Pharmacokinetics and biodistribution of the camptothecin-polymer conjugate IT-101 in rats and tumor-bearing mice

Cancer Chemother Pharmacol. 2006 May;57(5):654-62. doi: 10.1007/s00280-005-0091-7. Epub 2005 Aug 26.


Purpose: IT-101 is a camptothecin-polymer conjugate prepared by linking camptothecin (CPT) to a hydrophilic, cyclodextrin-based, linear polymer through ester bonds. In previous studies, these polymer conjugates with high molecular weights (ca 90 kDa) have shown significant antitumor effects against human colon carcinoma xenografts. The pharmacokinetics of IT-101 in plasma of rats and its biodistribution in nude mice bearing human LS174T colon carcinoma tumors is reported here.

Methods: Sprague-Dawley rats were injected intravenously with three different doses of IT-101. Serial plasma samples were analyzed for polymer-bound and unconjugated CPT by high-performance liquid chromatography (HPLC). Concentration vs time data were modeled using non-compartmentalized methods and compared to CPT alone injected intravenously at an equivalent dose. Tumor-bearing mice were injected intravenously with IT-101 and intraperitoneally with CPT alone, and sacrificed after 24 and 48 h, and serum, heart, liver, spleen, lungs and tumor collected. Tissue samples were extracted and analyzed for polymer-bound and unconjugated CPT by HPLC.

Results: Plasma concentrations and the area under the curve for polymer-bound CPT are approximately 100-fold higher than those of unconjugated CPT or CPT alone, injected intravenously at an equivalent dose. The plasma half-life of IT-101 ranges from 17 -20 h and is significantly greater than that of CPT alone (1.3 h). When CPT is conjugated to polymer, the biodistribution pattern of CPT is different from that taken alone. At 24 h post injection, the total CPT per gram of tissue is the highest in tumor tissue when compared to all other tissues tested. Tumor concentrations of active CPT released from the conjugate are more than 160-fold higher when administered as a polymer conjugate rather than as CPT alone.

Conclusions: The studies presented here indicate that intravenous administration of IT-101, a cyclodextrin based polymer-CPT conjugate, gives prolonged plasma half-life and enhanced distribution to tumor tissue when compared to CPT alone. The data also show that active CPT is released from the conjugate within the tumor for an extended period of time. These effects likely play a significant role in the enhanced antitumor activity of IT-101 when compared to CPT alone or irinotecan.

MeSH terms

  • Animals
  • Area Under Curve
  • Camptothecin / chemistry
  • Camptothecin / pharmacokinetics*
  • Camptothecin / therapeutic use
  • Chromatography, High Pressure Liquid
  • Colonic Neoplasms / metabolism*
  • Disease Models, Animal
  • Female
  • Half-Life
  • Humans
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Mice
  • Mice, Nude
  • Polymers / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • beta-Cyclodextrins / chemistry*


  • Polymers
  • beta-Cyclodextrins
  • Camptothecin