Tomato Bushy Stunt Virus Nanoparticles as a Platform for Drug Delivery to Shh-Dependent Medulloblastoma.

Chiara Lico,Roberta Bernini,Selene Baschieri,Luca Santi,Simonetta Pazzaglia,Caterina Arcangeli,Luca Marchetti,Flavia Novelli,Maurizio S Podda,Barbara Tanno,Paola Giardullo,Mariateresa Mancuso

doi:10.3390/ijms221910523

Abstract

Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.

Highlights

Chemotherapy plays a pivotal role in the fight against tumors; systemic administration often results in uneven biodistribution and produces severe effects on healthy cells, limited accumulation in the target tissue and emergence of drug-resistant cancer cells [1]
Construction, Production and Purification of WT and Chimeric Tomato bushy stunt virus (TBSV) NPs cTBSV NPs were constructed by engineering the viral genome to display on their surface tumor targeting peptides as fusion to the C-terminus of the coat protein (CP)
The peptide RGD, in single or double copy (RiGiD), found in the sequences of extracellular matrix proteins, was selected because it is able to bind to integrins, a family of transmembrane receptors overexpressed on different types of tumor cells, and cTBSV carrying this peptide was used as a positive control [13]

Summary

Introduction

Chemotherapy plays a pivotal role in the fight against tumors; systemic administration often results in uneven biodistribution and produces severe effects on healthy cells, limited accumulation in the target tissue and emergence of drug-resistant cancer cells [1]. Targeted treatments are urgent for tumors such as. Several nanoparticles (NPs)-based delivery systems have been developed in order to improve the pharmacokinetic and/or targeting of drugs [5]. These delivery systems, used to encapsulate, absorb or conjugate the therapeutic molecules, may allow the re-evaluation of compounds formerly considered too toxic for systemic administration

Methods

Results

Conclusion