Department of Organic Chemistry, Institute of Chemistry, University of Campinas (UNICAMP), P.O. Box 6154, CEP 13083-970 Campinas, São Paulo, Brazil.
Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), P.O. Box 6109, CEP 13083-865 Campinas, São Paulo, Brazil.
ACS Biomater Sci Eng. 2020 May 11;6(5):2929-2942. doi: 10.1021/acsbiomaterials.0c00057. Epub 2020 Apr 7.
Goniothalamin (GTN), a natural compound isolated from 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 -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 -GTN in a sustained manner. 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 -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. investigation confirmed the efficient release of -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 and findings suggest that the Ac-Dex NPs are a promising nanosystem for the sustained delivery of -GTN into tumors.
戈尼辛（GTN）是一种从 种植物中分离得到的天然化合物，先前已证明其对多种癌细胞系具有细胞毒性。然而，与许多天然和合成的抗癌化合物一样，GTN 对一些健康细胞也具有毒性，并且水溶性低，这降低了其生物利用度，使其无法作为抗肿瘤药物应用。为了改善 GTN 的药代动力学行为和对癌细胞的选择性，我们开发了一种聚合物纳米系统，其中 -GTN 被封装在具有高载药量的 pH 响应性乙酰化葡聚糖（Ac-Dex）纳米颗粒（NPs）中。动态光散射（DLS）分析表明，所得到的纳米颗粒具有约 100nm 的窄粒径分布，而电子显微镜（EM）图像显示纳米颗粒具有规则的球形形态，与 DLS 获得的粒径范围一致。稳定性和释放研究表明，GTN@Ac-Dex NPs 在生理条件（pH 7.4）下具有高稳定性，在略酸性条件（pH 5.5）下分解，以持续的方式释放 -GTN。细胞毒性测定表明，与空 Ac-Dex NPs 和游离 -GNT 相比，GTN@Ac-Dex NPs 显著增加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研究表明，GTN@Ac-Dex NPs 能够快速被癌细胞内化，并导致细胞死亡。体内研究证实了 GTN@Ac-Dex NPs 能够有效地从 GTN@Ac-Dex NPs 中释放 -GTN，从而延缓了前列腺癌转基因腺癌小鼠前列腺（TRAMP）模型的进展。此外，用 GTN@Ac-Dex NPs 治疗后的肝组织病理学评价未显示出毒性迹象。因此，体内和体外研究结果表明，Ac-Dex NPs 是一种有前途的纳米系统，可用于将 -GTN 持续递送至肿瘤部位。
