TRACEABLE CANCER-TARGETED NANOPARTICLES FOR LOCALIZED CHEMOTHERAPY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nanotechnology has opened new avenues toward the development of site specific chemotherapy. We are designing nanoparticles that carry either a chemotherapeutic or a contrast agent for magnetic resonance imaging for application in cancer treatment and diagnosis, respectively. Nanometer-sized particles have been shown to selectively accumulate in tumors due to immature, leaky vasculature. Our goal is to augment this selective accumulation by adding a targeting peptide to the nanoparticle surface. Our studies to date have focused on fabricating homogeneous populations of ~50, ~250, and ~500 nm nanoparticles of biodegradable poly(dl-lactic-co-glycolic acid) (PLGA). The cyclic peptide, cLABL, has been proven to bind with high affinity specificity to intracellular cell adhesion molecule-1 (ICAM-1), which is upregulated in lung cancer, pancreatic cancer, prostate cancer, etc. We have tethered cLABL to the surface of PLGA nanoparticles and quantified the surface density by a detecting the presence of the di-sulfide bond on the peptide via a ThioGlo fluorescence assay. To increase the accessibility of cLABL to ICAM-1 on the surface of cells, we have attached carbodiimide or polyethylene glycol spacers to the nanoparticle surface and subsequently reacted cLABL to the distal end of these spacers. In a parallel study, we have partnered with Dr. Mehmet Bilgen at the Hoglund Brain Imaging Center at the University of Kansas Medical Center to test our ability to encapsulate gadolinium into PLGA nanoparticles as an MRI contrast enhancing agent. He has verified the ability of these nanoparticle formulations to enhance magnetic resonance images in a concentration dependent manner. In ongoing studies, we are fabricating fluorescent nanoparticles with and without cLABL attached. These formulations will be incubated with cancerous Caco-2 or endothelial cell monolayers (HUVECs) to quantify the adhesion or endocytosis of cLABL-nanoparticles compared to unlabeled nanoparticles. In parallel, we plan to compare the biodistribution of cLABL-nanoparticles to unlabeled nanoparticles via MRI.