1. Introduction
Neurodegenerative disorders (NDs) are characterized by progressive damage in neurons and neuronal loss, leading to motor dysfunction and/or cognitive deficiency. Oxidative stress, chronic inflammation, and mitochondrial dysfunctions seem to be frequently involved in NDs, mainly in Alzheimer’s disease (AD) and Parkinson’s disease (PD) [
1,
2,
3,
4]. Oxidative stress is a phenomenon resulting from an imbalance between the production and accumulation of reactive oxygen species (ROS) in cells and tissues and the ability of cellular mechanisms to eliminate these byproducts. The main consequences of oxidative stress in these diseases are loss of glutathione, oxidative damage to DNA, proteins, and lipids. Tissues with high rates of metabolism such as the brain, heart, liver, and kidneys require high levels of antioxidants. Numerous studies have reported beneficial effects of antioxidant therapy in AD [
5,
6] and PD [
7]. Oxidative stress in the brain coupled with weakened antioxidant defenses can significantly impair functions of cellular organelles such as mitochondria, which results in the loss of synapses and cell death and leads to manifestation of the clinical symptoms associated with NDs [
8].
Idebenone (IDB,
Figure 1a), a short-chain benzoquinone, is a coenzyme Q10 analogue with a potent antioxidant activity. In cells and tissues, IDB is reduced by NAD(P)H quinone oxidoreductase 1 (NQO1) to the stable hydroquinone form, which is regarded as the active form of the molecule [
9]. When activated, the IDB molecule donates electrons to detoxify radicals and to support ATP synthesis in the mitochondrial respiratory chain [
10]. Like all quinones, it protects cell membranes and mitochondria from the action of ROS, prevents lipid peroxidation, and minimizes oxidative stress processes. Several articles have provided completely new insights into the mode of action of IDB. IDB has been reported to reduce inflammation in various test systems, such as neuroinflammation [
11,
12], nanotoxicity [
13], atherosclerosis [
14], and drug-induced inflammation [
15]. These effects cannot be explained by antioxidant activity or an increase in ATP synthesis alone. Inflammation is usually associated with hypoxia. It was recently described that, under hypoxia-reperfusion conditions, IDB prevents mtDNA release and subsequent activation of the inflammasome LNRP3, allowing IDB to intervene in one of the earliest steps of the pro-inflammatory cascade [
12]. Inflammation also has mitochondrial involvement, suggesting that inflammatory conditions of the CNS may be therapeutically targeted with IDB. Based on a new understanding of the molecular actions of this drug, it can be expected that new indications for IDB will be identified.
IDB was originally developed to treat AD and other cognitive impairments. Clinical trials show a lack of proven efficacy [
16]. After oral administration, IDB is rapidly absorbed from the gut and extensively metabolized in the liver, so that less than 1% reaches the circulation. This rate can be improved by incorporating IDB into various liquid formulations, such as suspensions, and by administering it together with fatty food [
17]. Even when taking these measures, bioavailability is less than 14% in humans. More than 99% of the circulating drug is bound to plasma proteins, which also reduces brain accumulation and hinders therapeutic potential.
IDB has a molecular weight of 338.44 g/mol, an aqueous solubility of 0.0163 mg/mL, and log P of 3.57 (DRUGBANK
®). Alternative dosage forms have been developed to improve the oral bioavailability of IDB, such as liposomes [
18], complexes with cyclodextrins [
19], and nanorods [
20]. All formulations showed increased water solubility of the drug and improved oral absorption. However, other strategies can be used to increase the distribution of IDE in the brain, making the treatment of CNS disorders more effective with respect to conventional forms. For example, intranasal administration of IDB-loaded polymeric nanoparticles (NPs) can provide direct delivery of drug molecules to the brain tissue via the olfactory and trigeminal nerve pathways, bypassing the blood–brain barrier (BBB) and the pre-systemic gastrointestinal and hepatic elimination [
21]. In addition, nose-to-brain drug transport is known to be very efficient in humans [
22]. In this way, the treatment of specific neurodegenerative disorders such as AD and PD may be more successful.
The mechanism of drug transport from the nose to the brain via the olfactory pathway is still unclear. Scientists have not investigated whether the drug is released in the nasal cavity and transported to the brain or whether the drug carriers are delivered directly via a neural connection [
23]. Most of the research has focused on increasing drug concentration in the brain and improving efficacy rather than evaluating drug transport mechanisms [
24]. The transport of formulations depends on their size, morphology, and surface characteristics [
21].
Poly-ε-caprolactone (PCL,
Figure 1b) is a biodegradable polyester with a low melting point of around 60 °C. It is usually prepared by ring-opening polymerization of ε-caprolactone. PCL degrades by hydrolysis of its ester linkages under physiological conditions and has therefore received much attention for use as an implantable biomaterial. Approved by the US Food and Drug Administration (FDA), PCL is used to develop drug delivery devices, sutures, or adhesion barriers [
25].
The aim of the present work was based on the design, development, and physicochemical characterization of biodegradable IDB-loaded PCL NPs, which can provide direct delivery of IDB to the CNS via intranasal administration. Additionally, the effect of the process variables emulsifier type and polymer molecular weight on structure, morphology, and entrapment efficiency was investigated.