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Enhancing the Anticancer Activity and Selectivity of Goniothalamin Using pH-Sensitive Acetalated Dextran (Ac-Dex) Nanoparticles: A Promising Platform for Delivery of Natural Compounds
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-03-26 , DOI: 10.1021/acsbiomaterials.0c00057 Carolyne B. Braga 1 , Larissa A. Kido 2 , Ellen N. Lima 2 , Celina A. Lamas 2 , Valéria H. A. Cagnon 2 , Catia Ornelas 1 , Ronaldo A. Pilli 1
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2020-03-26 , DOI: 10.1021/acsbiomaterials.0c00057 Carolyne B. Braga 1 , Larissa A. Kido 2 , Ellen N. Lima 2 , Celina A. Lamas 2 , Valéria H. A. Cagnon 2 , Catia Ornelas 1 , Ronaldo A. Pilli 1
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Goniothalamin (GTN), a natural compound isolated from Goniothalamus species, has previously demonstrated cytotoxic activity against several cancer cell lines. However, similarly to many natural and synthetic anticancer compounds, GTN presents toxicity toward some healthy cells and low aqueous solubility, decreasing its bioavailability and precluding its application as an antineoplastic drug. In our efforts to improve the pharmacokinetic behavior and selectivity of GTN against cancer cells, we developed a polymeric nanosystem, in which rac-GTN was encapsulated in pH-responsive acetalated dextran (Ac-Dex) nanoparticles (NPs) with high loadings of the bioactive compound. Dynamic light scattering (DLS) analysis showed that the nanoparticles obtained presented a narrow size distribution of around 100 nm in diameter, whereas electron microscopy (EM) images showed nanoparticles with a regular spherical morphology in agreement with the size range obtained by DLS. Stability and release studies indicated that the GTN@Ac-Dex NPs presented high stability under physiological conditions (pH 7.4) and disassembled under slightly acidic conditions (pH 5.5), releasing the rac-GTN in a sustained manner. In vitro assays showed that GTN@Ac-Dex NPs significantly increased cytotoxicity and selectivity against cancer cells when compared with the empty Ac-Dex NPs and the free rac-GNT. Cellular uptake and morphology studies using MCF-7 cells demonstrated that GTN@Ac-Dex NPs are rapidly internalized into the cancer cells, causing cell death. In vivo investigation confirmed the efficient release of rac-GTN from GTN@Ac-Dex NPs, resulting in the delay of prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Furthermore, liver histopathology evaluation after treatment with GTN@Ac-Dex NPs showed no evidence of toxicity. Therefore, the in vitro and in vivo findings suggest that the Ac-Dex NPs are a promising nanosystem for the sustained delivery of rac-GTN into tumors.
中文翻译：
使用pH敏感的乙酰化葡聚糖（Ac-Dex）纳米颗粒增强Goniothalamin的抗癌活性和选择性：天然化合物的有前途的平台。
鞘氨醇（GTN）是一种从淋菌属物种中分离的天然化合物，以前已证明其对几种癌细胞系具有细胞毒活性。但是，与许多天然和合成的抗癌化合物相似，GTN对某些健康细胞具有毒性，并且水溶性低，降低了其生物利用度，并排除了其作为抗肿瘤药的应用。我们在努力提高对癌细胞GTN的药代动力学行为和选择性，我们开发了一种聚合物纳米系统，其中RAC-GTN封装在具有高负载生物活性化合物的pH响应型缩醛葡聚糖（Ac-Dex）纳米颗粒（NPs）中。动态光散射（DLS）分析显示，所获得的纳米颗粒呈现出直径约为100 nm的窄尺寸分布，而电子显微镜（EM）图像显示的纳米颗粒具有规则的球形形态，与DLS获得的尺寸范围相符。稳定性和释放性研究表明，GTN @ Ac-Dex NP在生理条件下（pH 7.4）表现出高稳定性，在弱酸性条件下（pH 5.5）分解，从而持续释放rac -GTN。体外分析显示，与空的Ac-Dex NP和游离的rac -GNT相比，GTN @ Ac-Dex NPs显着提高了对癌细胞的细胞毒性和选择性。使用MCF-7细胞进行的细胞摄取和形态学研究表明，GTN @ Ac-Dex NP被迅速内化到癌细胞中，从而导致细胞死亡。体内研究证实了rac -GTN从GTN @ Ac-Dex NPs的有效释放，从而导致小鼠前列腺癌（TRAMP）转基因腺癌中前列腺癌进展的延迟。此外，用GTN @ Ac-Dex NP治疗后的肝组织病理学评估未显示毒性证据。因此，在体外和体内研究结果表明，Ac-Dex NPs是一个有前途的纳米系统，可将rac -GTN持续递送到肿瘤中。
更新日期：2020-03-26
中文翻译：
使用pH敏感的乙酰化葡聚糖（Ac-Dex）纳米颗粒增强Goniothalamin的抗癌活性和选择性：天然化合物的有前途的平台。
鞘氨醇（GTN）是一种从淋菌属物种中分离的天然化合物，以前已证明其对几种癌细胞系具有细胞毒活性。但是，与许多天然和合成的抗癌化合物相似，GTN对某些健康细胞具有毒性，并且水溶性低，降低了其生物利用度，并排除了其作为抗肿瘤药的应用。我们在努力提高对癌细胞GTN的药代动力学行为和选择性，我们开发了一种聚合物纳米系统，其中RAC-GTN封装在具有高负载生物活性化合物的pH响应型缩醛葡聚糖（Ac-Dex）纳米颗粒（NPs）中。动态光散射（DLS）分析显示，所获得的纳米颗粒呈现出直径约为100 nm的窄尺寸分布，而电子显微镜（EM）图像显示的纳米颗粒具有规则的球形形态，与DLS获得的尺寸范围相符。稳定性和释放性研究表明，GTN @ Ac-Dex NP在生理条件下（pH 7.4）表现出高稳定性，在弱酸性条件下（pH 5.5）分解，从而持续释放rac -GTN。体外分析显示，与空的Ac-Dex NP和游离的rac -GNT相比，GTN @ Ac-Dex NPs显着提高了对癌细胞的细胞毒性和选择性。使用MCF-7细胞进行的细胞摄取和形态学研究表明，GTN @ Ac-Dex NP被迅速内化到癌细胞中，从而导致细胞死亡。体内研究证实了rac -GTN从GTN @ Ac-Dex NPs的有效释放，从而导致小鼠前列腺癌（TRAMP）转基因腺癌中前列腺癌进展的延迟。此外，用GTN @ Ac-Dex NP治疗后的肝组织病理学评估未显示毒性证据。因此，在体外和体内研究结果表明，Ac-Dex NPs是一个有前途的纳米系统，可将rac -GTN持续递送到肿瘤中。
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