title: Formulation, characterization and tissue distribution of a novel pH-sensitive long-circulating liposome-based theranostic suitable for molecular imaging and drug delivery.
abstract: OBJECTIVE
  When designing liposome formulas for treatment and diagnostic purposes, two of the most common challenges are 1) the lack of a specific release mechanism for the encapsulated contents and 2) a short circulation time due to poor resistance to biological fluids. This study aimed to create a liposome formula with prolonged in vivo longevity and pH-sensitivity for cytoplasmic drug delivery.
  
  
  METHODS
  Liposomal particles were generated using hydrogenated soy (HS) phosphatidylcholine, cholesteryl hemisuccinate (CHEM), polyethylene glycol (PEG) and diethylenetriaminepentaacetic acid-modified phosphatidylethanolamine with film hydration and extrusion methods. The physicochemical properties of the different formulas were characterized. pH-sensitivity was evaluated through monitoring release of encapsulated calcein. Stability of the radiolabeled liposomes was assessed in vitro through incubation with human serum. The best formula was selected and injected into healthy rats to assess tissue uptake and pharmacokinetics.
  
  
  RESULTS
  Liposomal particles were between 88 and 102 nm in diameter and negatively charged on the surface. Radiolabeling of all formulas with indium-111 was successful with good efficiency. 1%PEG-HS-CHEM not only responded to acidification very quickly but also underwent heavy degradation with serum. The 4%PEG-HS-CHEM, which exhibited both comparatively good pH-sensitivity (up to 20% release) and satisfactory stability (stability >70% after 24 h), was considered the best candidate for in vivo evaluation. Tissue distribution of 4%PEG-HS-CHEM was comparable to that of 4%PEG-HS-Chol, a long-circulating but pH-insensitive control, showing major accumulation in liver, spleen, intestine and kidneys. Analysis of blood clearance showed favorable half-life values: 0.6 and 14 h in fast and slow clearance phases, respectively.
  
  
  CONCLUSIONS
  4%PEG-HS-CHEM showed promising results in pH-sensitivity, serum stability, tissue uptake and kinetics and is a novel liposome formulation for multifunctional theranostic applications.
authors.affiliation: Nordion Inc.; Cardiac Positron Emission Tomography (PET) Radiochemistry Research Core Laboratory, Canadian Molecular Imaging Center of Excellence, University of Ottawa Heart Institute.
authors.forename: Yin
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Nordion Inc.; Cardiac Positron Emission Tomography (PET) Radiochemistry Research Core Laboratory, Canadian Molecular Imaging Center of Excellence, University of Ottawa Heart Institute; Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wei
authors.affiliation: Cardiac Positron Emission Tomography (PET) Radiochemistry Research Core Laboratory, Canadian Molecular Imaging Center of Excellence, University of Ottawa Heart Institute; Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Petryk
authors.affiliation: Cardiac Positron Emission Tomography (PET) Radiochemistry Research Core Laboratory, Canadian Molecular Imaging Center of Excellence, University of Ottawa Heart Institute; Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Terrence D
authors.initials: TD
authors.lastname: Ruddy
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005452:Fluoresceins / Q000493:pharmacokinetics; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D000068936:Theranostic Nanomedicine / Q000379:methods; D014018:Tissue Distribution
chemical_list: D002788:Cholesterol Esters; D005452:Fluoresceins; D007205:Indium Radioisotopes; D008081:Liposomes; D010714:Phosphatidylethanolamines; C060068:diethylenetriaminetetraacetic acid; C483858:phosphatidylethanolamine; D011092:Polyethylene Glycols; D004369:Pentetic Acid; C013440:cholesteryl succinate; C007740:fluorexon
keywords: PEGylated liposome; cholesteryl hemisuccinate; hydrogenated soy phosphatidylcholine; long in vivo half-life; pH-triggered release