Abstract B46: Development of biodegradable Fn14-targeted nanoparticles for controlled drug delivery for invasive brain tumors
Authors: Perez Jimena G. , Schneider Craig S. , Connolly Nina , Winkles Jeffrey A. , Woodworth Graeme F. , Kim Anthony J. 
Published: May 2016

Abstract
Introduction: A major limitation associated with treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. Recent advances in nanotechnology have allowed the incorporation of different therapeutic and targeting agents into nanoparticles offering the potential for improved detection, prevention, and treatment of various cancers. A promising way to target brain-invading GBM cells is via targeted therapeutics that bind to the cell surface receptor fibroblast growth-factor-inducible 14 (Fn14), which is specifically upregulated on the surface of invading GBM cells.
Objective: In this study, we aim to develop a biodegradable nanoparticle platform that employs a dense, low-molecular weight PEG coating coupled with a Fn14-specific monoclonal antibody (mAb) in order to maximize brain tissue penetration and GBM cell targeting
Materials and Methods: We previously showed that PEG-coated model polystyrene (PS) nanoparticles conjugated to the Fn14 mAb named ITEM4 bind strongly and selectively to the Fn14 extracellular domain. We synthesized a variety of PS-based brain tissue penetrating PEG-coated nanoparticles and characterized the (i) specificity of nanoparticle binding to Fn14 and (ii) nonspecific binding to brain ECM components, using surface plasmon resonance (SPR) and multiple particle tracking (MPT) assays. In parallel, we are transferring these findings and methodology towards formulation of biodegradable drug-loaded nanoparticles with matched size, surface chemistries, and Fn14 binding affinities for controlled drug delivery into brain tumors. We are loading biodegradable nanoparticles, including poly(lactic-co-glycolic acid) (PLGA), polyglutamic acid (PGA), and polysebacic acid (PSA) polymer platforms, with chemotherapeutics (i.e. cisplatin and bis-chloroethylnitrosurea (BCNU)) to study the optimization of drug-loading with particle penetration and targeting.
Results: The equilibrium binding affinity (KD) of nanoparticles scaled nearly linear with the surface density of the ITEM4 molecules, indicating that the adhesiveness of nanoparticle formulations depends on the ITEM4 molecular presentation on the nanoparticle surface. PEG-coated Fn14-targeted nanoparticles of ~100 nm in diameter were able to rapidly penetrate brain tissue by MPT experiment in rat brain slices. In contrast, uncoated nanoparticles were immobilized in brain tissue. We have preliminary data that suggests we can develop biodegradable nanoparticles that provide sustained release of a wide range of rugs over several days. We have successfully encapsulated cisplatin and BCNU to the polymer backbone of PGA and PLGA containing a low-molecular weight PEG coating. Additional surface modifications have been made to enable Fn14 targeting by conjugating ITEM4 on the particle surface. Particles will undergo complete physicochemical characterization to optimize Fn14 targeting, nanoparticle movement, drug release kinetics, and in vivo efficacy.
Conclusion: We have developed a nanoparticle platform that can diffuse and penetrate within brain tissue and selectively target remote experimental GBM tumors. Using this approach we can optimize therapeutics versions to improve drug efficacy while limiting many of the side effects and risks of free drug and non-targeted therapies.
Citation Format: Jimena G. Perez, Craig S. Schneider, Nina Connolly, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim. Development of biodegradable Fn14-targeted nanoparticles for controlled drug delivery for invasive brain tumors. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B46.