Solid lipid nanoparticles for targeted brain drug delivery☆
Introduction
In the last decade, an emerging interest has been growing towards brain drug targeting where issues have been widely discussed [1], [2], [3], [4], [5], [6], [7], [8]. The increasing awareness of the lack of rational and common efforts among different and complementary research areas has pointed out the need for a deeper understanding and a closer collaboration among diverse research experts [7], [9] of the field. These issues along with poor knowledge regarding the physiology of the central nervous system (CNS) have been the main limiting factors in the development of effective drugs and appropriate drug delivery systems (DDS) for brain targeting [1], [2], [6], [7]. In fact, delivering drugs to the CNS is impaired by the presence of the blood-brain barrier (BBB) that represents the main obstacle for CNS drug development [2], [10].
A worrying updated picture of the worldwide CNS pathology incidence displayed that, in Europe alone, about 35% of the total burden of all diseases is caused by brain diseases [1] and about 1.5 billion people worldwide suffer from CNS disorders. Moreover, due to an average lifespan increase to almost 70 years of age at which about 50% of the population starts revealing evidence of Alzheimer's disease (AD) [5], an increase of CNS disorder global burden from the current 11% to 14%, is expected by 2020 [11]. For genetic, age and contingent reasons, most of the degenerative CNS pathologies, such as Creutzfeldt-Jakob's, Parkinson's (PD), Alzheimer's, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, are developing as a consequence of wrong lifestyle and increased risk factors, such as alcohol, drugs or dietary abuse as well as stress [12], [13], [14]. In addition, CNS involvement may occur because of primary effects of human immunodeficiency virus (HIV) infection or secondary effects of immune suppression. About 75% of patients with acquired immune deficiency syndrome eventually develop some features of subacute encephalitis and other secondary effects, such as primary CNS lymphoma and progressive multifocal leukoencephalopathy [12], [15], [16], [17], [18], [19], [20]. This emergency is becoming particularly serious in developing countries, as a result of a wide and uncontrolled spread of HIV infection.
In spite of this worrying picture, in the last number of years the CNS drug market has become the largest of all therapeutic areas, recording worldwide an amazing + 13% growth in 2003, reaching 77.2 billion USD [21]. This is also due to the advances reported in the treatment and understanding of some serious CNS pathologies [22], [23], [24], [25], [26], [27]. In this context, the pharmaceutical technology contribution to this area has been found of paramount importance [5], [6], [28], [29], [30]. Several DDS and strategies have been developed for the sole purpose of an effective drug deposition to the CNS [31], [32], [33], [34], [35], [36], while other carriers, fabricated for different aims, have been turned to a possible brain targeting application [27], [37]. Among others, nanoparticles (NPs) have been considered as carriers of election to overcome the BBB issue [36], [38], [39].
Several systems have been developed and among these, poly(ethylene glycol) (PEG) stabilized poly(lactide) (PLA) [40] and chitosan [41] NPs, conjugated with the peptidomimetic monoclonal antibody OX26, gave good results. NPs obtained by conjugating poly(lactide-co-glycolide) PLGA to five short synthetic peptides, to mimic the synthetic opioid peptide MMP-2200 [42], and a Lectin–PEG–PLA conjugated system [43] showed to be equally effective in brain targeting. Moreover, a significant brain uptake was achieved by using polysorbate 80 (P80) as a coating system [44], [45], [46].
Among other NP formulations, solid lipid nanoparticles (SLN) have recently found reappraisal as potential DDS for brain targeting [36], [38], [44], [47], [48], [49]. The present review will report the state of the art on surfactant-coated NPs designed for brain targeting, and the transfer of this technology to SLN and related carriers will be emphasized on the basis of their cytotoxicity, drug loading capacity, and production scalability. Besides, SLN physicochemical characteristics will be discussed in order to address the issues related to the development of suitable brain targeting formulations.
Section snippets
Blood-brain barrier biology
The brain is one of the most important organs of the human body, if not the most, and its homeostasis is of primary importance. In fact, specific interfaces, also referred to as barriers, tightly regulate the exchange between the peripheral blood circulation and the cerebrospinal fluid (CSF) circulatory system. These barriers are represented by the choroid plexus (CP) epithelium (blood-ventricular CSF), the arachnoid epithelium (blood-subarachnoid CSF), and the BBB (blood-brain interstitial
Brain drug delivery using surfactant coated polymeric nanoparticles
Out of the several different approaches previously mentioned, the use of NPs has been regarded as having great potential for the delivery of drugs into the CNS. The term NPs refers to well-defined particles ranging in size approximatively from 10 to 1000 nm (1 μm) [73] with a core-shell structure (nanocapsules) or a continuous matrix structure (nanospheres). The active compounds may be entrapped within NPs and/or adsorbed or bound to their surface. Different kinds of polymers such as
Preparation and sterilization
Many approaches for SLN preparation exist. The most common methods consist in high pressure homogenization at elevated or low temperatures, microemulsion, solvent emulsification–evaporation or –diffusion, w/o/w double emulsion and high speed stirring and/or sonication [47], [48], [49]. High pressure homogenization at elevated temperatures [145], [146] and microemulsion [147], [148], [149] are among the most versatile techniques and for this reason have been largely employed for SLN preparation.
SLN physicochemical features with respect to brain drug delivery
Lipids are rightly being considered as safe and useful materials for drug delivery [49], [135], [189], [190], [191], [192], [193]. Conventional lipid-based systems, consisting of emulsions and microemulsions, have been widely used to enhance bioavailability of class II molecules [194], and the absorption of class III molecules [194]. The stability of such systems is strictly related to particle size distribution, the lipid content, and the presence of a surfactant capable of stabilizing the
SLN for brain drug targeting
In the late '90s SLN were proposed for brain drug targeting application independently by two research groups [233], [234] even though the first proof of lipid particle transport across the BBB had already been provided [235].
Studying the pharmacokinetics of two anticancer agents, namely camptothecin and doxorubicin, drug accumulation into the brain was observed after both oral and i.v. administration when loaded into SLN [233], [234]. As previously shown with PACA NPs, better results in brain
Concluding remarks
The amazing growth in recent years of CNS drugs on the market has generated enormous research efforts in an attempt to develop new drugs for brain diseases. However, the main interest has been focused on the discovery of new therapeutic molecules rather than developing new approaches and systems to target actives to the brain. This is a general trend in pharmaceutical science. Since the importance of drug delivery to improve therapies was understood more than 30 years ago, it is deeply
Legend for lipid substances
Brij® 35: Polyoxyethylene (35) lauryl ether
Brij® 72: Polyoxyethylene 2 stearyl ether
Brij® 78: Polyoxyethylene (20) stearyl ether
Compritol® 888 ATO: Mixture of mono-, di-, and triglycerides of behenic acid (referred in the text as Compritol®)
Cremophor® ELR: Polyoxyethylated castor oil
Cremophor® RH40: Polyoxyl 40 hydrogenated castor oil
Cremophor® EL: Polyoxyl 35 castor oil
Dynasan® 114: Trimyristin
Dynasan® 118: Tristearin
Imwitor®: Glycerol monostearates
Pluronic® F68: Ethylene oxide/propylene oxide
Acknowledgment
Thanks are due to Miss Maria Vigilante for kindly revising the English version of the manuscript.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Lipid Nanoparticles: Recent Advances”.