤治療：從新穎生物標記研發到開發具治療潛力藥物

為了解決Vincristine的問題，作者高瑛 這樣論述：

神經膠質瘤(glioma)以及腦膜瘤(meningioma)是成人最常見的原發性腦腫瘤。然而，惡性多型性膠質母細胞瘤 (glioblastoma multiforme, GBM)以及惡性腦膜瘤往往侵襲性高、生長速度快、且對現有化療藥物或放射線治療具有耐受性。病人也常因反覆治療而遭受嚴重神經功能損壞，存活期也短，可見原發性腦瘤治療在臨床上仍然有許多亟待改善的空間，而我們的研究從開發新穎性生物標記，到開發具治療潛力之藥物的角度出發，希望能夠改善原發性腦腫瘤病人的預後。Shugoshin 2 (SGO2，SGOL2)在細胞分裂中扮演重要角色，我們發現在腦膠質瘤病人中，SGO2表現量高，腦膠質瘤的病

理等級也越惡性，病人的存活期也越短。接著我們也發現SGO2的mRNA以及蛋白質表現量在GBM細胞中較正常腦組織來得高。而藉由降低SGO2的表現，我們發現GBM細胞的生長、增生以及移行能力等都受到抑制。我們更進一步發現，SGO2在細胞內具有調控蛋白質間作用(protein-protein interaction network)的樞紐功能，且影響FOXM1以及AURKB的表現。故我們認為，SGO2有潛力成為GBM的新穎性生物標記。Disulfiram (DSF) 是一已廣泛應用於治療酒精成癮的藥物，且是銅(Cu)的螯合劑，最近研究發現DSF合併Cu在許多癌症都有抑制腫瘤生長的作用，然而DSF/C

u在腦膜瘤的作用則仍未知。我們發現，DSF/Cu可以抑制腦膜瘤細胞（Meningioma Adhesion Cell，MgACs）以及腦膜瘤類幹細胞（Meningioma Sphere Cells, MgSCs）的存活，而DSF與其他金屬離子併用則無法達到此效果。此外，DSF/Cu亦可以抑制腦膜瘤細胞的增生、增加細胞中銅離子的含量以及引發細胞老化。利用mRNA 微陣列及Ingenuity Pathway Analysis (IPA)，我們發現DSF/Cu可以引發MgACs的內質網壓力、活化PERK/eIF2 訊息路徑，進而引發細胞的適應反應、細胞凋亡以及自噬作用。最後，我們也發現DSF/Cu在

MgACs以及MgSCs可抑制不同ALDH 異構體的表現，同時也有抑制細胞內ALDH活性的能力。故我們認為，DSF/Cu的確有潛力成為腦膜瘤治療的新契機。期待藉由開發新穎性生物標記以及新式治療藥物的結果，未來能應用於臨床，造福原發性腦瘤患者，改善生活品質及預後。