Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain

Abstract

Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood–brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision “ideal” NTF for Parkinson’s disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed.

Superparamagnetic iron oxide enclosed hollow gold nanostructure with tunable surface plasmon resonances to promote near-infrared photothermal conversion

“…Compared to the plasmonic nanostructures summarized in Table S3, our SPIO-HGNS possess benefits, such as tunable SPR peak at the NIR region and functional sizes within 10-100 nm, which enable enhanced tumor uptake, efficient blood brain barrier crossing and deeper brain tissue penetration [54, 55, 56, 57]. We have also shown that Au coating displays excellent biocompatibility and efficient cellular uptake [8, 32].…”

Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease

“…Variation in the pathological secretion of collagen VI also provides a plausible explanation as to why GDNF treatments appear more efficient in Hol Tg/Tg [BL6] mice compared to Hol Tg/Tg [FVB] mice. Indeed, the extracellular matrix is a major determinant of GDNF diffusion and activity [ 45 , 46 ]. Accordingly, levels of collagen VI in the diseased segment might affect both the distribution of rectally administered GDNF and the subsequent response of targeted ENS progenitors.…”

Mechanistic Insights, Treatment Paradigms, and Clinical Progress in Neurological Disorders: Current and Future Prospects

“…NTFs are a group of neuropeptides (such as nerve growth factors) that support the development, maturation, and survival of neurons in the CNS. Nevertheless, NTFs prevent the loss of dopaminergic neurons and play a potential role in the treatment of PD [ 123 ]. However, the introduction of NTFs directly into the brain is limited, whether in terms of the cost issue, risky intracranial surgery, poor diffusion, and/or the failure to pass through the BBB.…”