索拉非尼包埋、自组装普鲁兰-硬脂酸生物聚合物衍生药物传递系统对 PLC/PRF/5 肝癌模型的作用。
Sorafenib-Entrapped, Self-Assembled Pullulan-Stearic Acid Biopolymer-Derived Drug Delivery System to PLC/PRF/5 Hepatocellular Carcinoma Model.
机构信息
Nano Drug Delivery Systems (NDDS), Cancer Biology Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
Research Scholar, Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, India.
出版信息
Int J Nanomedicine. 2022 Oct 31;17:5099-5116. doi: 10.2147/IJN.S377354. eCollection 2022.
PURPOSE
This study aimed to design a prototypic drug delivery system (DDS) made of an amphiphilic, pullulan (Pull)-derived biodegradable polymer for targeting the asialoglycoprotein receptor (ASGPR) overexpressed in HCC. Stearic acid (SA) was conjugated to increase the hydrophobicity of pullulan (Pull-SA).
METHODS
Pullulan (Pull) was linked to stearic acid (SA) after functional group modifications via EDC/NHS chemistry and characterized. Sorafenib tosylate (SRFT) was entrapped in pullulan-stearic acid nanoparticles (Pull-SA-SRFT) and its particle size, zeta potential, entrapment efficiency (EE), loading capacity (LC), and release efficiency was measured. The competence of Pull-SA-SRFT over SRFT in vitro was assessed using the ASGPR over-expressing PLC/PRF/5 hepatocellular carcinoma (HCC) cell line. This was done by studying cytotoxicity by MTT assay and chromosome condensation assay, early apoptosis by annexin-Pi staining, and late apoptosis by live-dead assay. The cellular uptake study was performed by incorporating coumarin-6 (C6) fluorophore in place of SRFT in Pull-SA conjugates. A biodistribution study was conducted in Swiss-albino mice to assess the biocompatibility and targeting properties of SRFT and Pull-SA-SRFT to the liver and other organs at 1, 6, 24, and 48 h.
RESULTS
The characterization studies of the copolymer confirmed the successful conjugation of Pull-SA. The self-assembled amphiphilic nanocarrier could proficiently entrap the hydrophobic drug SRFT to obtain an entrapment efficiency of 95.6% (Pull-SA-SRFT). Characterization of the synthesized nanoparticles exhibited highly desirable nanoparticle characteristics. In vitro, apoptotic studies urged that Pull-SA-SRFT nanoparticle was delivered more efficiently to HCC than SRFT. The cellular uptake study performed, gave propitious results in 4 hrs. The biodistribution study conducted in immunocompetent mice suggested that Pull-SA-SRFT was delivered more than SRFT to the liver when compared to other organs, and that the system was biocompatible.
CONCLUSION
Pull-SA-SRFT is a promisingly safe, biodegradable, cell-specific nanocarrier and a potential candidate to target hydrophobic drugs to HCC.
目的
本研究旨在设计一种由两亲性、支链淀粉衍生的可生物降解聚合物组成的原型药物传递系统（DDS），用于靶向在 HCC 中过表达的去唾液酸糖蛋白受体（ASGPR）。硬脂酸（SA）通过 EDC/NHS 化学与支链淀粉（Pull）连接以增加其疏水性。
方法
支链淀粉（Pull）通过 EDC/NHS 化学的官能团修饰后与硬脂酸（SA）连接，并进行了表征。将索拉非尼甲苯磺酸盐（SRFT）包封于支链淀粉-硬脂酸纳米颗粒（Pull-SA-SRFT）中，并测量其粒径、Zeta 电位、包封效率（EE）、载药量（LC）和释放效率。通过研究 ASGPR 过表达的 PLC/PRF/5 肝癌（HCC）细胞系中 SRFT 的体外竞争能力来评估 Pull-SA-SRFT 的性能。通过 MTT 测定法研究细胞毒性和染色体凝聚试验研究早期凋亡，通过 annexin-Pi 染色研究晚期凋亡，通过死活测定研究细胞摄取。通过用香豆素-6（C6）荧光团替代 Pull-SA 缀合物中的 SRFT 进行细胞摄取研究。在瑞士白化小鼠中进行生物分布研究，以评估 SRFT 和 Pull-SA-SRFT 在 1、6、24 和 48 小时时对肝脏和其他器官的生物相容性和靶向特性。
结果
共聚物的表征研究证实了 Pull-SA 的成功缀合。自组装的两亲性纳米载体能够有效地包封疏水性药物 SRFT，获得 95.6%的包封效率（Pull-SA-SRFT）。合成纳米粒子的特性研究表明其具有理想的纳米粒子特性。体外凋亡研究表明，Pull-SA-SRFT 纳米颗粒比 SRFT 更有效地递送到 HCC。进行的细胞摄取研究在 4 小时内给出了有利的结果。在免疫功能正常的小鼠中进行的生物分布研究表明，与其他器官相比，Pull-SA-SRFT 递送到肝脏的量多于 SRFT，并且该系统具有生物相容性。
结论
Pull-SA-SRFT 是一种有前途的安全、可生物降解、细胞特异性纳米载体，是将疏水性药物靶向 HCC 的潜在候选药物。
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