title: Formulation of hydrophobic therapeutics with self-assembling peptide and amino acid: A new platform for intravenous drug delivery.
abstract: Clinical application of hydrophobic therapeutics is restricted by lack of an efficient vehicle which permits their solubility in aqueous environments. We have previously developed a novel formulation strategy to deliver a hydrophobic Src inhibitor, PP2, involving combinations of one self-assembling peptide (SAP) and one of 4 selected amino acids (AAs). The present study aims to develop a generalized drug delivery platform for intravenous application of hydrophobic drugs by combining self-assembling peptide, amino acid and low concentration of co-solvent. A multi-step screening pipeline is established which includes assessment of drug solubility and physicochemical characteristics, as well as functional efficacy and safety in vitro and in vivo. Using PP2 as an exemplary hydrophobic compound, 480 different combinations of 6 SAPs, 20 naturally existing AAs at 2 concentrations, and 2 co-solvents were evaluated. Among the combinations, 60 formulae dissolved PP2; 10 of which significantly reduced thrombin-induced IL-8 production, a sign of inflammatory response, in normal human lung epithelial BEAS2B cells. These formulations did not show cytotoxicity alone, but 2 reduced cell viability with presence of thrombin. We then performed a double-blinded test in a rat model of pulmonary ischemia-reperfusion. PP2 formulated with EAK16-I peptide plus methionine and 2% ethanol were administrated intravenously, significantly reducing severity of lung injury. The SAP-AA formulation strategy was also successfully applied to other hydrophobic compounds, suggesting this strategy could be applicable to other hydrophobics for a variety of clinical applications.
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Shaun
authors: S
authors: Pacheco
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Takashi
authors: T
authors: Kanou
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Shan-Yu
authors: SY
authors: Fung
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Kenny
authors: K
authors: Chen
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Daiyoon
authors: D
authors: Lee
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: Xiaohui
authors: X
authors: Bai
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Shaf
authors: S
authors: Keshavjee
authors: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: mingyao.liu@utoronto.ca.
authors: Mingyao
authors: M
authors: Liu
mesh_terms: D000072283:A549 Cells; D061605:Administration, Intravenous; D000596:Amino Acids / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000596:Amino Acids; D009842:Oligopeptides
keywords: Amino acid; High-throughput screening; Hydrophobic therapeutics; Intravenous drug delivery; Nanotechnology; Self-assembling peptide