Engineering hepatitis B virus core particles for targeting HER2 receptors invitro and invivo.

Sara Bals,Chiaki Ogino,Akihiko Kondo,Julie Tzu-Wen Wang,Paul Brown,Khuloud T Al-Jamal,Mitla Garcia-Maya,Naomi O Hodgins,Rebecca Klippstein,Jane K Sosabowski,Yuya Nishimura,Izzat Fahimuddin Bin Mohamed Suffian,Hamed Heidari

doi:10.1016/j.biomaterials.2016.12.012

Abstract

Hepatitis B Virus core (HBc) particles have been studied for their potential as drug delivery vehicles for cancer therapy. HBc particles are hollow nano-particles of 30–34 nm diameter and 7 nm thick envelopes, consisting of 180–240 units of 21 kDa core monomers. They have the capacity to assemble/dis-assemble in a controlled manner allowing encapsulation of various drugs and other biomolecules. Moreover, other functional motifs, i.e. receptors, receptor binding sequences, peptides and proteins can be expressed. This study focuses on the development of genetically modified HBc particles to specifically recognise and target human epidermal growth factor receptor-2 (HER2)-expressing cancer cells, in vitro and in vivo, for future cancer therapy. The non-specific binding capacity of wild type HBc particles was reduced by genetic deletion of the sequence encoding arginine-rich domains. A specific HER2-targeting was achieved by expressing the ZHER2 affibodies on the HBc particles surface. In vitro studies showed specific uptake of ZHER2-ΔHBc particles in HER2 expressing cancer cells. In vivo studies confirmed positive uptake of ZHER2-ΔHBc particles in HER2-expressing tumours, compared to non-targeted ΔHBc particles in intraperitoneal tumour-bearing mice models. The present results highlight the potential of these nanocarriers in targeting HER2-positive metastatic abdominal cancer following intra-peritoneal administration.

Highlights

The effectiveness of detecting and treating cancer has remained a challenge for many researchers [1]
We focused on the development of genetically modified Hepatitis B Virus core (HBc) particles to recognise and target HER2expressing cancer cells in vitro and in vivo, qualitatively and quantitatively, for nucleic acid delivery applications
MDA-MB-231 cells treated with ZHER2-DHBc particles observed a lower value in fold increase whereas MDA-MB-468 cells exhibited the least (Fig. 4). These results indicate that specific uptake of ZHER2-DHBc particles in human epidermal growth factor receptor-2 (HER2) (þ) and cells occurs in a time- and dosedependent manner in accordance with HER2 expression levels in cells

Summary

Introduction

The effectiveness of detecting and treating cancer has remained a challenge for many researchers [1]. E-mail addresses: tumour drugs to achieve a therapeutic effect without causing severe systemic side effects has proven to be challenging [2]. To address these issues, many efforts have been put into developing specific targeted carriers that can deliver the desired cargo selectively to tumour sites. HBc particles are hollow nanoparticles, 30e34 nm in diameter with 7 nm thickness envelopes, consisting of 180e240 units of 21 kDa core monomers [7,8] They are capable of non-specific binding to various cell types via the action of positively-charged arginine-rich domain. It has been shown that other functional motifs i.e., receptors [12], proteins [13] and element recognising low molecular mass substrates [14], can be expressed by genetic modification to this region

Methods

Discussion

Conclusion