Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells

Abstract

A major limitation in the 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. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets.

Intramedullary spinal cord tumors: a review of current and future treatment strategies

“…These nanoparticles successfully penetrated brain parenchyma, but specifically bound glioblastoma cells, without significant off-target effects. 62 Additionally, the nanoparticles showed reduced nonspecific binding of the brain extracellular matrix. By specifically targeting cancer cells, as demonstrated via Fn14 conjugation in the Schneider et al study, 62 it is possible that nanoparticles that specifically target cancer cells could be effectively used to deliver drugs to remote tumor cells that otherwise escape resection.…”

“…However, there have been promising results from nanomedicine approaches to brain tumors. For instance, Schneider et al 62 show that the use of drug-loaded nanoparticles can be targeted to specifically bind glioblastoma cells via conjugation with the protein fibroblast growth factor-inducible 14 (Fn14). These nanoparticles successfully penetrated brain parenchyma, but specifically bound glioblastoma cells, without significant off-target effects.…”

Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma

“…NPs targeted to Fn14-positive GBM cells using a monoclonal antibody improved NP tumor localization and internalization. 48,68 Thus, a similar targeting strategy may enhance the delivery of platinum compounds specifically to GBM cells, improving efficacy and minimizing toxicity.…”

“…53 NPs may improve the delivery of therapeutics to invasive GBM cells by overcoming such drug delivery challenges. 48 Furthermore, a major reason for failure of platinumbased chemotherapeutics in GBM patients is off-target toxicity. NP formulations may effectively address this issue; indeed, NPs have been shown to reduce toxicity compared to free drug.…”

“…These strategies include (a) increasing BBB permeability, 45 (b) delivering cisplatin within biodegradable polymer implants in the tumor bed of patients, 46 and (c) bypassing the BBB via delivery under low sustained pressure ('convection') directly into the brain through an implanted catheter(s), an approach termed as convection enhanced delivery (CED). 47 The expanding field of nanomedicine offers a variety of drug formulation options to improve platinum-based therapies, such as (a) increased solubility and increased blood half-life, (b) reduced side-effects through targeted delivery and broader tissue distribution in mouse intracranial glioma models, 48 (c) controlled and sustained drug release, and (d) simultaneous incorporation and delivery of other anticancer drugs for combination therapy. 49 …”