Innovations_in_Molecular_Mechanisms_and_Tissue_Engineering_(Stem_Cell_Biology_and_Regenerative_Medicine)

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agent from days to months [ 299 ]. Already, this technology has been employed for

innovation upon and advancement of current clinical technologies, such as the

delivery of methylprednisolone.

Methylprednisolone (MPS) is used clinically to render neuroprotection by

suppressing primary infl ammation and lipid peroxidation when administered at

high doses in the acute phase of SCI ranging from moderate to severe [ 300 ].

However, the use of MPS is controversial as there is evidence that systemic admin-

istration of high doses of MPS may cause pneumonia, sepsis, and death [ 301 ].

MPS-loaded NPs have been studied extensively to improve drug effi cacy while

neutralizing some of the detrimental side effects associated with systemic high

doses. In hemi- section SCI models, both PLGA- NPs and carboxymethylchitosan/

polyamidoamine dendrimers loaded with MPS demonstrate signifi cantly improved

outcomes including reduction in lesion size, suppression of microglial and astro-

cytic responses, and improved axon regeneration [ 302 , 303 ]. It is likely that the

low-dose (approximately 20x less than clinically relevant systemic doses) and

reduction of freely circulating bioactive MPS are responsible for these improved

capabilities and may potentially augment the safety of clinical MPS use. Others

have investigated loading minocycline into polymeric polycaprolactone NPs [ 304 ].

Administration of minocycline- loaded NPs reduced the proliferation of microglia/

macrophages and modulated their morphology from activated to resting in vitro

[ 304 ]. Similarly, Racke et al. performed an in vitro comparison of treatment with

minocycline-loaded PEGylated liposomes with daily minocycline injections for the

treatment of CNS autoimmune diseases, fi nding that infrequent injections of PEG-

minocylcline liposomes are an effective alternative pharmacotherapy to daily injec-

tions [ 305 ]. In addition to drugs, neurotrophic factors have been loaded into NPs

and delivered to spinal cord lesion sites. YC Wang et al. performed intraspinal injec-

tions of glial cell-derived neurotrophic factor (GDNF) loaded PLGA-NPs in a rat

contusion SCI model [ 306 ]. The group reported increased neuronal survival as a

result of successful release of drug into the lesion site [ 306 ].

Given the innate drug delivery capabilities of NPs, particularly sustained intra-

cellular retention, it has been postulated that NPs may provide practical vehicles for

sustained gene transfer. While there has been a signifi cant amount of research per-

formed in other systems of the body, there is currently little work regarding NPs as

gene transfer vehicles in the CNS. Lu et al. performed a study investigating

liposome- mediated GDNF gene transfer to augment corticospinal tract recovery

after SCI lesion [ 307 ]. The group found that in vivo transfer of GDNF cDNA pro-

moted axonal regeneration and enhanced functional recovery, suggesting that lipo-

somal-mediated delivery of cDNA may be a practical gene transfer method. The

therapeutic effi cacy imparted from NPs in this application is likely due to their

ability to buffer therapeutic agents from degradation by lysosomal enzymes [ 308 ].

Hedley et al. demonstrated that DNA encapsulated in PLGA microspheres were

protected from nuclease activity in vitro compared to non-encapsulated DNA [ 308 ].

Due to the larger diameter of microspheres , they are more generally used for

cellular scaffolding and drug and bioactive factor delivery, with many of the

same properties as NPs. Through the use of biodegradable polymeric MPs and

A. Roussas et al.