Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid.
Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid.
复制标题
DOI：
10.1371/journal.pone.0089919
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Singh M
中科院分区：
文献类型：
--
作者：
Godugu C;Patel AR;Doddapaneni R;Somagoni J;Singh M
黄连素(BBR)和白桦酸(BA)的生物利用度低限制了这些具有临床应用前景的抗癌药物的发展。在本研究中，制备了喷雾干燥(SD)粘附性微粒制剂中的BBR和BA。我们实验室建立的专利双通道喷枪技术用于这两种制剂。用体外培养的Caco-2细胞单层进行胃肠通透性研究。研究了SD制剂在SD大鼠体内的口服生物利用度和药动学特征。A549原位和H1650转移性非小细胞肺癌模型用于抗癌评估。药代动力学研究表明，BBR和BA SD制剂分别导致3.46倍和3.90倍的血浆Cmax浓度显著升高。BBR和BA SD制剂的AUC水平分别增加了6.98倍和7.41倍。与未经处理的对照组相比，BBR和BA的SD制剂组的肿瘤体积分别减少了49.8%和53.4%。对切除的A549肿瘤组织的分子研究表明，SD形式的BBR导致Survivin、Bcl2、Cyclin D1、MMP9、HIF-1α、血管内皮生长因子和CD31的表达显著降低。裂解caspase3、P53和TUNEL的表达在SD配方中增加。对H1650肿瘤组织的RT-PCR分析表明，BA-SD组p38、磷酸化JNK、Bax、BAD、裂解caspase3和8mRNA的表达显著增加。长期服用BBR和BA SD制剂未显示任何毒性。由于BBR和BA的口服生物利用度显著提高，且具有良好的抗癌效果，我们的研究结果表明，喷雾干燥是BBR和BA口服给药的一种较好的替代剂型。
The poor bioavailability of Berberine (BBR) and Betulinic acid (BA) limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD) mucoadhesive microparticle formulations were prepared. A patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI) permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations. Pharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma Cmax concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549) tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1α, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity. Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA.