title: Accelerated oral nanomedicine discovery from miniaturized screening to clinical production exemplified by paediatric HIV nanotherapies.
abstract: Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes.
authors: Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK.
authors: Marco
authors: M
authors: Giardiello
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Neill J
authors: NJ
authors: Liptrott
authors: Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK.
authors: Tom O
authors: 0000-0002-9273-9173
authors: TO
authors: McDonald
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Darren
authors: D
authors: Moss
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Marco
authors: M
authors: Siccardi
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Phil
authors: P
authors: Martin
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Darren
authors: D
authors: Smith
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Rohan
authors: R
authors: Gurjar
authors: Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK.
authors: Steve P
authors: SP
authors: Rannard
authors: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool L69 3GF, UK.
authors: Andrew
authors: A
authors: Owen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002648:Child; D016503:Drug Delivery Systems; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D061466:Lopinavir / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000032:analysis; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: D019380:Anti-HIV Agents; D054852:Small Molecule Libraries; D061466:Lopinavir; D019438:Ritonavir