Current strategies for therapeutic drug delivery after traumatic CNS injury.

Therapeutic strategies for traumatic injuries in the central nervous system (CNS) are largely limited to the efficiency of drug delivery. Despite the disrupted blood-CNS barrier during the early phase after injury, the drug administration faces a variety of obstacles derived from homeostatic imbalance at the injury site. In the late phase after CNS injury, the restoration of the blood-CNS barrier integrity varies depending on the injury severity resulting in inconsistent delivery of therapeutics. This review intends to characterize those different challenges of the therapeutic delivery in acute and chronic phases after injury and discuss recent advances in various approaches to explore novel strategies for the treatment of traumatic CNS injury.

Intranasal administration of elastin-like polypeptide for therapeutic delivery to the central nervous system.

Bypassing the blood-brain barrier is one of the primary considerations when designing compounds intended to function in the central nervous system (CNS). Intranasal (IN) administration of otherwise blood-brain barrier impermeable molecules can result in high CNS concentrations and low systemic accumulation, indicating that IN administration may be a useful method of delivering therapeutics to the CNS. Elastin-like polypeptide (ELP) is a large, non-immunogenic, highly manipulable biopolymer with extensive evidence supporting its use as a carrier with the ability to improve drug pharmacokinetics and drug targeting. The ability of ELP to reach the CNS via IN administration has been shown previously. Previous studies have also identified the ability of cell penetrating peptides (CPPs) to increase the uptake of molecules in some instances, including via the IN route. Here, we compared and contrasted the biodistribution of ELPs with or without addition of the CPPs Tat or SynB1 via both the IN and intravenous routes. Administration of ELP via the IN route led to significant accumulation in the brain, especially in the olfactory bulbs. When injected intravenously, <3% of the ELP signal was present outside the vascular compartment. This contrasted with IN administration, which resulted in 79% of the fluorescence signal localized outside the vascular space. The fusion of Tat or SynB1 significantly altered the biodistribution of ELP, decreasing the total CNS accumulation following IN administration. The addition of CPPs to ELP increased their retention in the nasal epithelium. These results suggest ELP may represent an effective CNS delivery vector without further modification and that the addition of a CPP significantly influences biodistribution.

Challenges and new strategies for therapeutic peptide delivery to the CNS.

Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood-brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions.