title: PLGA-Mesoporous Silicon Microspheres for the in Vivo Controlled Temporospatial Delivery of Proteins.
abstract: In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microsphere based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both of the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributing to the control of the release profile of a reporter protein in vitro. The influence of MSV shape (hemispherical or discoidal) and size (1, 3, or 7 μm) on PLGA-MSV's morphology and size distribution was investigated. Second, the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV was varied. The composites were fully characterized by optical microscopy, scanning electron microscopy, ζ potential, Fourier transform infrared spectroscopy, and thermogravimetric analysis-differential scanning calorimetry, and their release kinetics over 30 days. PLGA-MSV's biocompatibility was assessed in vitro with J774 macrophages. Finally, the formulation of PLGA-MSV was selected, which concurrently provided the most consistent microsphere size and allowed for a zero-order release kinetic. The selected PLGA-MSVs were injected in a subcutaneous model in mice, and the in vivo release of the reporter protein was followed over 2 weeks by intravital microscopy, to assess if the zero-order release was preserved. PLGA-MSV was able to retain the payload over 2 weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the biocompatibility of the platform in vivo.
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.|‡Institute of Science and Technology for Ceramics, National Research Council of Italy, Via Granarolo 64, 48018 Faenza, Ravenna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Minardi
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.|§College of Materials Science and Engineering, University of Chinese Academy of Science, 19A Yuquanlu, Beijing 100049, China.
authors.forename: Laura
authors.initials: L
authors.lastname: Pandolfi
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Taraballi
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Enrica
authors.initials: E
authors.lastname: De Rosa
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Iman K
authors.initials: IK
authors.lastname: Yazdi
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Xeuwu
authors.initials: X
authors.lastname: Liu
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: †Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Ennio
authors.initials: E
authors.lastname: Tasciotti
mesh_terms: D065966:Absorption, Physicochemical; D000818:Animals; D002214:Capsules / Q000138:chemical synthesis*; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004058:Diffusion; D019344:Lactic Acid / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016062:Porosity; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012822:Silicon Dioxide / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid; D012822:Silicon Dioxide
keywords: PLGA; drug delivery; microsphere; silicon; tissue engineering