Featured Article: Delivery of chemotherapeutic vcMMAE using tobacco mosaic virus nanoparticles

Abstract

Due to side effects associated with systemic chemotherapy, there is an urgent need for the development of novel drug delivery systems. We focus on the highaspect ratio nanotubes formed by tobacco mosaic virus (TMV) to deliver antimitotic drugs targeted to non-Hodgkin's lymphoma. Many synthetic and biologic nanocarriers are in the development pipeline; the majority of systems are spherical in shape. This may not be optimal, because high-aspect ratio filaments exhibit enhanced tumor homing, increased target cell interactions and decreased immune cell uptake, and therefore have favorable properties for drug delivery compared to their spherical counterparts. Nevertheless, the synthesis of high-aspect ratio materials at the nanoscale remains challenging; therefore, we turned toward the nucleoprotein components of TMV as a biologic nanodrug delivery system. This work presents groundwork for the development of plant virus-based vehicles for use in cancer treatment. AbstractThe first-line treatment for non-Hodgkin's lymphoma is chemotherapy. While generally well tolerated, off-target effects and chemotherapy-associated complications are still of concern. To overcome the challenges associated with systemic chemotherapy, we developed a biology-inspired, nanoparticle drug delivery system (nanoDDS) making use of the nucleoprotein components of the tobacco mosaic virus (TMV). Virus-based nanoparticles, including the high-aspect ratio soft nanorods formed by TMV, are growing in popularity as nanoDDS due to their simple genetic and chemical engineerability, size and shape tunability, and biocompatibility. In this study, we used bioconjugation to modify TMV as a multivalent carrier for delivery of the antimitotic drug valine-citrulline monomethyl auristatin E (vcMMAE) targeting non-Hodgkin's lymphoma. We demonstrate successful synthesis of the TMV-vcMMAE; data indicate that the TMV-vcMMAE particles remained structurally sound with all of the 2130 identical TMV coat proteins modified to carry the therapeutic payload vcMMAE. Cell uptake using Karpas 299 cells was confirmed with TMV particles trafficking to the endolysosomal compartment, likely allowing for protease-mediated cleavage of the valine-citrulline linker for the release of the active monomethyl auristatin E component. Indeed, effective cell killing of non-Hodgkin's lymphoma in vitro was demonstrated; TMV-vcMMAE was shown to exhibit an IC 50 of $250 nM. This study contributes to the development of viral nanoDDS.

Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

“…Particle uptake studies confirmed internalization into endolysosomal components with likely protease-mediated drug release. In vitro studies confirmed cytotoxicity toward the non-Hodgkin's lymphoma cell line, Karpas 299, exhibiting an IC 50 of~250 nM [55].…”

Controlled phage therapy by photothermal ablation of specific bacterial species using gold nanorods targeted by chimeric phages

“…Thiol Functionalization of Phages. Phages were treated with SATP for chemical modification of accessible amine groups of the capsid based on a known protocol (56). See SI Appendix for more details.…”

Repurposing Plant Virus Nanoparticles

“…TMV has also been engineered as a drug carrying nanoparticle to combat non-Hodgkin’s lymphoma. Kernan et al (2017) conjugated the antimitotic drug valine-citrulline monomethyl auristatin E (vcMMAE) targeting non-Hodgkin’s lymphoma, to TMV nanoparticles [ 29 ]. The authors demonstrated that each of the coat proteins of TMV carried vcMMAE.…”