Abstract 4579: Pathogen-derived targets for the delivery of chemotherapeutics to the brain
Authors: McCall Rebecca L. , Householder Kyle T. , Chung Eugene P. , Sirianni Rachael W. 
Published: May 2015

Introduction

The blood-brain barrier (BBB) is a key obstacle to achieving better treatment of glioblastoma multiforme (GBM). Tight junctions in the BBB prevent the passage of most systemically administered drugs, and transport proteins within it, such as P-glycoprotein, serve to shuttle out any unrecognized molecules. Recently, receptor-mediated strategies for bypassing these barriers have come to the forefront as a novel way of promoting the passage of therapeutics into the brain. For example, the rabies virus is a well-known pathogen that travels to the brain via retrograde transport along the axons of affected peripheral nerves. By using a peptide derived from the primary protein involved in the transport of the rabies virus we remove the associated pathogenicity but maintain its neuroinvasive ability. In this work, our goal was to evaluate the ability of rabies virus glycoprotein peptide (RVG) to improve the accumulation of drug-loaded nanoparticles in the brain for the treatment of GBM. Drugs are slowly released from the nanoparticle over time, enabling effective treatment of intracranial tumors via systemic therapy.

Materials and Methods

PLGA nanoparticles encapsulating either a fluorescent small molecule for cell uptake studies or the chemotherapeutic camptothecin for tumor treatment studies were prepared via the single-emulsion method. Nanoparticles were surface-modified with either rabies virus glycoprotein (RVG, targeted) or biotin (control). Nanoparticle uptake in human and mouse GBM cells was quantified by measuring fluorescence in cell lysates. Orthotopic brain tumors were induced in albino C57BL/6 mice with GL261 luciferase-expressing cells. Tumor growth was monitored via non-invasive imaging of luciferase expression using the IVIS system.

Results and Discussion

PLGA nanoparticles were determined to be 124nm ± 41nm (RVG) or 134nm ± 39nm (biotin) in diameter. Cell data indicated an increase in the uptake of RVG particles compared to the biotin control, suggesting that the RVG peptide enhances the specificity of the nanoparticle internalization by GBM cells. Tumor growth was inhibited in vivo by ∼80% compared to the no-treatment group on day 19 post-tumor induction. Median survival time was increased from 13 days to 23 days (n=6) for RVG-modified, CPT-loaded nanoparticles vs no-treatment control, indicating a substantial treatment benefit.

Conclusion

Presented here are a series of in vitro and in vivo studies demonstrating that surface modification of polymeric nanoparticles with RVG facilitates their uptake in glioma cells specifically, and highly drug-loaded, systemically administered targeted formulations were capable of slowing the growth of tumor cells to increase survival in an orthotopic GBM mouse model. In future work, we are interested to explore other neurotropic pathogen and toxin mechanisms, such as tetanus toxin and chlorotoxin, to be able to target tumors for growth inhibition in vivo.

Citation Format: Rebecca L. McCall, Kyle T. Householder, Eugene P. Chung, Rachael W. Sirianni. Pathogen-derived targets for the delivery of chemotherapeutics to the brain. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4579. doi:10.1158/1538-7445.AM2014-4579