α-Tocopherol Succinate-Anchored PEGylated Poly(amidoamine) Dendrimer for the Delivery of Paclitaxel: Assessment of in Vitro and in Vivo Therapeutic Efficacy,Molecular Pharmaceutics

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α-Tocopherol Succinate-Anchored PEGylated Poly(amidoamine) Dendrimer for the Delivery of Paclitaxel: Assessment of in Vitro and in Vivo Therapeutic Efficacy
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-02-28 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b01232
Himanshu Bhatt ₁ , Sri Vishnu Kiran Rompicharla ₁ , Balaram Ghosh ₁ , Swati Biswas ₁

Affiliation

This study involves development of a dendrimer-based nanoconstruct by conjugating α-tocopheryl succinate (α-TOS) and polyethylene glycol (PEG) on a poly(amidoamine) dendrimer (G4 PAMAM) to improve intracellular delivery of a poorly water-soluble chemotherapeutic drug, paclitaxel (PTX). The conjugates were characterized by NMR, and PTX-loaded nanocarriers (G4-TOS-PEG-PTX) were evaluated for hydrodynamic diameter, polydispersity index (PDI), zeta potential, percentage encapsulation efficiency (%EE), and percentage drug loading (%DL). A hemolysis study was performed, which indicated that the synthesized dendrimer conjugates were not toxic to red blood cells; hence, they were biocompatible. A cellular uptake study in (B16F10 and MDA MB231) monolayer cells and 3D spheroids showed that α-TOS conjugation improved the time dependent uptake of nanosized dendrimer conjugates. The cell viability assay revealed that G4-TOS-PEG-PTX enhanced the cytotoxicity of PTX as compared to free PTX and PTX-loaded G4-PEG (G4-PEG-PTX) at tested concentrations. Correspondingly, the α-TOS-anchored dendrimer induced more apoptosis as compared to free PTX and G4-PEG-PTX. Moreover, the fluorescently labeled G4-TOS-PEG penetrated deeper into MDA MB231 3D spheroids as visualized by confocal microscopy. G4-TOS-PEG-PTX showed significant growth inhibition in 3D spheroids as compared to free PTX and G4-PEG-PTX. Further, the in vivo efficacy study using B16F10 xenografted C57Bl6/J mice indicated that the G4-TOS-PEG localized in tumor sections. G4-TOS-PEG-PTX reduced the tumor growth significantly compared to free PTX and G4-PEG-PTX. G4-TOS-PEG-PTX had more apoptotic potential in tumor sections as analyzed by TUNEL assay. Hence, the newly developed dendrimer conjugate, G4-TOS-PEG, has the potential to target loaded drug to the tumor, and G4-TOS-PEG-PTX has the potential to be utilized successfully in cancer treatment.

中文翻译：

α-生育酚琥珀酸酯锚定的聚乙二醇化聚酰胺酰胺树状聚合物用于紫杉醇的递送：体内和体外治疗功效的评估

这项研究涉及通过将α-生育酚琥珀酸酯（α-TOS）和聚乙二醇（PEG）结合在聚（酰氨基胺）树状聚合物（G4 PAMAM）上来开发基于树状聚合物的纳米结构，以改善水溶性差的化疗药物的细胞内递送，紫杉醇（PTX）。通过NMR对缀合物进行表征，并评估了载有PTX的纳米载体（G4-TOS-PEG-PTX）的流体动力学直径，多分散指数（PDI），ζ电位，包封率（％EE）和载药率（％） DL）。进行了溶血研究，结果表明合成的树枝状大分子结合物对红细胞无毒。因此，它们具有生物相容性。在（B16F10和MDA MB231）单层细胞和3D球体中进行的细胞摄取研究表明，α-TOS缀合可改善纳米树枝状聚合物缀合物的时间依赖性摄取。细胞活力分析表明，与游离PTX和载有PTX的G4-PEG（G4-PEG-PTX）相比，G4-TOS-PEG-PTX增强了PTX的细胞毒性。相应地，与游离PTX和G4-PEG-PTX相比，α-TOS锚定的树状聚合物诱导更多的细胞凋亡。此外，通过共聚焦显微镜观察，荧光标记的G4-TOS-PEG更深地渗透到MDA MB231 3D球体中。与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX在3D球体中显示出显着的生长抑制作用。此外，细胞活力分析表明，与游离PTX和载有PTX的G4-PEG（G4-PEG-PTX）相比，G4-TOS-PEG-PTX增强了PTX的细胞毒性。相应地，与游离PTX和G4-PEG-PTX相比，α-TOS锚定的树状聚合物诱导更多的细胞凋亡。此外，通过共聚焦显微镜观察，荧光标记的G4-TOS-PEG更深地渗透到MDA MB231 3D球体中。与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX在3D球体中显示出显着的生长抑制作用。此外，细胞活力分析表明，与游离PTX和载有PTX的G4-PEG（G4-PEG-PTX）相比，G4-TOS-PEG-PTX增强了PTX的细胞毒性。相应地，与游离PTX和G4-PEG-PTX相比，α-TOS锚定的树状聚合物诱导更多的细胞凋亡。此外，通过共聚焦显微镜观察，荧光标记的G4-TOS-PEG更深地渗透到MDA MB231 3D球体中。与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX在3D球体中显示出显着的生长抑制作用。此外，与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX在3D球体中显示出显着的生长抑制作用。此外，与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX在3D球体中显示出显着的生长抑制作用。此外，使用B16F10异种移植的C57B16 / J小鼠进行的体内功效研究表明，G4-TOS-PEG位于肿瘤切片中。与游离PTX和G4-PEG-PTX相比，G4-TOS-PEG-PTX显着降低了肿瘤的生长。如通过TUNEL分析所分析的，G4-TOS-PEG-PTX在肿瘤切片中具有更大的凋亡潜力。因此，新开发的树枝状大分子共轭物G4-TOS-PEG具有将负载药物靶向肿瘤的潜力，而G4-TOS-PEG-PTX具有成功用于癌症治疗的潜力。

更新日期：2019-02-28

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