Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug.
Water-soluble paclitaxel may cause less side effects and be less costly to administer in comparison to a taxol formulation using a cremophor EL/alcohol vehicle. In this study, polyethylene glycol (PEG; MW 5000) was conjugated to the 2' position of paclitaxel through a spacer succinyl group. PEG-paclitaxel as a non-ionic paclitaxel prodrug was highly water soluble (> 20 mg equiv. paclitaxel/ml). The release of paclitaxel from phosphate-buffered solution was pH dependent. The half-life of PEG-paclitaxel was 7.6, 54 and 311 min at pH 9.0, 7.4 and 6.0, respectively. PEG-paclitaxel inhibited the growth of B16 melanoma cells to an extent similar to that of paclitaxel. In MCA-4 mammary tumor-bearing mice, a single dose of PEG-paclitaxel (40 mg equiv. paclitaxel/kg body weight) significantly delayed tumor growth. The average number of days for the tumor to reach 12 from 8 mm in diameter increased from 6.5 days for control animals to 8.5 days for PEG-paclitaxel-treated animals and 9.4 days for paclitaxel-treated animals. These studies demonstrated that PEG may be used as an effective solubilizing carrier for paclitaxel.
Division of Diagnostic Imaging, University of Texas, MD Anderson Cancer Center, Houston 77030, USA.
C
C
Li
D
D
Yu
T
T
Inoue
D J
DJ
Yang
L
L
Milas
N R
NR
Hunter
E E
EE
Kim
S
S
Wallace
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D017239:Paclitaxel / Q000737:chemistry / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011355:Prodrugs; D011092:Polyethylene Glycols; D017239:Paclitaxel