title: Increasing the density of nanomedicines improves their ultrasound-mediated delivery to tumours.
abstract: Nanomedicines have provided fresh impetus in the fight against cancer due to their selectivity and power. However, these agents are limited when delivered intravenously due to their rapid clearance from the bloodstream and poor passage from the bloodstream into target tumours. Here we describe a novel stealthing strategy which addresses both these limitations and thereby demonstrate that both the passive and mechanically-mediated tumour accumulation of the model nanomedicine adenovirus (Ad) can be substantially enhanced. In our strategy gold nanoparticles were thoroughly modified with 2kDa polyethyleneglycol (PEG) and then linked to Ad via a single reduction-cleavable 5kDa PEG. The resulting Ad-gold-PEG construct was compared to non-modified Ad or conventionally stealthed Ad-poly[N-(2-hydroxypropyl)methacrylamide] (Ad-PHPMA). Notably, although Ad-gold-PEG was of similar size and surface charge to Ad-PHPMA the increase in density, resulting from the inclusion of the gold nanoparticles, provided a substantial enhancement of ultrasound-mediated transport. In an in vitro tumour mimicking phantom, the level and distance of Ad-gold-PEG transport was shown to be substantially greater than achieved with Ad-PHPMA. In in vivo studies 0.1% of an unmodified Ad dose was shown to accumulate in tumours, whereas over 12% of the injected dose was recovered from the tumours of mice treated with Ad-gold-PEG and ultrasound. Ultimately, a significant increase in anti-tumour efficacy resulted from this strategy. This stealthing and density-increasing technology could ultimately enhance clinical utility of intravenously delivered nanoscale medicines including viruses, liposomes and antibodies.
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Mo
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. Electronic address: robert.carlisle@eng.ox.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Carlisle
authors.affiliation: Clinical Pharmacology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK; Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Laga
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Myers
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Graham
authors.affiliation: Clinical Pharmacology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cawood
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.affiliation: Clinical Pharmacology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Leonard
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Constantin-C
authors.initials: CC
authors.lastname: Coussios
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006046:Gold / Q000008:administration & dosage / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050997:Nanomedicine; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D050130:Oncolytic Virotherapy; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000008:administration & dosage / Q000737:chemistry; D014465:Ultrasonics
chemical_list: D011109:Polymethacrylic Acids; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; C011533:Duxon; D006046:Gold
keywords: Delivery; Density; Pharmacokinetics; Stealthing; Tumour; Ultrasound; Virotherapy