Characterization of a Nanoparticle Drug Delivery System for the Treatment of Inflammation in Spinal Cord Injury

Papa, Simonetta Giulia (2017). Characterization of a Nanoparticle Drug Delivery System for the Treatment of Inflammation in Spinal Cord Injury. PhD thesis IRCCS - Istituto di Ricerche Farmacologiche Mario Negri.


Spinal cord injury (SCI) results from a mechanical primary injury that is followed by a multifactorial secondary injury which worsens the clinical course. Persistent inflammation is a crucial event during the secondary injury. Indeed, microglia/macrophage respond to traumatic stimuli by adopting an activated phenotype, which has a dual role. An M1 phenotype, associated with harmful effects, is expressed very early and persists for a long time in the injured site, whereas M2, associated with a beneficial phenotype, has only a transient expression in a subacute phase of the trauma. This suggests that microglia/macrophage mediated inflammation is a crucial therapeutic target.

Nanoparticles (NPs) are selectively engulfed by microglia/macrophage as part of their endocytic/phagocytic activity in removing foreign bodies. Microglia assume phagocytic activity after traumatic stimuli and this makes NPs an excellent tool for carrying drug to these cells. So, in order to counteract this deleterious pro-inflammatory response, we decided to maximize the efficacy of a well-known anti-inflammatory drug, minocycline, through a NPs delivery tool selectively targeted to microglia/macrophage. We developed and tested a new drug delivery nanocarrier (minocycline loaded in poly-ε-caprolactone NPs, PCL Mino) in vitro and in vivo. Specifically, we demonstrated a reduced activation of microglia/macrophage after PCL Mino treatment in vitro and a reduction of cells with phagocytic-like phenotype, up to 15 days tested in vivo. To clarify the involvement of the inflammatory response associated to microglia/macrophage in SCI progression, we treated SCI mice in acute and subacute phase. PCL Mino treatment, only when administered acutely after the damage, was able to ameliorate the locomotor activity up to 63 days post injury. Furthermore, we demonstrated that this treatment reduced M1 macrophages recruitment orchestrated by activated microglial cells via CCL2 chemokine in the damaged site, suggesting a deleterious effect in the early phase of the injury of these cells.

In conclusion, this delivery tool represents a new hope for SCI treatment by showing several advantages compared to conventionally administered anti-inflammatory therapy, such as maximization of therapeutic efficiency and reduction of side effects. Furthermore, the potential of transfer to clinical practice is aided by the large clinical use of minocycline and the high biocompatibility of the proposed NPs.

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