Chapter 5: Summary and Future prospects
B) The ways in which lipoproteins may be modified to act as contrast agents. (Adapted with permission from Cormode et al, 2010)
2.6.4 Nanotools for Neurotherapy
The need for a cost effective, rapid and highly sensitive diagnostic platform for early detection of biomarkers related to neurodegenerative diseases prompted the European union to initiate a multi-institute collaborative initiative for development of nanosystems for early diagnosis of neurodegenerative diseases (NADINE) in 2010.
paclitaxel by dual targeting of neo-vascualture and malignant cells. In another study, the same team managed to decorate the polymeric nanoparticles with aptamers specific for nucleolin which is over-expressed in both cancer cells and tumor vasculature (Guo et al, 2011). Nano-formulations of naturally occurring anti cancer compounds like reservatol was delivered by lipid based nanocapsules and were reported to inhibit glioma growth in vitro and in vivo (Figueiró et al, 2013). Another group demonstrated the efficiency of polymeric nanoparticles as vehichles for targeted gene delivery inside glioma. The Chlorotoxin conjugated PEG-PLA nanoparticles could efficiently cross the BBB and reach the perinuclear region, thereby facilitating the delivery of GFP encoding DNA inside tumor cells (Kievit et al, 2010). In order to obtain sustained release of drugs in situ, scaffolds in the form of nanofibers were found to hold potential as implants for glioma therapy. PLGA nanofibers loaded with paclitaxel exhibited sustained release of drug over 60 days in vitro on culture of C6 glioma cell line (Xie et al, 2006).
2.6.4.2 Nanotherapeutics in Alzheimer’s disease
Alzheimer’s disease (AD) is mainly caused by aggregation and accumulation of Aβ fibrils in the brain tissue. Hence most of the therapeutic strategies developed for AD has focussed on inhibition of amyloidogenesis and destruction of Aβ fibrils by targeted irradiation methods and localised delivery of anti-amyloid molecules. Metal ions like (Cu, Fe and Zn) tend to accumulate in ageing brain and have been shown to interact with and stabilize Aβ fibrils thereby facilitating progression of AD. By using Cu-chelator D-penicillamine conjugated with nanoparticles, scientists observed that it was possible to resolubilize Aβ1-42 aggregates (Cui et al, 2005). This showed that nanoparticle based platforms could be used to reduce metal ion accumulation thereby reversing many neurodegenerative diseases. Enhanced delivery of natural anti-oxidant and anti-amyloid compounds like curcumin can be achieved by employing biocompatible nanomaterials tagged with moieties that direct the nanoprobes into neuronal cells. Studies with curcumin loaded polymeric nanoparticles conjugated with Tet-1 peptide as well as enhanced delivery of curcumin into mice brain by PBCN-NP are some examples (Matthew et al, 2012;
Sun et al, 2010). Metallic nanoparticles like gold nanoparticles have been reported to inhibit Aβ fibril formation as well as aid in targeted photothermal (Triulzi et al, 2008) and microwave irradiation (Araya et al, 2008) for Aβ aggregates. Surface
modification of GNPs with COOH groups provided a net negative charge which was found to inhibit and redirect Aβ fibrillation (Liao et al, 2012). Apart from GNPs, Quantum dots (QDs) have also been conjugated with anti-amyloid molecules like N- acetyl-L-cysteine (NAC) which can inhibit fibrillation by quenching the nucleation and elongation processes (Xiao et al, 2010). Nano-formulations of polymeric materials like PEGylated poly-lactic acid (PLA) and polysaccharide nanogels (cholesterol bearing pullulan) also exhibited potential as platforms for targeting amyloid plaques (Zhang et al, 2014) and as chaperones inducing conformational change in Aβ fibrils respectively (Ikeda et al, 2006). Similarly, estradiol loaded polymeric nanoparticles were given orally in rat AD model, keeping in mind the enhanced risk of the disease in post menopausal women due to reduced estrogen levels. Nanoparticle mediated delivery aided in brain localisation of estradiol increasing bioavailability and therapeutic efficiency at lower drug concentration (Mittal et al, 2011). In a separate approach towards AD treatment an Italian group delivered Acetylcholine esterase inhibitor drug Tacrine via albumin nanoparticle. The intranasal delivery of the drug through nanocarrier was expected to increase bioavailability, enhance permeation and circulation time of the active ingredient (Luppi et al, 2011).
2.6.4.3 Nanotherapeutics in Parkinson’s disease
The second most prevalent neurodegenerative disorder after AD is Parkinson’s disease (PD). Although the pathophysiology of PD has been extensively studied, the disease etiology largely remains unknown (idiopathic) till date. PD is primarily associated with loss of dopaminergic neurons in the substantia nigra leading to deficiency of the neurotransmitter – Dopamine. In order to combat this deficiency, Levo-dopa (L-DOPA) which is a biological precursor of dopamine is generally administered to PD patients. The low bioavailability of L-DOPA upon systemic or oral administration has necessitated nanotechnology based delivery platforms to ensure efficient transport of dopamine across the BBB and maximum localization of the molecule in the brain. Initial attempts for site-specific delivery of dopamine to minimise its peripheral side effects were focussed on designing and biometric simulation of a prototype nano-enabled scaffold device (NESD) comprising of alginate scaffold embedded with dopamine loaded cellulose acetate phthalate (CAP) nanoparticles (Pillay et al, 2009). The device was implanted in the parenchyma of the frontal lobe of rats and was found to deliver dopamine over 30 days with 10 fold
more dopamine in CNS as compared to systemic concentration. Similar attempts for dopamine delivery were also made with chitosan nanoparticles (De Giglio et al, 2011). Intraperitoneal administration of dopamine loaded chitosan nanovectors were found to induce dose dependent increase of dopamine presence in the striatum as observed through in vivo brain microdialysis experiments. Other neuro-protecting molecules like corticotrophin hormone urocortin and genes encoding growth factors like GDNF also arrests development of Parkinsonism when administered through polymeric nanoparticles conjugated with lactoferrin (Hu et al, 2011;Huang et al, 2010). Similarly, angiopep conjugated dendrimers have been used to transport human GDNF genes into the affected areas of the brain for recovery of dopaminergic neurons and restore locomotory activity in Parkinson’s induced animal models (Huang et al, 2013). Oxidative stress is one of the main causes which result in loss of dopaminergic neurons in PD. Hence, attempts to specifically deliver antioxidants into the substantia nigra of diseased brain have also been reported. Cationic block copolymer polyethyleneimine-PEG (PEI-PEG) of 60-100nm size were loaded with catalase enzyme to form a nanozyme complex which exhibited longer stability in vitro and in vivo with 0.6% of the injected dose reaching the brain (Batrakova et al, 2007). Besides dopamine deficiency, another pathophysiology associated with PD is the accumulation of α-synuclein protein forming inclusions called Lewy bodies which are found distributed throughout a diseased brain. Gold nanoparticles were observed to act as chaperones, preventing the misfolding of α-synuclein and hence can be used as a therapeutic to sequester and regulate α-synuclein homeostasis (Yang et al, 2014; Yang et al, 2013). These pathophysiologies are ultimately responsible for deterioration of electrical activity in the thalamic, subthalamic nucleus, globus pallidus and medial globus pallidus region of the parkinsonian brain. Temporal administration of magneto electric nanoparticles facilitates non-invasive stimulation of these regions thorugh an external magnetic field thereby improving the brain’s electrical activivty (Yue et al, 2012).