Pacheco Shaun, Fung Shan-Yu, Liu Mingyao
Latner Thoracic Surgery Research Laboratories, University Health Network.
Department of Pediatrics, British Columbia Children's Hospital & University of British Columbia.
J Vis Exp. 2017 Sep 20(127):56158. doi: 10.3791/56158.
Self-assembling peptides (SAPs) are promising vehicles for the delivery of hydrophobic therapeutics for clinical applications; their amphipathic properties allow them to dissolve hydrophobic compounds in the aqueous environment of the human body. However, self-assembling peptide solutions have poor blood compatibility (e.g., low osmolarity), hindering their clinical application through intravenous administrations. We have recently developed a generalized platform for hydrophobic drug delivery, which combines SAPs with amino acid solutions (SAP-AA) to enhance drug solubility and increase formulation osmolarity to reach the requirements for clinical uses. This formulation strategy was thoroughly tested in the context of three structurally different hydrophobic compounds - PP2, rottlerin, and curcumin - in order to demonstrate its versatility. Furthermore, we examined effects of changing formulation components by analyzing 6 different SAPs, 20 naturally existing amino acids at low and high concentrations, and two different co-solvents dimethyl sulfoxide (DMSO) and ethanol. Our strategy proved to be effective in optimizing components for a given hydrophobic drug, and therapeutic function of the formulated inhibitor, PP2, was observed both in vitro and in vivo. This manuscript outlines our generalized formulation method using SAP-AA combinations for hydrophobic compounds, and analysis of solubility as a first step towards potential use of these formulations in more functional studies. We include representative solubility results for formulation of the hydrophobic compound, curcumin, and discuss how our methodology serves as a platform for future biological studies and disease models.
自组装肽（SAPs）是用于临床应用中疏水性治疗药物递送的有前景的载体；它们的两亲性使它们能够在人体的水性环境中溶解疏水性化合物。然而，自组装肽溶液的血液相容性较差（例如，低渗透压），这阻碍了它们通过静脉给药的临床应用。我们最近开发了一种用于疏水性药物递送的通用平台，该平台将自组装肽与氨基酸溶液（SAP-AA）相结合，以提高药物溶解度并增加制剂渗透压，从而达到临床使用要求。为了证明其通用性，在三种结构不同的疏水性化合物——PP2、rottlerin和姜黄素的背景下对这种制剂策略进行了全面测试。此外，我们通过分析6种不同的自组装肽、20种低浓度和高浓度的天然存在的氨基酸以及两种不同的助溶剂二甲基亚砜（DMSO）和乙醇，研究了改变制剂成分的效果。我们的策略被证明在优化给定疏水性药物的成分方面是有效的，并且在体外和体内都观察到了制剂抑制剂PP2的治疗功能。本手稿概述了我们使用SAP-AA组合用于疏水性化合物的通用制剂方法，以及作为这些制剂在更多功能研究中潜在应用的第一步的溶解度分析。我们给出了疏水性化合物姜黄素制剂的代表性溶解度结果，并讨论了我们的方法如何作为未来生物学研究和疾病模型的平台。
