Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma

DESCRIPTION (provided by applicant): The long-term clinical objective of this proposal Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma is the development of a novel therapeutic and diagnostic drug delivery technology for sp ecific use in the treatment of non-Hodgkin's lymphoma. The combination of non-invasive imaging techniques such as MRI and targeted drug delivery using PLGA nanoparticles is a primary focus of Carigent Therapeutics, and we believe that there are significant clinical benefits to be gained from such a technology. The controlled, sustained release of chemotherapeutics from biodegradable PLGA nanoparticles has been shown to be effective in increasing drug efficacy due to the ability to better deliver drug intrac ellularly and for extended periods of time. Carigent Therapeutics has developed a methodology for surface-modifying PLGA nanoparticles, enabling not only the addition of high densities of surface PEG groups to prevent clearance by the body, but also target ing moieties such as antibodies to improve the specificity and potency against specific cells. Additionally, we have shown that we can tether image contrast agents, including gadolinium, to enable non-invasive imaging techniques of particle biodistribution and drug delivery; this may lead to improved tumor identification and an overall reduction in exposure of patients compared to state of the art staging techniques relying on CT or PET. Towards this goal, the proposal is structured into 3 specific aims: (1 ) the formulation and characterization of PLGA nanoparticles with novel and proprietary surface modifications; (2) the in vitro optimization of nanoparticle surface composition; and (3) the in vivo evaluation of nanoparticle pharmacokinetics and distributi on in a mouse model, and diagnostic potential and drug efficacy in a murine lymphoma model. The early portions (specific aims 1 and 2) of the project involve the in vitro characterization and optimization of the nanoparticle system; including activity and release of drug from nanoparticles in a simulated physiologic environment. We believe that completion of these first two specific aims will lead to a doxorubicin-loaded, MR- sensitive nanoparticle capable of circulating for extended times, allowing localiz ation to, attachment, and internalization by B-cells. In specific aim 3, this optimized formulation will be tested in a mouse model of lymphoma to establish preclinical data on drug efficacy and diagnostic potential. PUBLIC HEALTH RELEVANCE: The proposal t itled Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma outlines the development of a tumor-targeting, MR-sensitive, doxorubicin-loaded polymeric nanoparticle designed to improve the safety and efficacy of doxorubicin while s imultaneously enabling non- invasive imaging of tumors and tracking of drug delivery. This technology will not only improve the safety and efficacy of a widely-used chemotherapeutic in the treatment of lymphoma, but also improve image-based staging techniq ues and tracking of drug delivery.