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      Nanomedicines for the Delivery of Biologics

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          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.

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          Most cited references55

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          Chaotic mixer for microchannels.

          It is difficult to mix solutions in microchannels. Under typical operating conditions, flows in these channels are laminar-the spontaneous fluctuations of velocity that tend to homogenize fluids in turbulent flows are absent, and molecular diffusion across the channels is slow. We present a passive method for mixing streams of steady pressure-driven flows in microchannels at low Reynolds number. Using this method, the length of the channel required for mixing grows only logarithmically with the Péclet number, and hydrodynamic dispersion along the channel is reduced relative to that in a simple, smooth channel. This method uses bas-relief structures on the floor of the channel that are easily fabricated with commonly used methods of planar lithography.
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            Engineered nanoparticles for drug delivery in cancer therapy.

            In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.
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              Lipid Nanoparticle Systems for Enabling Gene Therapies.

              Genetic drugs such as small interfering RNA (siRNA), mRNA, or plasmid DNA provide potential gene therapies to treat most diseases by silencing pathological genes, expressing therapeutic proteins, or through gene-editing applications. In order for genetic drugs to be used clinically, however, sophisticated delivery systems are required. Lipid nanoparticle (LNP) systems are currently the lead non-viral delivery systems for enabling the clinical potential of genetic drugs. Application will be made to the Food and Drug Administration (FDA) in 2017 for approval of an LNP siRNA drug to treat transthyretin-induced amyloidosis, presently an untreatable disease. Here, we first review research leading to the development of LNP siRNA systems capable of silencing target genes in hepatocytes following systemic administration. Subsequently, progress made to extend LNP technology to mRNA and plasmids for protein replacement, vaccine, and gene-editing applications is summarized. Finally, we address current limitations of LNP technology as applied to genetic drugs and ways in which such limitations may be overcome. It is concluded that LNP technology, by virtue of robust and efficient formulation processes, as well as advantages in potency, payload, and design flexibility, will be a dominant non-viral technology to enable the enormous potential of gene therapy.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                03 May 2019
                May 2019
                : 11
                : 5
                : 210
                Affiliations
                [1 ]The Academy of Pharmaceutical Sciences, 4 Heydon Road, Great Chishill, Royston SG8 8SR, UK
                [2 ]Advanced Drug Delivery, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Granta Park, Cambridge CB21 6GH, UK; Arpan.Desai@ 123456astrazeneca.com
                [3 ]Reading School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, UK; f.greco@ 123456reading.ac.uk
                [4 ]Global Product Development, Pharmaceutical Technology and Development, Operations, AstraZeneca, Macclesfield SK10 2NA, UK; Kathryn.Hill@ 123456astrazeneca.com
                [5 ]Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK; JonesAT@ 123456cardiff.ac.uk
                [6 ]Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK; r.j.mrsny@ 123456bath.ac.uk
                [7 ]Pharmaceutical and Pharmacological Sciences Department, University of Padova, F. Marzolo 5, 35131 Padova, Italy; gianfranco.pasut@ 123456unipd.it
                [8 ]Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK; yvonne.perrie@ 123456strath.ac.uk (Y.P.); philipp.seib@ 123456strath.ac.uk (F.P.S.)
                [9 ]Department of Oncology, Old Road Campus Research Building, Oxford OX3 7DQ, UK; len.seymour@ 123456oncology.ox.ac.uk
                [10 ]UCL School of Pharmacy, London WC1N 1AX, UK; ijeoma.f.uchegbu@ 123456pharmacy.ac.uk
                Author notes
                Author information
                https://orcid.org/0000-0002-2590-4634
                https://orcid.org/0000-0003-2781-8905
                https://orcid.org/0000-0001-8505-8516
                https://orcid.org/0000-0002-8754-0899
                Article
                pharmaceutics-11-00210
                10.3390/pharmaceutics11050210
                6572454
                31058802
                8a8a2b64-eef9-4f7e-9d05-97a15ee42821
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 April 2019
                : 04 April 2019
                Categories
                Meeting Report

                nanomedicines,drug delivery,sirna,mrna,dna,proteins,lipid nanoparticles,liposomes,viral vectors,endocytosis

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