The Centre for Advanced Imaging 3^rd Annual Symposium, 19^th of October, 2016.

Advances in materials synthesis have allowed for a multitude of well-defined biocompatible and stealthy nanoparticles of varying shape and size. For the treatment and diagnosis of cancer, these particles are often developed to exploit the enhanced permeability and retention (EPR) effect, but have limited in vivo efficacy due to their poor retention in tumour tissue. Addition of active targeting ligands with strong binding potentials to membrane receptors uniquely present on malignant cells have shown significant promise towards increasing the retention of nanoparticles in vivo. Many targeting vectors have been explored with some of the most promising types being antibodies; however, conjugation of these antibodies to the nanoparticles (NPs) using traditional chemistries is challenging and conditions can easily change per system. An ideal targeting system would be applicable to multiple types of NPs using a singular conjugation methodology. Recently, we have reported on the preparation of a bispecific antibody (BsAb) that has strong binding to VEGF receptors commonly overexpressed on cancer cells, and at its distal end an antibody specific towards methyl-terminated poly(ethyelene) glycol (PEG).¹ Herein we report the utility of this targeting method (Figure 1) toward the development of new diagnostic and therapeutic nanoparticles in murine models. Hyperbranched NPs constructed of methyl terminated PEG have been previously reported by us² and were used in this study to test the in vivo stability and efficacy of the targeting system in multiple tumour models.  The prepared BsAbs were conjugated to the radiolabelled NPs via a short incubation procedure and subsequently injected intravenously in two sets of Balb/c nude mice bearing either subcutaneous or xenograft tumours.  The biodistribution and tumour accumulation of the NPs were observed over several time points in vivo and ex vivo.  The BsAb targeted NPs were found to show higher accumulation in the tumour compared to the off-target control, and provide a promising and versatile targeting methodology for the investigation and treatment of tumours.

References:

1. C.B. Howard, et al., Advanced Healthcare Materials, Accepted. (DOI: 10.1002/adhm.201600263R1)
2. A.V. Fuchs, et al., Biomacromolecules, 2015, 16(10), 3235-3247.