评价新型 5-FU 类似物脂质体制剂珠贝在胰腺癌中的抗癌活性。

Evaluation of Anticancer Activity of Zhubech, a New 5-FU Analog Liposomal Formulation, against Pancreatic Cancer.

机构信息

College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.

Faculty of Health Sciences, University of Buea, Buea P.O. Box 63, Cameroon.

出版信息

Int J Mol Sci. 2023 Feb 21;24(5):4288. doi: 10.3390/ijms24054288.

DOI:10.3390/ijms24054288

PMID:36901721

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10002367/

Abstract

Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancers have been masked by high drug toxicities, adverse reactions, and resistance. The use of nanocarriers such as liposomes to overcome these unwanted effects has become very popular. This study aims to formulate 1,3-bistertrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and to evaluate itsstability, release kinetics, in vitro and in vivo anticancer activities, and biodistribution in different tissues. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticles (Rho-LnPs) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP), as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnPs in vivo using inductively coupled plasma mass spectrometry (ICP-MS). The mean hydrodynamic diameters of blank LnPs and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4 °C and 25 °C for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroid (IC = 3.4 ± 1.0 μM vs. IC = 6.8 ± 1.1 μM) and organoid (IC = 9.8 ± 1.4 μM vs. IC = 42.3 ± 1.0 μM) culture models. Confocal imaging confirmed a high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor-efficacy studies in a PDX bearing mouse model revealed a more than 9-fold decrease in mean tumor volumes in Zhubech-treated (108 ± 13.5 mm) compared to 5-FU-treated (1107 ± 116.2 mm) animals, respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

摘要

预计到 2030 年，胰腺癌将成为美国第二大癌症相关死亡原因。由于药物毒性、不良反应和耐药性等问题，各种胰腺癌最常用的系统治疗方法的疗效已被掩盖。使用脂质体等纳米载体来克服这些不良影响已经变得非常流行。本研究旨在制备 1,3-双(2-特丁氧基羰基甲氧基)-5-氟尿嘧啶（MFU）负载的脂质体纳米粒（Zhubech），并评价其稳定性、释放动力学、体外和体内抗癌活性以及在不同组织中的分布。通过粒径分析仪测定粒径和zeta 电位，通过共聚焦显微镜测定罗丹明包封脂质体纳米粒（Rho-LnPs）的细胞摄取率。合成并将钆己酸（Gd-Hex）包封于脂质体纳米粒（LnP）中（Gd-Hex-LnP），作为模型对比剂，通过电感耦合等离子体质谱法（ICP-MS）评价 Gd 纳米粒在体内的生物分布和积累。空白 LnPs 和 Zhubech 的平均水动力直径分别为 90.0 ± 0.65nm 和 124.9 ± 3.2nm。在 4°C 和 25°C 下，Zhubech 的水动力直径在 30 天的溶液中高度稳定。Zhubech 制剂中 MFU 的体外药物释放符合 Higuchi 模型（R 值=0.95）。用 Zhubech 处理的 Miapaca-2 和 Panc-1 细胞的活力均降低，在 3D 球体（IC=3.4±1.0μM 对 IC=6.8±1.1μM）和类器官（IC=9.8±1.4μM 对 IC=42.3±1.0μM）培养模型中，细胞活力比 MFU 处理的细胞低 2 倍或 4 倍。共聚焦成像证实了罗丹明包封的 LnP 被 Panc-1 细胞以时间依赖性方式摄取。在携带 PDX 的小鼠模型中的肿瘤疗效研究表明，与 5-FU 治疗（1107±116.2mm）相比，Zhubech 治疗（108±13.5mm）的平均肿瘤体积减少了 9 倍以上。本研究表明，Zhubech 可能是一种用于治疗胰腺癌的潜在药物递送候选物。