San Anselmo María, Lancelot Alexandre, Egido Julia E, Clavería-Gimeno Rafael, Casanova Álvaro, Serrano José Luis, Hernández-Ainsa Silvia, Abian Olga, Sierra Teresa
Instituto de Nanociencia y Materiales de Aragón (INMA), University of Zaragoza-CSIC, Pedro Cerbuna 12, 50009 Zaragoza, Spain.
Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain.
Pharmaceutics. 2020 Nov 7;12(11):1062. doi: 10.3390/pharmaceutics12111062.
The use of nanocarriers has been revealed as a valid strategy to facilitate drug bioavailability, and this allows for expanding the drug libraries for the treatment of certain diseases such as viral diseases. In the case of Hepatitis C, the compounds iopanoic acid and 3,3',5-triiodothyroacetic acid (or tiratricol) were identified in a primary screening as bioactive allosteric inhibitors of viral NS3 protease, but they did not exhibit accurate activity inhibiting viral replication in cell-based assays. In this work, dendritic nanocarriers are proposed due to their unique properties as drug delivery systems to rescue the bioactivity of these two drugs. Specifically, four different amphiphilic Janus dendrimers synthesized by combining 2,2'-(hydroxymethyl)propionic acid (-MPA) and 2,2'-(glyciloxy)propionic acid (-GMPA) functionalized with either hydrophilic or lipophilic moieties at their periphery were used to entrap iopanoic acid and tiratricol. Interestingly, differences were found in the loading efficiencies depending on the dendrimer design, which also led to morphological changes of the resulting dendrimer aggregates. The most remarkable results consist of the increased water solubility of the bioactive compounds within the dendrimers and the improved antiviral activity of some of the dendrimer/drug aggregates, considerably improving antiviral activity in comparison to the free drugs. Moreover, imaging studies have been developed in order to elucidate the mechanism of cellular internalization.
纳米载体的使用已被证明是提高药物生物利用度的有效策略，这有助于扩大用于治疗某些疾病（如病毒性疾病）的药物库。以丙型肝炎为例，在初步筛选中确定碘番酸和3,3',5-三碘甲状腺乙酸（或曲洛司坦）为病毒NS3蛋白酶的生物活性变构抑制剂，但在基于细胞的试验中，它们并未表现出抑制病毒复制的准确活性。在这项工作中，由于其作为药物递送系统的独特性质，提出了树枝状纳米载体，以挽救这两种药物的生物活性。具体而言，通过将2,2'-（羟甲基）丙酸（-MPA）和2,2'-（甘氨酰氧基）丙酸（-GMPA）在其外围用亲水性或亲脂性部分官能化而合成的四种不同的两亲性Janus树枝状聚合物被用于包裹碘番酸和曲洛司坦。有趣的是，根据树枝状聚合物的设计，在负载效率上发现了差异，这也导致了所得树枝状聚合物聚集体的形态变化。最显著的结果包括树枝状聚合物中生物活性化合物的水溶性增加，以及一些树枝状聚合物/药物聚集体的抗病毒活性提高，与游离药物相比，抗病毒活性有显著提高。此外，已经开展了成像研究以阐明细胞内化机制。
