Pharmacokinetics and tissue distribution of PGG-paclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts.
OBJECTIVE
PGG-PTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(L-gamma-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or PGG-PTX in mice.


METHODS
Both [3H]PTX and PGG-[3H]PTX were administered as an IV bolus injection to mice bearing SC NCI-H460 lung cancer xenografts at a dose of 40-mg PTX equivalents/kg. Plasma, tumor, major organs, urine, and feces were collected at intervals out to 340 h. Total taxanes, taxane extractable into ethyl acetate, and native PTX were quantified by liquid scintillation counting and HPLC.


RESULTS
Conjugation of PTX to the PGG polymer increased plasma and tumor Cmax, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from tumor. In plasma injection of PGG-PTX increased total taxane AUC0-340 by 23-fold above that attained with PTX. In tumors, it increased the total taxane by a factor of 7.7, extractable taxane by 5.7, and native PTX by a factor of 3.5-fold. Conjugation delayed and reduced total urinary and fecal excretion of total taxanes.


CONCLUSIONS
Incorporation of PTX into the PGG-PTX polymer significantly prolonged the half-life of total taxanes, extractable taxane, and native PTX in both the plasma and tumor compartments. This resulted in a large increase in the amount of active PTX delivered to the tumor. PGG-PTX is an attractive candidate for further development.
Wang
Xinghe
X
Biogroup, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058, USA.
Zhao
Gang
G
Van
Sang
S
Jiang
Nan
N
Yu
Lei
L
Vera
David
D
Howell
Stephen B
SB
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry*; D014018:Tissue Distribution; D014316:Tritium; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004151:Dipeptides; D010455:Peptides; D014316:Tritium; C047442:gamma-glutamylglutamine; D017239:Paclitaxel