Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In Silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents
Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In Silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents
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DOI：
10.1021/acsabm.9b00419
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发表时间：
2019-08-19
影响因子：
4.7
通讯作者：
Kumar, M. N. V. Ravi
中科院分区：
文献类型：
--
作者：
Arora, M.;Ganugula, R.;Kumar, M. N. V. Ravi
药物输送的一个主要挑战是加强药物跨越生物屏障的运输，如小肠、血脑屏障和血视网膜/眼屏障，并有效地到达作用部位，同时将全身影响降至最低。近年来，携带细胞表面受体被认为是一种可行的跨越生物屏障的主动药物输送策略。然而，用于将药物靶向质膜受体的配体往往不得不与内源性配体竞争，从而限制了它们与细胞表面的结合和它们的跨屏障运输。为了解决这个问题，伽马酸(GA)被认为是转铁蛋白受体(TFR)的非竞争性配体，转铁蛋白受体是存在于各种屏障上的受体。然而，GA在TFR上的结合部位仍然未知，这是建立结构-活性关系的关键一步。在电子结合位置预测工具中，盲法对接和分子对接模拟证实TFR上的GA结合位置与转铁蛋白结合的铁结合位置无关。这些GA-偶联聚酯被加工成适合药物输送应用的纳米颗粒，该纳米颗粒在调节条件下具有良好的储存稳定性。传统上，GA一直被用作一种抗癌化合物，需要进行安全评估。在健康啮齿动物身上进行的初步研究表明，重复口服10次没有不良影响。这项工作将利用独特的非竞争性纳米系统在纳米医学领域产生范式转换和新知识，这些纳米系统不与内源性转铁蛋白竞争。
A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often have to compete against endogenous ligands, thereby limiting their binding to the cell surface and their transport across barriers. To address this problem, gambogic acid (GA) was identified as a noncompetitive ligand specific to the transferrin receptor (TfR), a receptor present on various barriers. However, the binding sites of the GA on TfR remain unknown, an essential step toward establishing structure-activity relationships. In silico binding site prediction tools, blind docking, and molecular docking simulation confirm that the GA binding site on the TfR is independent of the transferrin-bound iron binding sites. The GA-conjugated polyesters were processed into nanoparticles suitable for drug delivery applications that possess excellent storage stability under regulatory conditions. Traditionally, GA has been used as an anticancer compound that warrants safety assessment. The preliminary studies in healthy rodents on 10-repeated oral doses show no adverse effects. This work will generate paradigm shifting, new knowledge in the field of nanomedicines using unique noncompetitive nanosystems that do not compete with endogenous transferrin.