Abstract
Neurodegenerative diseases (ND) are characterized by the progressive loss of neuronal structure or function mostly associated with neuronal death. The presence of the blood–brain barrier (BBB) is considered the main obstacle that prevents the penetration of almost all drugs rendering the diseases untreatable. Currently, one of the most promising approaches for drug delivery to the brain is by employing endogenous transcytosis to improve endothelial cell uptake. This study aimed to exploit this potential route of enhanced drug uptake through the design and characterization of low generations lysine dendrons with further functionalization of dendron with ApoE-derived peptide (AEP) ligand to improve cellular uptake and targeting of delivery to the brain. Dendrons and peptide were synthesized using solid phase peptide chemistry and the products were characterized by mass spectrometry and high performance liquid chromatography which confirmed the successful synthesis of dendrons and functionalization with the AEP. Cell viability and lactate dehydrogenase release were conducted to study the cytotoxicity of the materials against an immortalized brain endothelial cell line (bEnd.3) which demonstrated that no toxicity was seen at the concentration range used (up to 400 μM) for up to 48 h incubation. Cellular uptake of the synthesized molecules was examined using confocal microscopy and flow cytometer which clearly showed the cellular uptake of the dendronised carrier systems and that the highest percentage of cellular uptake was achieved with the AEP-functionalized dendron. This study has therefore demonstrated the successful synthesis of dendronised carrier systems with the potential to act as carriers for improved delivery and targeting the brain.
Highlights
The early diagnosis and efficacious treatment of neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, are significantly compromised by the presence of the blood–brain barrier (BBB), a membrane made of astrocytes and endothelial cells connected by tight junctions that prevents the sufficient penetration of almost all drugs, genes and imaging agents to the brain (Re et al, 2012; Wyss, 2016)
The mass spectrum of the receptor-mediated transcytosis (RMT)-competent AEPdendron presented in Figure 5 demonstrates the successful synthesis and functionalization of the dendronised peptide with a theoretical MW of 1,479 Da
As many therapeutics are unable to permeate in to the brain endothelium, several strategies to improve the delivery of molecules including drugs, genes and imaging agents to the CNS have been developed including local injection or BBB opening or enhancing the permeability across the barrier through targeted delivery (Boer and Gaillard, 2007)
Summary
The early diagnosis and efficacious treatment of neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis, are significantly compromised by the presence of the blood–brain barrier (BBB), a membrane made of astrocytes and endothelial cells connected by tight junctions that prevents the sufficient penetration of almost all drugs, genes and imaging agents to the brain (Re et al, 2012; Wyss, 2016). Transport-vector strategies have recently been developed to deliver bioactive molecules with low BBB permeability to the brain (Kumar et al, 2015) These strategies capitalize either on the temporary destabilization of the tight junction sealing the extracellular endothelial space or on the internalization of macromolecules by the endothelial cells (Khawli and Prabhu, 2013). In the latter approach, the design of the transport-vector is based on the exploitation of the two main transcytosis pathways: (i) the adsorptive-mediated transcytosis (AMT) relying on the ability of hydrophobic molecules to penetrate the phospholipidic plasmalemma (Herve et al, 2008) and (ii) the receptor-mediated transcytosis (RMT) exploiting the biospecific recognition of ligands by cell receptors involved in the transport of molecules essential to the brain physiology (Chen and Liu, 2012)
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