Sedky Nada K, Braoudaki Maria, Mahdy Noha Khalil, Amin Kenzy, Fawzy Iten M, Efthimiadou Eleni K, Youness Rana A, Fahmy Sherif Ashraf
Department of Biochemistry, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation R5 New Garden City, New Administrative Capital Cairo Egypt.
Department of Clinical, Pharmaceutical, and Biological Science, School of Life and Medical Sciences, University of Hertfordshire Hatfield AL10 9AB UK.
Nanoscale Adv. 2023 Sep 15;5(19):5399-5413. doi: 10.1039/d3na00368j. eCollection 2023 Sep 26.
Herein, thermo-responsive liposomes (TLs) loaded with Asp (Asp/TLs) were produced by self-assembling DPPC, DSPE-PEG2000, and cholesterol. The preparation variables were optimized using the Box-Behnken design (BBD). The optimized Asp/TLs exhibited an average particle size of 114.05 ± 1.56 nm, PDI of 0.15 ± 0.015, zeta potential of -15.24 ± 0.65 mV, and entrapment efficiency (EE%) of 84.08 ± 2.75%. In addition, under physiological conditions, Asp/TLs showed spherical shape, outstanding stability and thermo-triggered the release of Asp at 38 °C, reaching the maximum Asp release at 40 °C. The MTT assay showed that the optimal Asp/TLs exhibited the highest cytotoxic activity upon exposure to mild hyperthermia (40 °C) against the invasive triple-negative breast cancer cell line (MDA-MB-231) when compared to other preparations. The IC of Asp/TLs (40 °C) was estimated at 0.9 μg mL, while that of free Asp (40 °C) was 3.83 μg mL. As such, the optimal Asp/TLs were shown to increase the cytotoxic activity of Asp by 4-fold upon exposure to mild hyperthermia. The IC values of Asp and Asp/TLs without exposure to 40 °C were 6.6 μg mL and 186 μg mL, respectively. This indicated that Asp was released only when placed at 40 °C. The apoptosis assay revealed that Asp/TLs (40 °C) caused a remarkable increase in the percentage of cell population among both the late apoptosis and necrosis quartiles, as well as a significant decline in the viable cell quartile ( ≤ 0.001) when compared to Asp (40 °C). Asp/TLs (40 °C) and Asp (40 °C) could stimulate the intrinsic apoptosis pathway by upregulating the apoptotic genes and , while downregulating the anti-apoptotic genes, and . The free Asp (40 °C) increased the gene expression of and by 4.4- and 5.2-folds, while reducing the expression of and by 50% and 73%, respectively. The optimal Asp TLs (40 °C) manifested more potent effects as demonstrated by the upregulation of , , and by 5.6-, 7.2-, and 1.3-folds, as well as the downregulation of and by 70% and 85%, respectively. As such, the optimal Asp TLs (40 °C) treatment displayed the most potent cytotoxic profile and induced both apoptosis and necrosis in MDA-MB-231.
在此，通过自组装二棕榈酰磷脂酰胆碱（DPPC）、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG2000）和胆固醇制备了负载天冬酰胺（Asp）的热敏脂质体（Asp/TLs）。使用Box-Behnken设计（BBD）对制备变量进行了优化。优化后的Asp/TLs平均粒径为114.05±1.56nm，多分散指数（PDI）为0.15±0.015，ζ电位为-15.24±0.65mV，包封率（EE%）为84.08±2.75%。此外，在生理条件下，Asp/TLs呈球形，具有出色的稳定性，并在38℃时热触发Asp的释放，在40℃时达到最大Asp释放量。MTT试验表明，与其他制剂相比，最佳的Asp/TLs在轻度热疗（40℃）下对侵袭性三阴性乳腺癌细胞系（MDA-MB-231）表现出最高的细胞毒性活性。Asp/TLs（40℃）的半数抑制浓度（IC）估计为0.9μg/mL，而游离Asp（40℃）的IC为3.83μg/mL。因此，最佳的Asp/TLs在轻度热疗时显示出将Asp的细胞毒性活性提高4倍的效果。未暴露于40℃的Asp和Asp/TLs的IC值分别为6.6μg/mL和186μg/mL。这表明Asp仅在置于40℃时才释放。凋亡试验显示，与Asp（40℃）相比，Asp/TLs（40℃）导致晚期凋亡和坏死四分位数中的细胞群体百分比显著增加，而存活细胞四分位数显著下降（≤0.001）。Asp/TLs（40℃）和Asp（40℃）可通过上调凋亡基因和，同时下调抗凋亡基因和来刺激内源性凋亡途径。游离Asp（40℃）使和的基因表达分别增加4.4倍和5.2倍，同时使和的表达分别降低50%和73%。最佳的Asp TLs（40℃）表现出更显著的效果，如、和分别上调5.6倍、7.2倍和1.3倍，以及和分别下调70%和85%。因此，最佳的Asp TLs（40℃）处理表现出最有效的细胞毒性特征，并在MDA-MB-231中诱导凋亡和坏死。
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