Abstract
Gene delivery holds therapeutic promise for the treatment of neurological diseases and spinal cord injury. Although several studies have investigated the use of non-viral vectors, such as polyethylenimine (PEI), their clinical value is limited by their cytotoxicity. Recently, biodegradable poly (lactide-co-glycolide) (PLGA) nanospheres have been explored as non-viral vectors. Here, we show that modification of PLGA nanospheres with 3β-[N-(N′,N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) enhances gene transfection efficiency. PLGA/DC-Chol nanospheres encapsulating DNA were prepared using a double emulsion-solvent evaporation method. PLGA/DC-Chol nanospheres were less cytotoxic than PEI both in vitro and in vivo. DC-Chol modification improved the uptake of nanospheres, thereby increasing their transfection efficiency in mouse neural stem cells in vitro and rat spinal cord in vivo. Also, transgene expression induced by PLGA nanospheres was higher and longer-lasting than that induced by PEI. In a rat model of spinal cord injury, PLGA/DC-Chol nanospheres loaded with vascular endothelial growth factor gene increased angiogenesis at the injury site, improved tissue regeneration, and resulted in better recovery of locomotor function. These results suggest that DC-Chol-modified PLGA nanospheres could serve as therapeutic gene delivery vehicles for spinal cord injury.
Highlights
The delivery of therapeutic genes has been developed as a potential treatment for central nervous system injury [1,2]
Zeta potentials of nanospheres depended on their composition, with PLGA nanospheres containing the highest amount of DC-Chol undergoing a negative–to-positive inversion of zeta potential (Table 1)
We investigated methods for preparing cationic PLGA nanospheres as non-viral vectors for gene delivery
Summary
The delivery of therapeutic genes has been developed as a potential treatment for central nervous system injury [1,2]. The use of viral vectors to deliver genes has been in experimental animal models [3,4]. Viral vectors induce a strong immune and inflammatory response, limiting their clinical application [5,6]. In contrast to viral vectors, non-viral vectors such as copolymers and cationic lipids and liposomes are advantageous due to their low toxicity, low tendency to induce immune responses, high tissue-specific targeting, good ease and scale of production, and good handling properties [7,8,9]. PLOS ONE | DOI:10.1371/journal.pone.0147389 January 29, 2016
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