Research paper
Current insights on lipid nanocarrier-assisted drug delivery in the treatment of neurodegenerative diseases

https://doi.org/10.1016/j.ejpb.2020.01.005Get rights and content

Abstract

The central nervous system (CNS) is vulnerable to pathologic processes that lead to the development of neurodegenerative disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases, Multiple sclerosis or Amyotrophic lateral sclerosis. These are chronic and progressive pathologies characterized by the loss of neurons and the formation of misfolded proteins. Additionally, neurodegenerative diseases are accompanied by a structural and functional dysfunction of the blood–brain barrier (BBB). Although serving as a protection for the CNS, the existence of physiological barriers, especially the BBB, limits the access of several therapeutic agents to the brain, constituting a major hindrance in neurotherapeutics advancement. In this regard, nanotechnology-based approaches have arisen as a promising strategy to not only improve drug targeting to the brain, but also to increase bioavailability. Lipid nanocarriers such as liposomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), microemulsions and nanoemulsions, have already proven their potential for enhancing brain transport, crossing more easily into the CNS and allowing the administration of medicines that could benefit the treatment of neurological pathologies.

Given the socioeconomic impact of such conditions and the advent of nanotechnology that inevitably leads to more effective and superior therapeutics for their management, it is imperative to constantly update on the current knowledge of these topics. Herein, we provide insight on the BBB and the pathophysiology of the main neurodegenerative disorders. Moreover, this review seeks to highlight the several approaches that can be used to improve the delivery of therapeutic agents to the CNS, while also offering an extensive overview of the latest efforts regarding the use of lipid-based nanocarriers in the management of neurodegenerative diseases.

Introduction

The nervous system is unparalleled in the vast complexity of thought processes and actions it performs [1]. Together with the endocrine system, it is one of two main control centres that are crucial for maintaining body homeostasis [2]. Neurons of the CNS are highly sensitive and fragile structures, needing a continual supply of gases and nutrients in order to function properly and efficiently transmit electrical signals [3]. The brain, neurons and associated cells are surrounded and bathed by fluids, which not only provide the most convenient ionic and nutrient microenvironment, delivering all the required substances and removing waste, but also protect against mechanical disturbances. Hence, in order to maintain the ideal microenvironment for the nervous system, a strict regulation of the volume, composition and turnover of these fluids is critical [4]. This is achieved by a series of acellular and cellular barriers that collectively protect the neural tissues from fluctuations in blood composition [5].

Highly specialized endothelial cells establish the most strict and complex barrier in the brain, the BBB, which effectively separates the blood from the interstitial fluid of the brain. The choroid plexus epithelium constitutes the blood-cerebrospinal fluid barrier (BCSFB), while the avascular arachnoid epithelium, which is located under the dura mater and totally encases the brain, forms the arachnoid barrier, partitioning the blood from the cerebrospinal fluid (CSF)-drained subarachnoid space [6].

At each site, three key aspects regulate molecular and cellular traffic. Diffusion restraint arises from a combination of mechanisms that include [7]:

  • (i)

    structural characteristics of the tight junctions (TJs) and of the cell membranes;

  • (ii)

    membrane transporters that mediate the efflux and the uptake of molecules, along with vesicular structures, which are responsible for transcytosis of larger molecules (e.g. proteins and peptides);

  • (iii)

    presence of drug-metabolizing enzymes across the interfaces, as well as intracellularly.

The aforementioned barriers are dynamic, with the ability to reply to regulatory signals from both the blood and the brain side [8]. However, they can become significantly disturbed due to pathological conditions, such as trauma, intracerebral haemorrhage, ischemic injury, neurodegenerative processes, vascular disorder or inflammation. In circumstances such as these, red blood cells, plasma components and leukocytes, which normally have their entry limited by those barriers, can cross into the brain and generate neurotoxic products that might compromise synaptic and neuronal functions [9].

Notwithstanding the presence of intrinsic protection mechanisms, the nervous system is susceptible and can be impaired through a multitude of damages, embodied by more than 600 identified medical conditions. Special emphasis must be given to neurodegenerative diseases. Among these, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS) are reported as the most prevalent in the world population [10].

The available therapies for these neurodegenerative diseases are limited, intending only to treat the symptoms. Presently, none of the existing medicines is able to stop or delay the continuous neuronal loss [11]. Notwithstanding the existence of several potential therapeutic agents, the development of new effective alternatives remains one of the main challenges, since their success is severely hindered by the protective barriers that surround the CNS [12]. In fact, the BBB is a major hurdle, as it blocks the passage of more than 98% of all small molecules and close to 100% of large ones (including polypeptides, recombinant proteins, monoclonal antibodies and those based on RNA interference technologies) from penetrating the CNS [13]. Additionally, there are other factors that may compromise the treatment, including late onset of action or several side effects associated with non-specific distribution/accumulation of neurotherapeutics [14]. Therefore, innovative therapeutic alternatives capable of penetrating the BBB are critical [15].

Different approaches for drug delivery to the brain are reported in the literature, such as intranasal delivery, intracerebroventricular and intracerebral administrations or transient disruption of the BBB in response to physical, chemical or biological stimuli [16]. However, most of these methods not only are invasive and expensive, but also bring up issues pertaining patient comfort and risk of infection or toxicity. Therefore, their wide-scale implementation is very difficult [16], [17]. In recent years, the advent of nanotechnology has provided new opportunities to overcome the limitations that arise when targeting drugs to CNS through conventional delivery mechanisms [18].

Drug-loaded nanosystems are relevant and useful for the management of neurodegenerative disorders [19]. In particular, lipid-based formulations such as liposomes, lipid nanoparticles (SLN and NLC), microemulsions or nanoemulsions, have been extensively exploited to mediate targeting to the CNS and overcome the factors that impede the delivery of therapeutic agents through the BBB. These nanosystems have several advantages that make them highly attractive colloidal carriers for brain delivery over other nanocarriers [20], [21], [22], [23]. As a result of their potential to escape phagocytosis by the reticuloendothelial system (RES) and to naturally enter the brain capillary endothelial cells (BCECs), these systems have become one of the main focus in CNS nanomedicine research [13]. Furthermore, through surface modification and coating, lipid nanocarriers can be engineered to interact with particular types of molecules or cell receptors present in the BBB, thereby not only enhancing brain targeting ability, but also improving the bioavailability and CNS concentration of certain drugs which normally cannot cross the BBB [19], [24].

This review intends to bring to the forefront the advances and challenges of using lipid nanosystems as a promising strategy to improve the management of neurodegenerative diseases. As a starting point, a concise description on the anatomophysiology of the BBB and the BBB transport systems is given. Afterwards, an explanation of the key neurodegenerative disorders and related approved drug therapies is provided. The final sections describe the current approaches to direct and increase the release of neurotherapeutic agents in the CNS and report the main findings of the most recent and relevant studies regarding lipid nanosystems in the treatment of the mentioned pathologies.

Section snippets

The Blood-Brain Barrier (BBB)

The BBB acts as a vital border among the circulating blood and the neural tissue [25]. Given its distinctive anatomical features, it plays a crucial role in controlling the traffic through the CNS, having a variety of functions. Firstly, it preserves the internal brain environment, i.e. maintains the CSF and the interstitial fluid composition within extremely regulated limits, so that the neurons can fulfil their complex integrative roles [26], [27]. This homeostasis of the CNS is achieved by a

Neurodegenerative diseases

Neurodegenerative disorders are a growing risk to the state of human health. Owing partially to a rise of the elderly population in recent years, such age-dependent diseases are increasing their prevalence worldwide [68]. The advent of technology and science has not only led to an increase in life expectancy, but also to a bigger susceptibility to neurodegenerative diseases [69]. These illnesses are characterized by neuronal loss in the brain and/or spinal cord. Examples of neurodegenerative

Current approaches for enhanced delivery of therapeutics to the CNS

The effective treatment of brain diseases is hampered by the selective permeability and tight regulation of the BBB, preventing most of the neuroactive molecules from entering the CNS [171]. Considerable strides have been made towards improving the uptake of diagnostic and therapeutic agents into the brain. For this purpose, in combination with new developments in BBB investigation, various approaches have been exploited, which can be categorized in [172]: (a) Invasive techniques, including

Future perspectives and conclusions

Neurodegenerative diseases constitute a serious health epidemic and a major challenge for sustainable development [287]. A main reason for the failure of promising neurotherapeutic candidates is the existence of selective and impermeable cellular interfaces such as the BBB. In fact, the BBB is a double-edged sword, since while it helps maintain an optimal and constant milieu for neuronal function, it also restricts most drugs passing from the circulatory system to the brain. Consequently, there

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). The authors also acknowledge the Portuguese Foundation for Science and Technology (FCT) for financial support in the framework of the Strategic Funding UID/Multi/04546/2019.

Figures 1 and 2 were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License.

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