Hebei Key Laboratory of Neuropharmacology, Department of Pharmacy, Hebei North University, Zhangjiakou 075000, Hebei Province, China.
Department of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan Province, China.
J Photochem Photobiol B. 2024 Sep;258:112999. doi: 10.1016/j.jphotobiol.2024.112999. Epub 2024 Aug 2.
5-Aminolevulinic acid (5-ALA) is a prodrug of porphyrin IX (PpIX). Disadvantages of 5-ALA include poor stability, rapid elimination, poor bioavailability, and weak cell penetration, which greatly reduce the clinical effect of 5-ALA based photodynamic therapy (PDT). Presently, a novel targeting nanosystem was constructed using gold nanoparticles (AuNPs) as carriers loaded with a CSNIDARAC (CC9)-targeting peptide and 5-ALA via Au-sulphur and ionic bonds, respectively, and then wrapped in polylactic glycolic acid (PLGA) NPs via self-assembly to improve the antitumor effects and reduce the side effect. The successful preparation of ALA/CC9@ AuNPs-PLGA NPs was verified using ultraviolet-visible, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The analyses revealed good sphericity with a particle size of approximately140 nm, Zeta potential of 10.11 mV, and slow-controlled release characteristic in a weak acid environment. Confocal microscopy revealed targeting of NCL-H460 cells by NPs by actively internalising CC9 and avoiding the phagocytic action of RAW264.7 cells, and live fluorescence imaging revealed targeting of tumours in tumour-bearing mice. Compared to free 5-ALA, the nanosystem displayed amplified anticancer activity by increasing production of PpIX and reactive oxygen species to induce mitochondrial pathway apoptosis. Antitumor efficacy was consistently observed in three-dimensionally cultured cells as the loss of integrity of tumour balls. More potent anti-tumour efficacy was demonstrated in xenograft tumour models by decreased growth rate and increased tumour apoptosis. Histological analysis showed that this system was not toxic, with lowered liver toxicity of 5-ALA. Thus, ALA/CC9@AuNPs-PLGA NPs deliver 5-ALA via a carrier cascade, with excellent effects on tumour accumulation and PDT through passive enhanced permeability and retention action and active targeting. This innovative strategy for cancer therapy requires more clinical trials before being implemented.
5-氨基酮戊酸（5-ALA）是卟啉 IX（PpIX）的前体药物。5-ALA 的缺点包括稳定性差、消除迅速、生物利用度低、细胞穿透力弱，这大大降低了基于 5-ALA 的光动力疗法（PDT）的临床效果。目前，构建了一种新型靶向纳米系统，该系统使用金纳米粒子（AuNPs）作为载体，分别通过 Au-硫键和离子键负载 CSNIDARAC（CC9）靶向肽和 5-ALA，然后通过自组装包裹在聚乳酸-羟基乙酸共聚物（PLGA） NPs 中，以提高抗肿瘤效果并降低副作用。使用紫外可见光谱、傅里叶变换红外光谱和 X 射线光电子能谱验证了 ALA/CC9@AuNPs-PLGA NPs 的成功制备。分析表明，该纳米系统具有良好的球形度，粒径约为 140nm，Zeta 电位为 10.11mV，在弱酸环境中具有缓慢的控制释放特性。共焦显微镜显示 NPs 通过主动内化 CC9 并避免 RAW264.7 细胞的吞噬作用来靶向 NCL-H460 细胞，活荧光成像显示肿瘤在荷瘤小鼠中的靶向性。与游离 5-ALA 相比，该纳米系统通过增加 PpIX 和活性氧的产生来诱导线粒体途径凋亡，从而显示出增强的抗癌活性。在三维培养细胞中观察到肿瘤球完整性丧失，表明该纳米系统具有更强的抗肿瘤功效。在异种移植肿瘤模型中，通过降低生长速度和增加肿瘤凋亡，观察到更强的抗肿瘤功效。组织学分析表明，该系统没有毒性，降低了 5-ALA 的肝毒性。因此，ALA/CC9@AuNPs-PLGA NPs 通过载体级联递药，通过被动增强通透性和保留作用和主动靶向作用，对肿瘤积累和 PDT 具有优异的效果。这种用于癌症治疗的创新策略需要更多的临床试验才能实施。
