Magnetic casein-CaFe2O4 nanohybrid carrier conjugated with progesterone for enhanced cytotoxicity of citrus peel derived hesperidin drug towards breast and ovarian cancer.
磁性 casein-CaFe2O4 纳米杂化载体结合黄体酮增强柑橘皮来源的橙皮苷药物对乳腺癌和卵巢癌的细胞毒性。
- 作者列表："Purushothaman BK","Maheswari PU","Begum KMMS
:A novel progesterone-receptor targeted nanohybrid carrier based delivery of hesperidin was investigated in the present work. Casein‑calcium ferrite nanohybrid carrier was synthesized using desolvation followed by ionic-gelation. The citrus peel extracted hesperidin drug (CHD) was encapsulated in the carrier via pH based coacervation, after which the targeting ligand progesterone was conjugated through activate ester procedure. The carrier formulation was characterized using techniques like XRD, FTIR, SEM, VSM and DLS. The bioactive components in CHD were analyzed using HPLC. Taguchi optimization gave a maximum of 89.54% hesperidin encapsulation in the carrier. Incorporation of superparamagnetic calcium ferrite nanoparticles resulted in improved drug encapsulation and magnetic induced drug delivery. The carrier exhibited a stimuli-responsive drug release behavior, with good stability at physiological pH (7.4) and a higher release under acidic pH (5.4 and 1.2) favoring anticancer applications. The drug release followed Fickian diffusion mechanism as predicted by different kinetic models. Cell viability assay on L929 fibroblast cells verified the biocompatibility of the formulation. The specific recognition and targeted chemotherapy rendered by the progesterone-conjugated carrier enhanced the cytotoxicity of CHD against SKOV-3 ovarian and MDA-MB-231 breast cancer cells, resulting in a significant 30-fold reduction in the (Half-maximal inhibitory concentration) IC50 values.
: 本工作研究了一种新型孕激素受体靶向纳米杂化载体为基础的橙皮苷递送。采用去溶剂化后离子凝胶化合成了 casein ‑ 铁酸钙纳米杂化载体。通过 pH 凝聚法将提取的橙皮苷药物 (CHD) 包裹在载体中，然后通过活化酯程序将靶向配体孕酮偶联。使用 XRD 、 FTIR 、 SEM 、 VSM 和 DLS 等技术对载体配方进行了表征。采用高效液相色谱法分析冠心病中的生物活性成分。Taguchi 优化在载体中给予最多 89.54% 的橙皮苷包封。掺入超顺磁性铁酸钙纳米颗粒可改善药物包封和磁诱导给药。该载体表现出刺激响应性的药物释放行为，在生理 pH (7.4) 下具有良好的稳定性，在酸性 pH (5.4 和 1.2) 下具有较高的释放，有利于抗癌应用。药物释放遵循不同动力学模型预测的 Fickian 扩散机制。L929 成纤维细胞上的细胞活力测定验证了制剂的生物相容性。孕激素结合载体的特异性识别和靶向化疗增强了冠心病对 SKOV-3 卵巢癌和 MDA-MB-231 乳腺癌细胞的杀伤作用。导致 (半数最大抑制浓度) IC50 值显著降低 30 倍。
METHODS::Altered aerobic glycolysis is an important feature of cancer cell energy metabolism, known as the Warburg effect. Cervical cancer is one of the most common causes of cancer death in females. However, the roles of aerobic glycolysis in the development of cervical cancer are still poorly defined. Here, we identified a transcription factor (TF), ETS-related gene (ERG), as a new regulator of cancer progression and the glycolysis process in cervical cancer. In this study, we found that ectopic expression of ERG enhanced the capacity of aerobic glycolysis and increased glucose uptake, lactate production, and ATP generation. ERG overexpression increased and ERG knockdown decreased the anchorage independent cell growth and cell invasion in cervical cancer cells. Mechanistically, we propose that ERG regulates the expression of hexokinase 2 (HK2) and phosphoglycerate kinase 1 (PGK1) in the glycolytic pathway by directly binding to their promoters. A gain-of-function study showed that the knockdown or overexpression of HK2 and PGK1 abolished the increased or decreased aerobic glycolysis and cervical cancer progression induced by stable ectopic expression or depletion of ERG, respectively. Taken together, our findings suggest that ERG plays a potential role in the progression of cervical cancer, and could serve as a novel biomarker and potential therapeutic target in cervical cancer.
METHODS:INTRODUCTION:Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women. METHODS:De-identified residual specimens from women aged 16-24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay. RESULTS:Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5-5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6-23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6-52.0%) of women. CONCLUSIONS:HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.
METHODS::Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that a HPV58E7 natural variant, T20I/G63S (designated as V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalise and transform primary cells, as well as degrading pRB more effectively than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of AKT and K-Ras/ERK signalling pathways, V1 consistently showed greater oncogenicity compared with prototype and other variants, as demonstrated by increased cell proliferation, migration and invasion, as well as induction of larger tumours in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 compared with prototype and all other common variants. Since V1 is more commonly found in Eastern Asia, our report provides insight into the design of HPV-screening assays and selection of components for HPV vaccines in this region.IMPORTANCE Epidemiological studies have revealed that a wild type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of its greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of AKT and K-Ras/ERK signalling pathways, thereby, explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumours, all to a greater extent than prototype HPV58 and other common variants.