Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements

Abstract

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.cancer ͉ camptothecin ͉ cyclodextrin ͉ polymer ͉ intracellular delivery C hemotherapeutics are the mainstay of cancer treatment for advanced and/or metastatic tumors. However, their effectiveness is typically limited by toxicity in healthy, normal tissues with rapidly dividing cells, such as bone marrow or the gastrointestinal tract. One approach to increase the therapeutic index of chemotherapeutics is site-directed delivery by using various carrier systems. Numerous types of delivery technologies have been developed for this purpose, such as liposomes (1, 2), conjugates with antibodies or small molecules targeted to tumor antigens (3, 4), and macromolecular polymer carriers (5). Carrier-drug composites are nanoscaled therapeutics, and nanoparticle cancer therapeutics that have been used in humans have been reviewed elsewhere (6).The use of nanoscaled therapeutics takes advantage of the unique tumor physiology characterized by a high density of abnormal blood vessels, high vascular permeability, and decreased rate of clearance due to a lack of lymphatic drainage, all of which act together to cause accumulation of macromolecules through the enhanced permeability and retention (EPR) effect (7). The magnitude of this effect is affected by a number of parameters that are either host-related (tumor perfusion, vascularity, vascular permeability) or nanoparticle-related (plasma half-life, clearance, hydrodynamic size, surface char...

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…PET studies of CRLX101 show that polymer-conjugated CPT has a t 1/2 of approximately 24 h in mice, and that the measured tumor permeability data are consistent with an approximately 30-nm nanoparticle and not an individual polymer strand (13). Additionally, PET-labeled single polymer strands cleared from mice via urinary excretion in less than 1 h. Imaging of mouse tumors indicates that CRLX101 does reach tumors intact (13), and high-resolution TEM images reveal direct visual evidence for intact nanoparticles within tumor cells (15). Thus, we will refer to the polymer-conjugated CPT as the nanoparticle CRLX101.…”

“…The synthesis and properties of preclinical nanoparticles of CRLX101 have been described previously (12)(13)(14)(15)(16)(17)(18). The nanoparticles were 20 to 30 nm in diameter, and characterization studies demonstrated that all the polymer chains were contained within the nanoparticles (i.e., no free polymer chains) (13).…”

“…The diameter of approximately 20 to 30 nm allows for movement through solid tumors (13,21) and the slightly negative ζ-potential at this size helps to minimize uptake by the mononuclear phagocyte system (22). CRLX101 is designed to have high solubility, to circulate and extravasate into solid tumors via their leaky vascular as an intact nanoparticle (13,15), to enter cancer cells, and to slowly release the active form of CPT for extended periods of time to enhance its mechanism of action (16).…”

“…CRLX101 has been shown to circulate in rodents with a t 1/2 of approximately 1 d (13,14) and accumulate in solid tumor xenografts as an intact nanoparticle (13). Additionally, the CRLX101 nanoparticles have been observed [by transmission EM (TEM) images] to localize into cancer cells in a mouse xenograft from a tail vein injection (15).…”

“…The CRLX101 nanoparticle is designed to disassemble when the CPT is released to give individual polymer strands that are synthesized to have molecular weights sufficiently small to allow for clearance via the kidney (Fig. 1B) (12,13).…”