title: Selective nanovector mediated treatment of activated proinflammatory microglia/macrophages in spinal cord injury.
abstract: Much evidence shows that acute and chronic inflammation in spinal cord injury (SCI), characterized by immune cell infiltration and release of inflammatory mediators, is implicated in development of the secondary injury phase that occurs after spinal cord trauma and in the worsening of damage. Activation of microglia/macrophages and the associated inflammatory response appears to be a self-propelling mechanism that leads to progressive neurodegeneration and development of persisting pain state. Recent advances in polymer science have provided a huge amount of innovations leading to increased interest for polymeric nanoparticles (NPs) as drug delivery tools to treat SCI. In this study, we tested and evaluated in vitro and in vivo a new drug delivery nanocarrier: minocycline loaded in NPs composed by a polymer based on poly-ε-caprolactone and polyethylene glycol. These NPs are able to selectively target and modulate, specifically, the activated proinflammatory microglia/macrophages in subacute progression of the secondary injury in SCI mouse model. After minocycline-NPs treatment, we demonstrate a reduced activation and proliferation of microglia/macrophages around the lesion site and a reduction of cells with round shape phagocytic-like phenotype in favor of a more arborized resting-like phenotype with low CD68 staining. Treatment here proposed limits, up to 15 days tested, the proinflammatory stimulus associated with microglia/macrophage activation. This was demonstrated by reduced expression of proinflammatory cytokine IL-6 and persistent reduced expression of CD68 in traumatized site. The nanocarrier drug delivery tool developed here shows potential advantages over the conventionally administered anti-inflammatory therapy, maximizing therapeutic efficiency and reducing side effects.
authors.affiliation: Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" , via La Masa 19, 20156 Milan, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Papa
authors.forename: Filippo
authors.initials: F
authors.lastname: Rossi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mariani
authors.forename: Massimiliano
authors.initials: M
authors.lastname: De Paola
authors.forename: Ilaria
authors.initials: I
authors.lastname: Caron
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bisighini
authors.forename: Eliana
authors.initials: E
authors.lastname: Sammali
authors.forename: Claudio
authors.initials: C
authors.lastname: Colombo
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.forename: Jacopo
authors.initials: J
authors.lastname: Lucchetti
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.forename: Massimo
authors.initials: M
authors.lastname: Morbidelli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perale
authors.forename: Davide
authors.initials: D
authors.lastname: Moscatelli
authors.forename: Pietro
authors.initials: P
authors.lastname: Veglianese
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry; D002470:Cell Survival; D018920:Coculture Techniques; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D020100:Hydrogels / Q000737:chemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology*; D008911:Minocycline / Q000008:administration & dosage*; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D045663:Quantum Dots; D012235:Rhodamines / Q000737:chemistry; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000628:therapy*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001672:Biocompatible Materials; D020100:Hydrogels; D015850:Interleukin-6; D008911:Minocycline; D011091:Polyesters; D011092:Polyethylene Glycols; D011108:Polymers; D012235:Rhodamines; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C016240:polycaprolactone; C029773:rhodamine B