# Neurorotrophic Factors in Glaucoma and Innovative Delivery Systems
## 3 Advances in Drug and Gene Delivery Systems for Neuroprotection in Glaucoma  
### Routes of Administration and Devices  
Among neuroprotective molecules, NTFs represent promising candidates for their recognized effectiveness in promoting neuronal recovery in human subjects and in experimental models of glaucoma. However, their use for treatment of retinal and/or optic nerve diseases are limited by short half-life in vivo and low bioavailability. Therefore, these compounds require multiple topical or intravitreal administrations to achieve therapeutic effects in the posterior ocular segment. Sustained delivery to the back of the eye probably represents the major difficulty that has most seriously hindered clinical application of NTFs for treatment of glaucoma. In recent years, increasing interest has been addressed to the development of intraocular drug delivery systems in order to provide therapeutic levels of neuroprotective agents in a targeted, local, and sustained way to the retina and optic nerve. Figure 2: Neurootrophic factors (NTFs) multiple signaling pathways. The tropomyosin receptor kinases (TrkA, TrkB, and TrkC) promote neuronal survival through the activation of the Ras/ERK/mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, and the phospholipase C (PLC)-\(\gamma\) pathway. The low-affinity neurotrophin receptor p75 NTR induces cell death through the activation of caspases, c-JUN N-terminal kinase (JNK), and fast-associated protein with death domain (FADD) pathways, but it is able to induce cell survival through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)/mTOR pathway and AKT in dependence of Trk receptors concurrent expression. The GDNF\(\alpha\) receptor and tyrosine kinase RET receptor activate PLC-\(\gamma\), Ras/ERK/ MAPK and PI3K pathways. The CNTFR\(\alpha\) receptor and the two subunits gp130 and leukemia inhibitory factor (LIFR) receptor activate the JAK/STAT, Ras/ERK/MAPK, and PI3K pathways. Novel drug delivery systems consist of technologies and materials allowing for considerable benefits over conventional formulations such as improvement in bioavailability and therapeutic efficacy, sustained and controlled release, reduction of dosing schedule frequency with consequent better tolerability, and patient compliance [98]. The ocular barrier represents substantial constraints for topically applied ophthalmic drugs in terms of rapid tear fluid clearance and drainage, relative impermeability of the corneal epithelium, and potential systemic toxicity related to conjunctival and nasolacrimal absorption [99; 100]. Alternatively, intravitreal administration offers the advantage of direct access to the vitreous cavity, but it represents an invasive treatment option and increases the risk of ocular complications (endophthalmitis, IOP increase, uveitis, cataract formation, vitreous hemorrhage, and retinal detachment) [99; 100]. In addition, it has been demonstrated that, after intravitreal injection, NTFs in the vitreous humor are rapidly degraded by resident microglia in the retina or by free or degenerating RGC-induced extracellular proteases [101]. The trans-scleral route is less invasive and safer than IVT, but it requires drugs to cross the sclera, choroid blood flow, and RPE, resulting in low bioavailability, especially for large molecules such as NTs [99; 100]. Similarly, the suprachoroidal route is at lower risk of side effects if compared with IVT, but it is not a valid choice for large molecules since it is associated with slow diffusion from suprachoroidal space to choroid and retina, and rapid clearance of drug via adjacent choroidal blood vessels [100; 102]. Conversely, intravenous route is associated with invasive procedure, systemic side effects, and is subjected to blood-retinal barrier (BRB) crossing [103].