title: Injectable long-acting systems for Radix Ophiopogonis polysaccharide based on mono-PEGylation and in situ formation of a PLGA depot.
abstract: BACKGROUND
  Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(D,L-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study.
  
  
  METHODS
  Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo.
  
  
  RESULTS
  Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone.
  
  
  CONCLUSIONS
  Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.
authors.affiliation: College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: XiaoLi
authors.initials: X
authors.lastname: Shi
authors.affiliation: College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lin
authors.affiliation: Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: XiangWei
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China ; Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000737:chemistry*; D005630:Fructans / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D031441:Ophiopogon / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011760:Pyrrolidinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D014783:Viscosity
chemical_list: D003692:Delayed-Action Preparations; D004365:Drugs, Chinese Herbal; D005630:Fructans; D011760:Pyrrolidinones; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; C038678:N-methylpyrrolidone
keywords: Radix Ophiopogonis polysaccharide; conjugation; in situ-forming system; poly(d,l-lactide-co-glycolide) copolymer; polyethylene glycol