3P BIOTECHNOLOGIES, INC. — Department of Health and Human Services SBIR Phase II: 102

Description

Technical AbstractAs with many chemotherapeutic drugstaxanes exhibit poor oral bioavailabilityhencethey are administered intravenouslyi vThis regimen results in significant toxicitiesdue to both the high drug dose and vehicleCremophore ELRusedAttempts made to develop an oral chemotherapeuticusing liposomes and polymeric nanoparticles as carriershave not made it to the clinicdue to their inherent limitationsIn Phase IP Biotechnologies proposed to develop aplatformtechnology for the oral delivery of chemo drugs and other therapeutics via bovine milk derived nanoparticles known as exosomesThe Phase I specific aims were toisolate and characterize milk exosomesprepare exosomalExoformulations of the chemo drugpaclitaxelPACand the plant therapeuticwithaferin AWFAandshow that Exo formulations enhance therapeutic responses while lacking toxicityPhase I proved feasible based on the following findingsadifferential centrifugation of raw bovine milk provided exosomesbexosomes were taken up by cells in vitro and in vivocExo formulations of PACExoPACTMWFAExoWFATMand other compounds were developedwhich showed higher anti proliferativeanti inflammatoryand anti cancer activities vsthe free drugs against lung cancer cellsboth in vitro and in vivoand dmilk exosomes lacked cross species reactivity in wild type miceAdditional data generated preliminary to Phase II showed that bovine colostrum powder produces exosomes with a yield and purity that are several fold higher than can be obtained from fresh milkresulted in significantly higher drug loading than milkand that exosomes can be functionalized with folic acid for tumor targetingIn Phase IIa team of multidisciplinary researchers will advance this technology by pursuing the following specific aimsEstablish the reproducibility of colostrum exosome yieldmaximize drug loading of the taxane PACidentify and optimize loading of a tumor targeting ligandand test the resulting formulations for antiproliferative and anti inflammatory activities against human lung cancer cells in vitroDetermine the efficacy of Exo formulation of PACExoPACTMand functionalized ExoPACTM for tumor targetabilityminimizing off target sitesusing orthotopic xenograftpatient derived tumor xenograftPDXand K ras spontaneous tumorsDetermine toxicities of the ExoPACTM and functionalized ExoPACTM formulationsanalyze blood and tissue levels of PACPK PD studiesand determine stability of the formulationsThe innovation lies in the use of standardized colostrum derivedfunctionalized exosomes for oral delivery for cancer therapeutics to circumvent bioavailability issuesThe current taxane therapeutic market is dominated by a single productAbraxanean i valbumin PAC productA product that performs similar to or better than Abraxanewould potentially generate U Sand worldwide markets of over $billion and $billionrespectivelyIf we are successful in achieving our objectives we will apply for Phase IIbwhere we will establish large scale production of ExoPACTM and will conduct Phaseclinical trialsOncologists on the Advisory Board ofP Biotechnologies will guide as we advance these drug formulations