Abstract：
Breast cancer is reported as one of the most prevalent non-cutaneous malignancies in women. Venetoclax (VEN) is an approved BCl-2 inhibitor for the treatment of chronic myeloid leukemia with very limited oral bioavailability and exhibits an enormous impact on breast cancer. In the current investigation, venetoclax-loaded self-nanoemulsifying drug delivery systems (VEN-SNEDDS) were designed and fabricated to improve the aqueous solubility, permeability, and anticancer efficacy of VEN. Various surface-active parameters of the reconstituted SNEDDS were determined to scrutinize the performance of the selected surfactant mixture. Central composite design (CCD) was used to optimize the VEN-SNEDDS. The globule size of reconstituted VEN-SNEDDS was 71.3 ± 2.8 nm with a polydispersity index of 0.113 ± 0.01. VEN-SNEDDS displayed approximately 3-4 fold, 6-7 fold, and 5-6 fold reduced IC50 as compared to free VEN in MDA-MB-231, MCF-7, and T47 D cells, respectively. VEN-SNEDDS showed greater cellular uptake, apoptosis, reactive oxygen species generation, and higher BAX/BCL2 ratio with decreased caspase 3 and 8 and BCL-2 levels in the MDA-MB-231 cells compared to pure VEN. VEN-SNEDDS exhibited approximately fivefold enhancement in Cmax and an improved oral bioavailability compared to VEN suspension in in vivo pharmacokinetic studies.
摘要：
据报道，乳腺癌是女性最常见的非皮肤恶性肿瘤之一。维奈托克（VEN）是一种批准的BCl-2抑制剂，用于治疗慢性粒细胞白血病，口服生物利用度非常有限，对乳腺癌具有巨大影响。在目前的调查中,设计并制造了载有venetoclax的自纳米乳化药物递送系统（VEN-SNEDDS），以提高水溶性，渗透性,和VEN的抗癌功效。确定重构的SNEDDS的各种表面活性参数以仔细检查所选表面活性剂混合物的性能。中央复合设计(CCD)用于优化VEN-SNEDDS。重构的VEN-SNEDDS的小球尺寸为71.3±2.8nm，多分散指数为0.113±0.01。VEN-SNEDDS显示大约3-4倍，6-7折，在MDA-MB-231、MCF-7和T47D细胞中，与游离VEN相比，IC50降低了5-6倍，分别。VEN-SNEDDS显示更大的细胞摄取，凋亡，活性氧的产生，与纯VEN相比，MDA-MB-231细胞中的半胱天冬酶3和8以及BCL-2水平降低的BAX/BCL2比率更高。在体内药代动力学研究中，与VEN悬浮液相比，VEN-SNEDDS的Cmax增强约五倍，口服生物利用度提高。
