Intracellular delivery of methylprednisolone by dendrimer-based nanoparticles improves the locomotor outcomes after spinal cord injury

last updated: 2013-04-10
TitleIntracellular delivery of methylprednisolone by dendrimer-based nanoparticles improves the locomotor outcomes after spinal cord injury
Publication TypeConference Abstract -ISI Web of Science Indexed
Year of Publication2012
AuthorsCerqueira S. R., Oliveira J. M., Silva B. L., Silva N. A., Mano J. F., Sousa N., Salgado A. J., and Reis R. L.

Spinal cord injuries (SCI) still remain a major challenge in current biomedical
research. In spite of several advances in the understanding of
its mechanisms there has not been an equal significant translation into
the clinics. As a result, there is no effective treatment that can overcome
the biochemical and cellular adverse reactions that lead to a chronic
severely impaired condition. One of the first opportunities to minimize
these drastic consequences is to control the secondary events that follow
the trauma. We are proposing the local delivery of an anti-inflammatory
corticosteroid - methylprednisolone (MP) - in an attempt to
modulate the noxious effects of the inflammation in the acute SCI. A
sustained delivery as the one provided by these nanoparticles (NP) can
be highly advantageous, maximizing the drug’s potency in the target
site. Therefore, we synthesized MP-loaded NPs composed of an inner
poly/(amido)amine (PAMAM) dendrimeric core and grafted with carboxymethylchitosan
(CMCht). Chemical and biological characterization
studies were carried out showing that the NPs are stable in acidic
and neutral buffer solutions. Also, the viability of primary glial cultures
was not compromised by the presence of 200 lg/mL of NP. In turn, an
MP action in microglial cultures was observed in dosages above 1 mg/
mL showing that MP is being released from the NPs inside the cells.
The uptake profile of these NPs is time dependent and reaches itsmaximum
24 h after incubation with astrocytes, oligodendrocytes and
microglia. In a preview of a possible therapeutic effect, the NPs were
administered in hemisected spinal cord injured rats. To assess the efficacy
of local injections around the lesion site the animals were sacrificed
3 h after surgery and frozen sections were observed. The
fluorescently labeled-NPs were detected in the injury and in the surrounding
spinal tissue indicating a successful delivery of the NP to the
spinal tissue. The local injections were repeated in hemisected rats that
were kept for 1 month, performing the BBB locomotory test weekly.
Significant differences in the BBB test were found between the MPloaded
NPs injected rats and the sham group as well as the ones
injected with MP, demonstrating a favorable action of the MP-NPs in
the acute phase of the injury. This work revealed that sustained delivery
of MP via a NP system can be highly beneficial in the management
of the secondary injury that follows SCI improving the overall functional
outcome of the injured animals.

JournalJournal of Tissue Engineering and Regenerative Medicine
Date Published2012-10-19
PublisherJohn Wiley
Keywordsdendrimer nanoparticles, spinal cord injury
Peer reviewedno

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