Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) micelles for rapamycin delivery: in vitro characterization and biodistribution.
Our objective was to synthesize an amphiphilic diblock copolymer for micellar delivery of rapamycin. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) (PEG-b-PBC) with different hydrophobic core lengths were synthesized from methoxy poly(ethylene glycol) and 2-methyl-2-benzoxycarbonyl-propylene carbonate through ring-opening polymerization using 1,8-diazabicycloundec-7-ene as a catalyst. The critical micelle concentration of PEG-b-PBC was around 10(-8) M and depends on the hydrophobic core length. Rapamycin was effectively incorporated into micelles and drug loading increased with increasing hydrophobic core length, with maximal drug loading of 10% (w/w, drug/polymer), drug loading efficiency of about 85%, and mean particle size of around 70 nm. The drug release profile was also dependent on the hydrophobic core length and the drug release from PEG(114) -b-PBC(30) micelles was the slowest. We also determined the toxicity of rapamycin micelles on insulinoma (INS-1E) β-cells and human islets. Encapsulation of rapamycin into PEG-b-PBC micelles reduced its toxicity. Biodistribution of rapamycin-loaded PEG-b-PBC micelles was determined after systemic administration into mice. Rapamycin-loaded PEG-b-PBC micelles showed little difference in pharmacokinetics and biodistribution characteristics in mice compared with rapamycin carrying nanosuspension. In conclusion, rapamycin formulated with PEG-b-PBC micelles showed significantly reduced toxicity on INS-1E β-cells and human islets, but had similar biodistribution profiles as those of nanosuspensions.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38103, USA.
Wenli
W
Lu
Feng
F
Li
Ram I
RI
Mahato
D000818:Animals; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry; D011126:Polypropylenes / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D012995:Solubility; D013499:Surface Properties; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000737:chemistry; D014018:Tissue Distribution
D004337:Drug Carriers; D007166:Immunosuppressive Agents; D008823:Micelles; D011126:Polypropylenes; D013501:Surface-Active Agents; C560733:poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate); D011092:Polyethylene Glycols; D020123:Sirolimus