Fluorescent nanoparticles to improve resections of microscopic pancreatic tumors

ABSTRACT A primary challenge in pancreatic cancer is preventing tumor recurrence in patients following acurative intentresection procedureyear survival rateIt is believed thatin a subset of patientsthe primary cause of tumor recurrence is small sub cm and sub mm disease that is unseen andthereforeun resected at the time of surgeryTo address this problemresearchers are developing new Fluorescently Guided Cytoreductive SurgeryFGCStechniques with the goal of enabling surgeons to intraoperatively detect and resect sub cm and sub mm tumorsThese techniques administer a fluorescent probe such as a fluorescently conjugated antibodysmall moleculepeptidequantum dot or nanoparticle that localizes to tumors thereby facilitating identification of tumor tissueLocalization to the tumor is generally achieved via one of two broadly classified targeting strategiesPassive Targetingvia the enhanced permeability and retentionEPReffectorActive Targetingthrough the incorporation of a targeting moiety or antibody into the probeHowevernone of these technologies is able to identify sub cm and sub mm diseaseThis proposal develops a novelpatentedfluorescent probethehighlyfluorescent rhodamine labeled expansile nanoparticleHFR eNPthat targets tumors via a unique MaterialsBased Targeting strategyThis mechanism leverages both the material functionality of the nanoparticle polymere gswellingand fundamental pathophysiological properties of tumorse gincreased metabolic rateto achieve tumor specific localization with andgtaccuracyWe hypothesize that by using HFR eNPs to guide cytoreductive surgery of disseminated sub cm and sub mm tumorswe will significantly improve overall survival compared to unguided resectionsPreliminary data demonstrateHFR eNPs possesstofold increased fluorescence compared to equivalent concentrations of free rhodamine and can be sterilized with gamma irradiation without significant loss of this fluorescencelarge scale production of HFR eNPs on a clinicali eliter batchscalenon toxicity of the HFR eNPs in vitro and in vivosensitive and specific localization to sub cm and sub mm pancreatic tumors in vivoandproof of concept HFR eNP guided cytoreductive surgery to remove largeandgtcmsub cm and sub mm tumors in vivoTwo key Go No Go decisions regarding the commercialization of this technology are addressed in this proposalFirstin order to be used clinicallya sterilization protocol must be developed that does not alter the HFR eNP polymer or quench the rhodamine fluorescenceAndfollowing sterilizationthe in vivo functionality tumor localization of the particles must be confirmedSecondthe benefit afforded by using HFR eNPs to guide the resection of pancreatic tumorsin particular sub cm and sub mm tumorsmust be quantified through an in vivo cytoreductive surgery modelThusthe aims of this proposal areAimSterilize HFR eNPs via Gamma irradiation and confirm tumor localization post sterilizationAimDetermine the improvement to survival afforded by HFR eNP guided surgical resections PROJECT NARRATIVE A subset of pancreatic cancer patients are candidates to receivecompletetumor resectionsi eremoval of all tumorwhich is expected to be curativehowevermost of these patients suffer from high rates of tumor recurrence a problem that likely occurs because of small sub centimeter and sub millimeter tumors that are unseenand therefore un removedat the time of surgeryThis SBIR Phase I proposal furthers the development of a highly fluorescent nanoparticle technology that employs a novel Materials Based Targeting strategy to localize specifically to sub cm and sub mm tumorsThese nanoparticleswhose fluorescence can be seen with the naked eyethis is in contrast to most fluorescent surgical guides which require complicated and expensive cameras and imaging equipment to seemay provide an inexpensiveeasy to use technology that will enable surgeons to obtain more complete removal of pancreatic tumors andtherebyto improve patient outcomes and survival