Abstract：
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.
摘要：
5-氨基乙酰丙酸(5-ALA)是卟啉IX(PpIX)的前药。5-ALA的缺点包括稳定性差，快速消除,生物利用度差,和微弱的细胞渗透，这大大降低了基于5-ALA的光动力疗法（PDT）的临床效果。目前,使用金纳米颗粒（AuNP）作为载体，通过Au-硫和离子键负载CSNIDARAC（CC9）靶向肽和5-ALA，构建了一种新型靶向纳米系统，分别,然后通过自组装包裹在聚乳酸乙醇酸（PLGA）NPs中，以提高抗肿瘤效果并减少副作用。ALA/CC9@AuNPs-PLGANP的成功制备使用紫外-可见光进行验证，傅里叶变换红外光谱,和X射线光电子能谱。分析显示球形度良好，粒径约为140nm，Zeta电位为10.11mV，和在弱酸性环境中缓慢控制释放的特性。共聚焦显微镜显示，NPs通过主动内化CC9并避免RAW264.7细胞的吞噬作用而靶向NCL-H460细胞，和实时荧光成像揭示了荷瘤小鼠的肿瘤靶向性。与免费的5-ALA相比，纳米系统通过增加PpIX和活性氧的产生以诱导线粒体途径凋亡而显示出增强的抗癌活性。在三维培养的细胞中始终观察到抗肿瘤功效，因为肿瘤球的完整性丧失。在异种移植肿瘤模型中，通过降低的生长速率和增加的肿瘤凋亡证明了更有效的抗肿瘤功效。组织学分析表明，该系统没有毒性，降低5-ALA的肝毒性。因此，ALA/CC9@AuNPs-PLGANPs通过载波级联提供5-ALA,通过被动增强的渗透性和保留作用以及主动靶向对肿瘤积累和PDT具有优异的效果。这种癌症治疗的创新策略在实施之前需要更多的临床试验。
