Babič Andrej, Herceg V, Bastien E, Lassalle H-P, Bezdetnaya L, Lange Norbert
School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, 1211, Geneva 4, Switzerland.
School of Pharmaceutical Sciences, University of Lausanne, Lausanne, Switzerland.
Nanoscale Res Lett. 2018 Jan 11;13(1):10. doi: 10.1186/s11671-017-2408-y.
Protoporphyrin IX (PpIX) as natural photosensitizer derived from administration of 5-aminolevulinic acid (5-ALA) has found clinical use for photodiagnosis and photodynamic therapy of several cancers. However, broader use of 5-ALA in oncology is hampered by its charge and polarity that result in its reduced capacity for passing biological barriers and reaching the tumor tissue. Advanced drug delivery platforms are needed to improve the biodistribution of 5-ALA. Here, we report a new approach for the delivery of 5-ALA. Squalenoylation strategy was used to covalently conjugate 5-ALA to squalene, a natural precursor of cholesterol. 5-ALA-SQ nanoassemblies were formed by self-assembly in water. The nanoassemblies were monodisperse with average size of 70 nm, polydispersity index of 0.12, and ζ-potential of + 36 mV. They showed good stability over several weeks. The drug loading of 5-ALA was very high at 26%. In human prostate cancer cells PC3 and human glioblastoma cells U87MG, PpIX production was monitored in vitro upon the incubation with nanoassemblies. They were more efficient in generating PpIX-induced fluorescence in cancer cells compared to 5-ALA-Hex at 1.0 to 3.3 mM at short and long incubation times. Compared to 5-ALA, they showed superior fluorescence performance at 4 h which was diminished at 24 h. 5-ALA-SQ presents a novel nano-delivery platform with great potential for the systemic administration of 5-ALA.
原卟啉IX（PpIX）作为通过施用5-氨基乙酰丙酸（5-ALA）衍生的天然光敏剂，已在几种癌症的光诊断和光动力治疗中得到临床应用。然而，5-ALA在肿瘤学中的更广泛应用受到其电荷和极性的阻碍，这导致其穿过生物屏障并到达肿瘤组织的能力降低。需要先进的药物递送平台来改善5-ALA的生物分布。在此，我们报告了一种递送5-ALA的新方法。采用角鲨烯化策略将5-ALA与胆固醇的天然前体角鲨烯共价偶联。5-ALA-SQ纳米组装体通过在水中自组装形成。纳米组装体呈单分散状态，平均尺寸为70nm，多分散指数为0.12，ζ电位为+36mV。它们在几周内表现出良好的稳定性。5-ALA的药物负载量非常高，为26%。在人前列腺癌细胞PC3和人胶质母细胞瘤细胞U87MG中，在与纳米组装体孵育后体外监测PpIX的产生。在短期和长期孵育时，与1.0至3.3mM的5-ALA-Hex相比，它们在癌细胞中产生PpIX诱导的荧光方面更有效。与5-ALA相比，它们在4小时时表现出优异的荧光性能，在24小时时这种性能减弱。5-ALA-SQ提出了一种新型纳米递送平台，具有用于5-ALA全身给药的巨大潜力。
