Ninja Theranostics for overcoming the drug delivery barriers to pediatric brain tumor

Ninja Theranostics for overcoming the drug delivery barriers to pediatric brain tumor Project Summary Abstract Pediatric brain tumorsPBTsare the leading cause of cancer related morbidity and mortality among childrenVincristineVCRhas been approved to treat PBTsbut its inability to cross blood brain barrierBBBblood brain tumor barriersBBTBand dose limiting neuropathy have greatly limited its clinical applicationThus the main challenge is to deliver sufficient amount of drugs to the hard reached PBTswhile multiple barriers including the severe destabilizing condition in the bloodBBB BBTBrelatively weak enhanced permeability and retentionEPReffects in brain tumorand limited uptake in tumor cells should all be taken into consideration to design a whole process delivery strategyThe goal of this SBIR is to develop a highly effective and less toxic Ninja type nanoparticle loaded VCRNinja Vagainst PBTs in preclinical animal modelsproviding validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to the FDANinja V could overcome multi barriers with several ultimate techniquesIt integrates unique stimuliresponsive crosslinking strategy and transformable multistage targeting approachsequentially targeting BBB BBTB with glucose transporter as well as tumor cells via overexpressed sialic acidin a simple one designThis nanoparticle could allow image guided drug deliveryimprove the drug delivery efficacyand minimize the neurotoxicityOur hypotheses areThe transformable multistage targeting Ninja V will be able to cross the BBB BBTB and facilitate the delivery of encapsulated drugs specifically to PBTs with enhanced tumor cell uptake and deep tissue penetrationthus greatly improving the therapeutic index and minimizing the toxicityandthe Ninja V consist of stimuli responsive crosslinkages will minimize premature drug release in blood circulation allow while sparing normal brain tissue and normal organsand therefore will be more efficacious and less toxic against PBTs compared to the free drug formState of the art design of nanocarriers via engineering telodendrimers with well defined structures represents the frontier development of the nanomedicinein terms of ease of large scale productionfine tunable and highly reproducible structure and propertiesIt will address many translational barriers of nanotherapeutic agentsThis simple and unique design of crosslinking and dual targeting nanoparticles with sequential targeting capabilityand stimuli responsive and transformable properties are highly innovativeIt is an excellent approach to prevent premature drug release during circulation and deliver high concentrations of drug to tumorsIt is expected that this research will lead to a new method for the management of PBTs Narrative The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of vincristineNinja Vfor pediatric brain cancer therapyUnique features of Ninja V areithere is minimal premature drug release from the cross linked nanoparticles in blood circulationiidecorated with glucose derivatives allowing glucose transporter mediated transcyosis through the BBB BBTBiiitumor microenviroemnt acidic pH responsive transformation into smaller nanoparticlesandltnmallowing efficiently penetrating poorly permeable tumors including PBTsivsecondary tumor sialic acid targeting strategy greatly enhance the uptake into tumor cellsvthe stability and targeting effects could be fine tuned via different ratios of telodendrimers with boronate acid and glucose derivativeandvidecrease neurotoxicityWe expect this smart nanoparticle drug to be much more efficacious and less toxic than the conventional and liposomal vincristine formulationsThis project will have a tremendous impact on the improvement of survival rate and quality of life of patients with pediatric brain tumors