LAMNOTHERAPEUTICS, INC. — Department of Health and Human Services SBIR Phase I: NICHD

Description

DESCRIPTION provided by applicant Treatment of high risk neuroblastoma remains one of the greatest challenges for pediatric oncologists Vincristine VCR is effective for the treatment of neuroblastoma The clinical efficacy of VCR is limited however due to its neurotoxic effect unfavorable pharmacokinetics and poor drug exposure and delivery to target tissues Marqibo r is the first liposomal formulation of VCR that could improve the pharmacokinetics and toxicity profiles of VCR However the lack of pegylation and relatively large size nm of Marqibo r may result in unfavorable biodistribution and less deeper tumor penetration Marqibo r is only used in clinic to treat adults with a very rare type of leukemia called Philadelphia chromosome negative Ph acute lymphoblastic leukemia ALL The safety and effectiveness of Marqibo r in pediatric patients have not been established It has been reported that smaller nanoparticles such as nm micelles could penetrate poorly permeable tumors for a better anti tumor effect The smart VCR loaded micellar nanoparticles nano VCR with smaller size nm and on demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against neuroblastoma therefore have great commercial potentials to lead to a marketable VCR nanoformulation for the treatment of neuroblastoma The overall goal of this Phase I SBIR proposal is to develop highly effective and less toxic micellar formulation of VCR against neuroblastoma in preclinical animal models providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA Our hypotheses are i The smaller crosslinked micelle formulation of VCR nano VCR compared to its free form are more efficacious and less toxic against neuroblastoma ii Fine tuning the level of disulfide crosslinking of nano VCR will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells therefore will greatly improve the efficacy and toxicity profile and iii N acetyl cysteine when administered to the animal hrs after the initial administration of nano VCR will further improve its therapeutic index Nano VCR will be further decorated with a highly potent ligand to enhance their targeting capability to av integrin overexpressed in neovasculatures of neuroblastoma In this proposal these hypotheses will be tested in murine neuroblastoma tumor model The project addresses a critical issue in neuroblastoma therapy to reduce drug toxicity and increase drug efficacy State of the art design of the nanocarriers via engineering telodendrimers with well defined structures represents the frontier development of the nanomedicine in terms of multiple functions fine tunable and highly reproducible structure and properties The use of reversibly crosslinked micelles with fine tuned stability and on demand drug releasing property to delivery VCR against neuroblastoma is highly innovative Itandapos s an excellent approach to prevent pre mature drug release during circulation and deliver high concentrations of drug to tumor site It is expected that this research will lead to new approach for neuroblastoma therapy PUBLIC HEALTH RELEVANCE The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of VCR nano VCR for neuroblastoma therapy Unique features of nano VCR are i the size of the micelle formulation of VCR is under nm which is more suitable for penetrating poorly permeable tumors including metastatic neuroblastoma ii there is minimal premature drug release from the cross linked nanoparticles in blood circulation iii a highly potent av integrin targeting ligand will be used to facilitte in vivo delivery of nano VCR to high risk neuroblastoma iv VCR resistance may be overcome by using these nanoparticles that are not recognized by P glycoprotein one of the main mediators of multidrug resistance thereby resulting in an increased intracellular concentration of drugs v the stability and drug release of nano VCR can be fine tuned via different level of disulfide crosslinking which will greatly improve the pharmacokinetics efficacy and toxicity profile and vi NAC will be used as an on demand drug release triggering agent to enhance the therapeutic efficacy of the nanoparticle drugs We expect these smart nanoparticle drugs to be much more efficacious and less toxic than the conventional and liposomal VCR formulations This project will have a tremendous impact on the improvement of survival rate and quality of life of pediatric patients with neuroblastoma