Ninja Theranostics for overcoming the drug delivery barriers to pediatric brain tumor Project Summary/Abstract Pediatric brain tumors (PBTs) are the leading cause of cancer-related morbidity and mortality among children. Vincristine (VCR) has been approved to treat PBTs, but its inability to cross blood brain barrier (BBB)/blood brain tumor barriers (BBTB) and dose-limiting neuropathy have greatly limited its clinical application. Thus the main challenge is to deliver sufficient amount of drugs to the hard reached PBTs, while multiple barriers including the severe destabilizing condition in the blood, BBB/BBTB, relatively weak enhanced permeability and retention (EPR) effects in brain tumor, and limited uptake in tumor cells should all be taken into consideration to design a whole-process delivery strategy. The goal of this SBIR is to develop a highly effective and less toxic Ninja-type nanoparticle loaded VCR (Ninja-V) against PBTs in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to the FDA. Ninja-V could overcome multi-barriers with several ultimate techniques. It integrates unique stimuli- responsive crosslinking strategy and transformable multistage targeting approach (sequentially targeting BBB/BBTB with glucose transporter as well as tumor cells via overexpressed sialic acid) in a simple one design. This nanoparticle could allow image-guided drug delivery, improve the drug delivery efficacy, and minimize the neurotoxicity. Our hypotheses are: 1) The 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 penetration, thus greatly improving the therapeutic index and minimizing the toxicity. and 2) the Ninja-V consist of stimuli-responsive crosslinkages will minimize premature drug release in blood circulation allow while sparing normal brain tissue and normal organs, and therefore will be more efficacious and less toxic against PBTs compared to the free drug form. State-of-the-art design of nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of ease of large-scale production, fine-tunable and highly reproducible structure and properties. It will address many translational barriers of nanotherapeutic agents. This simple and unique design of crosslinking and dual targeting nanoparticles with sequential targeting capability, and stimuli-responsive and transformable properties are highly innovative. It is an excellent approach to prevent premature drug release during circulation and deliver high concentrations of drug to tumors. It is expected that this research will lead to a new method for the management of PBTs.
The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of vincristine (Ninja-V) for pediatric brain cancer therapy. Unique features of Ninja-V are (i) there is minimal premature drug release from the cross-linked nanoparticles in blood circulation; (ii) decorated with glucose derivatives allowing glucose transporter mediated transcyosis through the BBB/BBTB; (iii) tumor microenviroemnt acidic pH responsive transformation into smaller nanoparticles (<30 nm) allowing efficiently penetrating poorly permeable tumors including PBTs; (iv) secondary tumor sialic acid targeting strategy greatly enhance the uptake into tumor cells; (v) the stability and targeting effects could be fine-tuned via different ratios of telodendrimers with boronate acid and glucose derivative; and (vi) decrease neurotoxicity; We expect this smart nanoparticle drug to be much more efficacious and less toxic than the conventional and liposomal vincristine formulations. This project will have a tremendous impact on the improvement of survival rate and quality of life of patients with pediatric brain tumors.
