In 2017, World Health Organization have recognized dementia as a public health priority and for this reason have endorsed the ¿Global action plan on the public health response to dementia 2017-2025¿, to improve the research about it.
Dementia or Alzheimer¿s disease (AD) is a chronic and irreversible neurodegenerative disorder which mainly affects the older people worldwide. Currently, there is no treatment available to cure dementia or to alter its progressive course, for this reason the treatment of AD still remains a great challenge and the development of new strategies represents an active area of research. The major obstacle for the treatment of AD is the presence of the blood-brain barrier (BBB), that protects the brain from pathogens and toxic substances, including drugs and for maintaining its homeostasis. Many studies have demonstrated the promising effects of medicinal plant extracts on several CNS diseases including AD, in particular, curcumin (CUR) extracted from Curcuma longa.
The aim of this project is to develop novel drug delivery system, able to deliver into the brain a natural compound CUR useful for the treatment of AD, co-entrapped with a gas.
To get this aim, we will go beyond the state-of-art of contrast agents and theranostic agents, tailoring phospholipid coating of nanobubbles to bypass the blood-brain barrier and deliver active substances to the brain inducing considerably less, if any, peripheral uptake and adverse effect than conventional formulation.
The aim of this project is the development of a theranostic carrier able to deliver curcumin into the CNS.
To get this aim, we will go beyond the state-of-art of contrast agents and theranostic agents.
Currently, UCAs are available only as contrast agent for diagnostic imaging in order to increase the low back-scatter of the blood.
The therapeutic application of UCAs as drug carriers is severely limited by some their physical-chemical characteristics.
The goal of this project will be to formulate nanobubbles able to simultaneously entrap a contrast agent and an active compound.
The obtained system will provide diagnostic support and therapeutic treatment. In fact, since NBs can reflect the US, it should be possible not only to localise the drug release but also to provide an image of this process and facilitate the access of the drug to the brain through cavitation and sonoporation mechanisms.
As commercially available UCAs, to formulate C-NBs will be selected safe, biocompatible, biodegradable and regulatory admitted substances, in particular: phospholipids or non-ionic surfactants and cholesterol for the shell, well known for their biocompatibility, and a perfluorocarbon, as contrast agent, a bioinert gas.
At present, the limited efficacy of the available therapies for AD has encouraged the search for new treatments. In this regard, several investigations undertaken in different experimental models have suggested that curcumin could be helpful in AD treatment.
Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia.
Moreover, CUR shows important anti-inflammatory and antioxidant properties that allow it to be applied as treatment for several emerging pathologies. Remarkably, there are an elevated number of publications deriving from the terms ¿curcumin¿ and ¿curcumin brain diseases¿, which highlights the increasing impact of this polyphenol and the high number of study groups investigating their therapeutic actions.
However, limitations in the bioavailability of curcumin have hindered its use and promoted the search for suitable vehicles to improve its pharmacological activity. In fact, the low permeability of CUR is related to its chemical degradation, high rate of biotransformation and rapid systemic elimination, resulting in low CUR absorption and poor bioavalilability [1]. Consequently, high doses of this compound are necessary to produce detectable plasma concentration, with the risk of causing additional complication to off-target tissues. In fact, after oral administration, most of CUR is metabolised by liver and intestine and a small quantity still remains detectable in the organs [2]. Currently (11-06-2019), the Italian Healthy Department has recalled from the market several supplements with curcumin after 18 warning of suspected acute hepatitis related to curcumin consumption. The studies to verify this instance are under revision, in particular because in literature data CUR seems to show hepatoprotective effects [3].
Therefore, the encapsulation of CUR into NBs will increase its bioavailability, in vivo stability and solubility, allowing to considerably decrease the injected dose.
Furthermore, the goal of this research project will be possibility of C-NBs to specifically target the brain allow curcumin to rich directly the brain, decreasing the concentration of this compound in other tissues [4].
Moreover, some reviews have shown the neuroprotective effect of CUR against brain injury after intracerebral haemorrhage-induced BBB disruption in animal models, suggesting its possible help for BBB reconstitution after NBs administration.
For these reasons, this study could open the way for further development of research on novel theranostic agents able to improve brain delivery and targeting.
References
[1] Del Prado-Audelo M. et al., Biomolecules, 9, 56, 201, 2019
[2] Prasad S et al., Cancer Res Treat, 46, 2¿18, 2014
[3] Farzaei MH et al., Nutrients, 10, 855, 2018
[4] Yavarpour-Bali et al., Int J Nanomedicine, 14, 4449¿4460, 2019
[5] Zhang ZY et al., Mol Neurobiol, 54, 1-14, 2017