IT-101, a
cyclodextrin polymer-based nanoparticle containing
camptothecin, is in clinical development for the treatment of
cancer. Multiorgan pharmacokinetics and accumulation in
tumor tissue of
IT-101 is investigated by using PET.
IT-101 is modified through the attachment of a 1,4,7,10-tetraazacyclododecane-1,4,7-Tris-acetic
acid ligand to bind (64)Cu(2+). This modification does not affect the particle size and minimally affects the surface charge of the resulting nanoparticles. PET data from (64)Cu-labeled
IT-101 are used to quantify the in vivo biodistribution in mice bearing Neuro2A s.c.
tumors. The (64)Cu-labeled
IT-101 displays a biphasic plasma elimination. Approximately 8% of the injected dose is rapidly cleared as a low-molecular-weight fraction through the kidneys. The remaining material circulates in plasma with a terminal half-life of 13.3 h. Steadily increasing concentrations, up to 11% injected dose per cm(3), are observed in the
tumor over 24 h, higher than any other tissue at that time. A 3-compartment model is used to determine vascular permeability and nanoparticle retention in
tumors, and is able to accurately represent the experimental data. The calculated
tumor vascular permeability indicates that the majority of nanoparticles stay intact in circulation and do not disassemble into individual
polymer strands. A key assumption to modeling the
tumor dynamics is that there is a "sink" for the nanoparticles within the
tumor. Histological measurements using confocal microscopy show that
IT-101 localizes within
tumor cells and provides the sink in the
tumor for the nanoparticles.