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Pharmacokinetic and Pharmacodynamic Evaluation of Resveratrol Loaded Cationic Liposomes for Targeting Hepatocellular Carcinoma
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-07-27 , DOI: 10.1021/acsbiomaterials.0c00429 Satveer Jagwani 1, 2 , Sunil Jalalpure 1, 2 , Dinesh Dhamecha 2 , Kiran Jadhav 1 , Raghvendra Bohara 3, 4
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-07-27 , DOI: 10.1021/acsbiomaterials.0c00429 Satveer Jagwani 1, 2 , Sunil Jalalpure 1, 2 , Dinesh Dhamecha 2 , Kiran Jadhav 1 , Raghvendra Bohara 3, 4
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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The destructive nature of the disease makes it difficult for clinicians to manage the condition. Hence, there is an urgent need to find new alternatives for HCC, as the role of conventional cytotoxic drugs has reached a plateau to control HCC associated mortality. Antioxidant compounds of plant origin with potential anti-tumor effect have been recognized as alternate modes in cancer treatment and chemoprevention. Resveratrol (RS) is a model natural nonflavonoid drug known for its anti-cancer activity. However, its clinical application is limited due to its poor bioavailability. The current research work aims to formulate, optimize, and characterize RS loaded cationic liposomes (RLs) for specific delivery in HCC. The optimized liposomes formulation (RL5) was spherical with a vesicle size (VS) of 145.78 ± 9.9 nm, ζ potential (ZP) of 38.03 ± 9.12 mV, and encapsulation efficiency (EE) of 78.14 ± 8.04%. In vitro cytotoxicity studies in HepG2 cells demonstrated an improved anti-cancer activity of RL5 in comparison with free RS. These outcomes were supported by a cell uptake study in HepG2 cells, in which RL5 exhibited a higher uptake than free RS. Furthermore, confocal images of HepG2 cells after 3 and 5 h of incubation showed higher internalization of coumarin 6 (C6) loaded liposomes (CL) as compared to those of the free C6. Pharmacokinetic and pharmacodynamic (prophylactic and therapeutic treatment modalities) studies were performed in N-nitrosodiethylamine (NDEA-carcinogen) induced HCC in rats. Pharmacokinetic evaluation of RL5 demonstrated increased localization of RS in cancerous liver tissues by 3.2- and 2.2-fold increase in AUC and Cmax, respectively, when compared to those of the free RS group. A pharmacodynamic investigation revealed a significant reduction in hepatocyte nodules in RL5 treated animals when compared to those of free RS. Further, on treatment with RL5, HCC-bearing rats showed a significant decrease in the liver marker enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, total bilirubin levels, γ-glutamyl transpeptidase, and α-fetoprotein), in comparison with that of the disease control group. Our findings were supported by histopathological analysis, and we were first to demonstrate that NDEA induced detrimental effect on rat livers was successfully reversed with the treatment of RL5 formulation. These results implied that delivery of RS loaded cationic liposomes substantially controlled the severity of HCC and that they can be considered as a promising nanocarrier in the management of HCC.
中文翻译：
白藜芦醇负载阳离子脂质体靶向肝细胞癌的药代动力学和药效学评价
肝细胞癌（HCC）是全球范围内与癌症相关的死亡的主要原因之一。这种疾病具有破坏性，因此临床医生很难控制该病。因此，迫切需要寻找新的HCC替代品，因为常规细胞毒性药物的作用已达到控制HCC相关死亡率的平台。具有潜在抗肿瘤作用的植物来源的抗氧化剂已被认为是癌症治疗和化学预防的替代方式。白藜芦醇（RS）是一种模型天然非类黄酮药物，以其抗癌活性而闻名。但是，由于其生物利用度差，其临床应用受到限制。当前的研究工作旨在为肝癌中的特定递送制定，优化和表征载有RS的阳离子脂质体（RLs）。对HepG2细胞的体外细胞毒性研究表明，与游离RS相比，RL5的抗癌活性有所提高。这些结果得到了HepG2细胞摄取研究的支持，其中RL5的摄取高于游离RS。此外，在孵育3和5小时后，HepG2细胞的共聚焦图像显示，与游离C6相比，香豆素6（C6）脂质体（CL）的内在化程度更高。在N中进行了药代动力学和药效学（预防和治疗方法）研究-亚硝基二乙胺（NDEA-致癌物）诱导大鼠肝癌。RL5的药代动力学评估表明，与游离RS组相比，RLC在癌性肝组织中的定位增加了AUC和Cmax分别增加了3.2倍和2.2倍。药效学研究表明，与游离RS相比，RL5处理动物的肝细胞结节明显减少。此外，用RL5治疗的荷肝大鼠肝组织标志物酶（丙氨酸转氨酶，碱性磷酸酶，天冬氨酸转氨酶，总胆红素水平，γ-谷氨酰转肽酶和α-甲胎蛋白）显着降低。疾病对照组。我们的发现得到了组织病理学分析的支持，我们首先证明了RL5制剂可以成功逆转NDEA对大鼠肝脏的有害作用。这些结果表明，负载RS的阳离子脂质体的递送基本上控制了HCC的严重性，并且它们可以被认为是在HCC管理中有希望的纳米载体。
更新日期：2020-09-14
中文翻译：
白藜芦醇负载阳离子脂质体靶向肝细胞癌的药代动力学和药效学评价
肝细胞癌（HCC）是全球范围内与癌症相关的死亡的主要原因之一。这种疾病具有破坏性，因此临床医生很难控制该病。因此，迫切需要寻找新的HCC替代品，因为常规细胞毒性药物的作用已达到控制HCC相关死亡率的平台。具有潜在抗肿瘤作用的植物来源的抗氧化剂已被认为是癌症治疗和化学预防的替代方式。白藜芦醇（RS）是一种模型天然非类黄酮药物，以其抗癌活性而闻名。但是，由于其生物利用度差，其临床应用受到限制。当前的研究工作旨在为肝癌中的特定递送制定，优化和表征载有RS的阳离子脂质体（RLs）。对HepG2细胞的体外细胞毒性研究表明，与游离RS相比，RL5的抗癌活性有所提高。这些结果得到了HepG2细胞摄取研究的支持，其中RL5的摄取高于游离RS。此外，在孵育3和5小时后，HepG2细胞的共聚焦图像显示，与游离C6相比，香豆素6（C6）脂质体（CL）的内在化程度更高。在N中进行了药代动力学和药效学（预防和治疗方法）研究-亚硝基二乙胺（NDEA-致癌物）诱导大鼠肝癌。RL5的药代动力学评估表明，与游离RS组相比，RLC在癌性肝组织中的定位增加了AUC和Cmax分别增加了3.2倍和2.2倍。药效学研究表明，与游离RS相比，RL5处理动物的肝细胞结节明显减少。此外，用RL5治疗的荷肝大鼠肝组织标志物酶（丙氨酸转氨酶，碱性磷酸酶，天冬氨酸转氨酶，总胆红素水平，γ-谷氨酰转肽酶和α-甲胎蛋白）显着降低。疾病对照组。我们的发现得到了组织病理学分析的支持，我们首先证明了RL5制剂可以成功逆转NDEA对大鼠肝脏的有害作用。这些结果表明，负载RS的阳离子脂质体的递送基本上控制了HCC的严重性，并且它们可以被认为是在HCC管理中有希望的纳米载体。
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