title: Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.
abstract: An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK. tomm@liv.ac.uk.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Town
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK. tomm@liv.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Giardiello
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Rohan
authors.initials: R
authors.lastname: Gurjar
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool, L69 3GF, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.affiliation: Centre for Materials Discovery, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.
authors.forename: Michael E
authors.identifier: http://orcid.org/0000-0003-1474-1267
authors.initials: ME
authors.lastname: Briggs
authors.affiliation: Department of Mechanical, Materials and Aerospace Engineering, School of Engineering University of Liverpool, George Holt Building, Brownlow Hill, Liverpool, L69 3GH, UK.
authors.forename: Riaz
authors.initials: R
authors.lastname: Akhtar
authors.affiliation: Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK. tomm@liv.ac.uk.
authors.forename: Tom O
authors.identifier: http://orcid.org/0000-0002-9273-9173
authors.initials: TO
authors.lastname: McDonald
mesh_terms: D000178:Acrylamides; D000180:Acrylic Resins; D000818:Animals; D003692:Delayed-Action Preparations; D004285:Dogs; D016503:Drug Delivery Systems; D005782:Gels; D061985:Madin Darby Canine Kidney Cells; D053761:Nanocomposites; D053758:Nanoparticles; D011108:Polymers
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D003692:Delayed-Action Preparations; D005782:Gels; D011108:Polymers; C000609880:poly(N-isopropylacrylamide-co-allylamine); C067295:N-isopropylacrylamide