Nanomedicines for the Delivery of Biologics.

John Wahlich,Ijeoma F Uchegbu,Francesca Greco,Kathryn Hill,Arpan Desai,Arwyn T Jones,Leonard W Seymour,Randall J Mrsny,Yvonne Perrie,Gianfranco Pasut,F Philipp Seib

doi:10.3390/pharmaceutics11050210

Abstract

A special symposium of the Academy of Pharmaceutical Sciences Nanomedicines Focus Group reviewed the current status of the use of nanomedicines for the delivery of biologics drugs. This meeting was particularly timely with the recent approval of the first siRNA-containing product Onpattro™ (patisiran), which is formulated as a lipid nanoparticle for intravenous infusion, and the increasing interest in the use of nanomedicines for the oral delivery of biologics. The challenges in delivering such molecules were discussed with specific emphasis on the delivery both across and into cells. The latest developments in Molecular Envelope Technology® (Nanomerics Ltd, London, UK), liposomal drug delivery (both from an academic and industrial perspective), opportunities offered by the endocytic pathway, delivery using genetically engineered viral vectors (PsiOxus Technologies Ltd, Abingdon, UK), Transint™ technology (Applied Molecular Transport Inc., South San Francisco, CA, USA), which has the potential to deliver a wide range of macromolecules, and AstraZeneca’s initiatives in mRNA delivery were covered with a focus on their uses in difficult to treat diseases, including cancers. Preclinical data were presented for each of the technologies and where sufficiently advanced, plans for clinical studies as well as early clinical data. The meeting covered the work in progress in this exciting area and highlighted some key technologies to look out for in the future.

Highlights

Biologics drugs are challenging to deliver because, apart from failing to meet Lipinski’s ‘rule of five’ criteria, the large molecules tend to be unstable both in vitro requiring care in formulation to prevent aggregation etc. and in vivo due to chemical and enzymatic degradation
AstraZeneca has explored how to widen the therapeutic window of lipid nanoparticles and has used high throughput screening to identify small molecules that will enhance lipid nanoparticles—mRNA delivery
The recent FDA approval of OnpattroTM, the first siRNA drug, which is formulated as an injectable lipid complex demonstrates the potential of this field

Summary

Discussion

The Academy of Pharmaceutical Sciences (APS, the professional body for Pharmaceutical Scientists in the UK) hosted a meeting of its Nanomedicines Focus Group at the University of Reading on 18th July. AstraZeneca has explored how to widen the therapeutic window of lipid nanoparticles and has used high throughput screening to identify small molecules that will enhance lipid nanoparticles—mRNA delivery They found that there was a huge variation in how different cell types are transfected with lipid nanoparticles and that there was typically no correlation between uptake and transfection (as compounds may enter the cell through an endocytic pathway but are not released from the endosomes). Intravenous and intra-tumoural delivery of the virus in a Phase 1 study using patients with various epithelial cancers showed high local CD8+ cell infiltration in 80% of tested tumour samples, suggesting a potential EnAd-driven immune response [63]. Professor Seymour [66] has reviewed the contribution that European scientists have made to the impact oncolytic viruses will have in cancer treatment and highlighted the future promise for the technology

Findings

Conclusions

Blockbuster Biologics 2017