Abstract SY20-03: Micelle-based targeting radio-nanotheranostic agents against cancer

Abstract

Abstract We have developed a novel amphiphilic polymer (telodendrimer), comprised of linear polyethylene glycol and cholic acid cluster, that can self-assemble under aqueous condition to form stable micelles. We have succeeded in loading the nanoparticles with several different hydrophobic drugs. These include paclitaxel, etoposide, vincristine, doxorubicin, bortezomib, sorafenib, lapatinib, temsirolimus, and dexamethasone. This nanoplatform is highly versatile. Particle size can be readily tuned by varying the configuration and composition of the telodendrimer. Nanoparticles of various sizes loaded with DiD, a near infrared hydrophobic dye, were prepared and their biodistribution evaluated in nude mice bearing ovarian cancer xenografts. Particles smaller than 60 nm preferentially targeted the tumors whereas particles at 150 nm were found to concentrate at the liver and lung but with low tumor uptake. The surface chemistry can be easily modified by tethering various acidic or basic peptides to the distal polyethylene glycol tail of the telodendrimers. Undesirable liver uptake was very high for those nanoparticles with high surface charges, either positive or negative. In contrast, liver uptake was very low but tumor uptake was very high when the surface charge was slightly negative. Ligation of tumor targeting ligands to the particle surface further improved tumor targeting and intracellular uptake at the tumor site, resulting in better therapeutic efficacy in xenograft model. In addition to xenograft models, we have also demonstrated that the nanoparticles could preferentially target early spontaneous mammary tumors of PyV-MT transgenic mice. We have just completed a phase I study of placiltaxel-loaded nanoparticles in companion dogs with lymphoma and showed that the drug is safe. Maximum tolerated dose (MTD) was determined to be 97mg/meter square. A phase II study of the same nanoformulation in companion dogs with solid tumor is ongoing. The nanoparticles are stable both in vitro and in vivo. Additional stability of the nanoparticles can be achieved by chemical stitching of adjacent telodendrimers with disulfide bonds after drug loading. Such crosslinked nanoparticles are extremely stable, even in the presence of sodium dodecyl sulfate, a strong ionic detergent. Drug release from crosslinked nanoparticles is much slower than that from non-crosslinked nanoparticles. However, upon addition of 10 mM of glutathione, drug release rate from the crosslinked nanoparticles paralleled that of the non-crosslinked nanoparticles. Since glutathione level is high at the tumor site and inside the tumor cells, it is expected that the disulfide bonds of such crosslinked nanoparticles will be reduced after taken up by tumor cells. Therapeutic studies in xenograft model indeed confirmed that crosslinked paclitaxel-loaded nanoparticle was more efficacious than non-crosslinked nanoparticles. For radioimaging studies, the lysine side chain of telodendrimers was radioiodinated with [I-125]-labeled Bolton-Hunter reagent and then loaded with paclitaxel to form stable [I-125]-labeled nanoparticles. MicroCT/SPECT imaging study with this novel radioprobe in nude mice bearing ovarian cancer xenograft revealed gradual uptake of the radioprobe by the tumor within the first 24 hours. At the 24-hour timepoint, significant amount of radioprobe remained in the circulation. However, by 48 hours, most of the circulating radioprobe disappeared while tumor uptake remained high as late as 94 hours. Liver, spleen, lung and renal uptake were minimal. Together, these studies suggest that an optimal therapeutic nanoparticle should be less than 60 nm in diameter, have slightly negative surface charge, display cancer targeting and pro-endocytotic ligand(s), and be cross-linked by disulfide bonds after drug loading. Such nanoparticle drug is expected to have minimal premature drug release, be preferentially taken up by solid tumors via the enhanced permeability (EPR) effect, enter the tumor cells via the tumor cell targeting ligands, and drug released inside the tumor cells where the glutathione level is high. The addition of an imaging radionuclide to such nanoparticle will make it a highly effective radio-nanotheranostic agent against cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY20-03. doi:10.1158/1538-7445.AM2011-SY20-03