PEG conjugated N-octyl-O-sulfate chitosan micelles for delivery of paclitaxel: in vitro characterization and in vivo evaluation.
A series of novel chitosan derivatives (mPEGOSC) with hydrophobic moieties of octyl and hydrophilic moieties of sulfate and polyethylene glycol monomethyl ether (mPEG) groups were synthesized. The values of critical micelle concentration (CMC) were found to be 0.011-0.079 mg/ml, and the log CMC was linearly relative to four structure parameters, degree of substitution (DS) of chitosan unit, sulfate group, PEG unit and octyl group by mole per kilogram. Paclitaxel (PTX)-loaded micelles were prepared with the highest loading rate of 42.6%. In vivo-in vitro correlations of PTX-loaded micelles was designed and conducted, including interaction of the drug-loaded micelles with protein and the kinetics of PTX-loaded micelles below CMC. mPEG2000 and mPEG5000 on the surface of micelles provided stronger inhibition to protein adsorption compared with mPEG1100, and the micelles based on mPEGOSC with higher DS of chitosan unit (mol/kg) shown slower dissociation when diluted below CMC. The pharmacokinetic research of PTX-loaded micelles based on OSC (PTX-OSC), PTX-loaded micelles based on mPEGOSC (PTX-mPEGOSC) and Taxol was carried out in rat. The area under the plasma concentration time curve (AUC (0-t(n))) of PTX-mPEGOSC2000M was 10.21+/-2.12 microg h/ml, which were 2.93 times higher than PTX-OSC and 0.83 times lower than Taxol. Rate constant of distribution phase (alpha) and rate constant of elimination phase (beta) were analyzed by linear regression with the absorbance of protein to micelles (A) and the fraction of intact micelles at 10 min (f(t, 10 min)). The tissue distribution studies in mice indicated that PTX-mPEGOSC2000M micelles were phagocytized less than PTX-OSC micelles by reticuloendothelial system (RES). Furthermore, higher targeting efficiency of PTX-mPEGOSC2000M to uterus (including ovary) was estimated. On the basis of these results, it could be a promising PTX-encapsulated formulation for the chemotherapy of ovarian cancer.
College of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Guowei
G
Qu
Zhong
Z
Yao
Can
C
Zhang
Xiaoli
X
Wu
Qineng
Q
Ping
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; C528556:N-octyl-O-sulfate chitosan; D011092:Polyethylene Glycols; D048271:Chitosan; D017239:Paclitaxel