Journal of Drug Targeting, 2013, 21(10):1001-11.

Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas

Vu Phan, Jarvis Walters, Bill Brownlow, et al

Arizona College of Osteopathic Medicine, Midwestern University , Glendale, AZ , USA; et al

Clinical use of genistein against cancer is limited by its extremely low aqueous solubility, poor bioavailability and pharmacokinetics. Based on structural analogy with steroidal compounds, liposomal vehicle compositions were designed and optimized for maximum incorporation of genistein's flavonoid structure. Model conventional and stealth liposomes of genistein (GenLip)--incorporating unsaturated phospholipids and cholesterol--have demonstrated enhanced drug solubilization (over 350-folds > aqueous drug solution), shelf-life stability, and extended release profile. Owing to effective cellular delivery, preservation of genistein's antioxidant activity was confirmed through marked neutralization of peroxides via GenLip, in both quantitative and microscopic fluorescent-probe oxidation assays. Furthermore, significant broad-spectrum anticancer efficacy of GenLip, in murine and human cancer cell lines (p < 0.05-0.001), was achieved in a concentration and time-dependent manner--approx. 5-7 lower IC50 values versus all non-incorporated drug controls. Indicative of key pro-apoptotic activity, GenLip produced DNA laddering, with 1/3 of free drug solution content, and resulted in the highest induction level of P53-independent apoptotic pathway markers, compared to all treatments, in our assays (namely, mitochondrial polarization, and caspase-3/7 enzymes). Our proof-of-principle pharmaceutical design of genistein-loaded liposomes shows optimal loading capacity and physico-chemical properties, which improved cellular delivery and specific pro-apototic effectiveness of incorporated drug, against various cancers.

英国《靶向药物杂志》，2013年12月

优化的脂质体金雀异黄素在乳腺癌、 卵巢癌和前列腺癌中通过特异性诱导细胞凋亡增强了细胞毒性

潘巫，贾维斯  沃尔特斯，比尔 布朗，等

美国格伦代尔西部大学骨科医学院等

金雀异黄素治疗癌症的临床使用受到限制由于其极低的水溶性、 可怜的生物利用度和药代动力学。基于其类似于固醇类化合物的结构，设计和优化了脂质体载体复合物用于最大程度地负载金雀异黄素的黄酮化合物结构。金雀异黄素常规和隐形脂质体的模型 (GenLip) — — 加入非饱和的磷脂和胆固醇 — — 已经被证明增强药物的水溶性 (超过 350 倍 > 水性药液)，保质期稳定性和延长的释放方式。由于有效的细胞内释放，通过标记过氧化物通过 GenLip的中立性，定量和显微荧光探针氧化法证实了金雀异黄素抗氧化活性的保存。此外，广谱抗癌疗效显著的 GenLip，在小鼠和人肿瘤细胞 （p < 0.05-0.001）中，得到了浓度和时间依赖性剂量，大约 5-7倍 低于 IC50 值相对于所有非负载药物对照样相比。关键的促凋亡活性，GenLip 产生的 DNA 阶梯，1/3 的游离药物溶液成分，并导致最高的P53 独立性凋亡通路标记的诱导水平，与所有的治疗方法相比，在我们的检测 （即，线粒体极化和半胱氨酸蛋白酶-3/7 酶）中。我们的原理验证对负载金雀异黄素脂质体的药物设计表明最佳的负载能力和理化性质，提高了细胞内释放和特定预凋亡效果的药物，可以预防多种癌症。