Neural drug delivery systems

Neural drug delivery is the next step beyond the basic addition of growth factors to nerve guidance conduits. Drug delivery systems allow the rate of growth factor release to be regulated over time, which is critical for creating an environment more closely representative of in vivo development environments.^[1] Delivery systems can have many different uses; however, the emphasis of the discussion here will be on the need for drug delivery systems in nervous system injuries.

First principles

A major challenge of delivering growth factors to lesions in the spinal cord is the high clearance and removal due to the high turnover rate of the cerebrospinal fluid. One way to overcome this is to use a drug delivery system that slowly releases the growth factors over a prolonged period of time.^[2] One previously developed affinity-based drug delivery system regulates the slow release of growth factors by binding them to heparin in fibrin gels. In addition to the fibrin gel there are three main components to the heparin-based delivery system (HBDS): a synthetic linker peptide, the polysulfated glycosaminoglycan heparin, and the growth factors being delivered.^[2] The synthetic linker peptide is covalently crosslinked to the fibrin gels and is noncovalently linked to heparin, which noncovalently links the desired growth factor to be delivered. The release of the growth factor from heparin is mediated by cell-activated plasmin degradation. When axons extend into the gel, they activate the conversion of plasminogen to plasmin, thereby initiating plasmin degradation of the fibrin gel and release of a growth factor such as NT-3. This drug delivery system has been used extensively to deliver growth factors with a high affinity for heparin, such as basic fibroblast growth factor. It has even been used for some growth factors with lower affinities such as nerve growth factor and NT-3.^[2] When HBDS was used to deliver NGF and NT-3, dorsal root ganglion neurite extension was enhanced by 75% and 54% over the controls which included the growth factors freely in media.^[2] This drug delivery system presents promising potential for in vivo use as an effective way to deliver growth factors to spinal cord lesions and thus promote regeneration.

Delivering growth factors

It is also challenging to deliver growth factors to the central nervous system, because most proteins are not able to cross the blood–brain barrier and therefore, cannot be delivered via systemic administration. The most desirable method of delivering growth factors such as nerve growth factor is locally because then only nanogram quantities are needed to supply therapeutic levels to the targeted cell population.^[3] A controlled delivery system is needed in order to supply growth factor locally. Another drug delivery system that has been well characterized is poly(ethylene-co-vinyl acetate) (EVAc). EVAc matrices have been approved for use by the Food and Drug Administration. Protein release occurs mainly by diffusion, which can be regulated by changing the mass within the polymer matrix. In order to better determine appropriate dosages from EVAc matrices, a study was done to determine how cell density and cell type affect the rate at which a delivered protein is eliminated; NGF was released into PC12 and developing fetal brain cells distributed throughout collagen gels.^[3] It was found that both the cell type and the cell density affected the rate of NGF elimination from the gels, suggesting that elimination is a cell-mediated process. The results were compared to a model that was developed to predict the effects of cell type and density on elimination. One specific reason for differences between the data and the model predictions could be because the model does not account for the change increases in cell number due to replication.^[3] This study is important for enhancing the ability to accurately deliver the desired dosage to the target tissue based on the amount of growth factor initially in the delivery matrices.

References

1. ↑ Lavik, E. and R. Langer, Tissue engineering; current state and perspectives. Applied Microbiology Biotechnology, 2004. 65: p. 1-8
2. 1 2 3 4 Taylor, S.J., J.W. McDonald, and S.E. Sakiyama-Elbert, Controlled release of neurotrophin-3 from fibrin gels from spinal cord injury. Journal of Controlled Release, 2004. 98: p. 281-294.
3. 1 2 3 Mahoney, M.J., et al., Impact of cell type and density on nerve growth factor distribution and bioactivity in 3-Dimensional collagen gel cultures. Tissue Engineering, 2006. 12(7): p. 1915-1927