Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier
Authors Vieira DB, Gamarra LF
Received 14 July 2016
Accepted for publication 7 September 2016
Published 18 October 2016 Volume 2016:11 Pages 5381—5414
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Akshita Wason
Peer reviewer comments 3
Editor who approved publication: Prof. Dr. Thomas J Webster
Débora B Vieira,1 Lionel F Gamarra1,2
1Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil
Abstract: This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood–brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer’s, Parkinson’s, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood–brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.
Keywords: Alzheimer, Parkinson, stroke, cerebral ischemia, glioma, liposomes, blood–brain barrier
In the 1880s, Paul Ehrlich intravenously injected dyes (eg, trypan) into animals, and observed that the dyes were able to stain all organs except for the brain. He concluded that the brain had a lower affinity to the dye when compared to other organs.1 In 1913, Edwin Goldmann, a student of Ehrlich, did the opposite, and injected the very same dyes directly to the cerebrospinal fluid of animal brains. He found that in this case, the dyes readily stained the brain and not the other organs.2 These experiments clearly demonstrated the existence of a separation between the blood and the brain. However, in 1898, Max Lewandowsky was the first to postulate the existence of a specialized barrier at the level of cerebral vessels: the blood–brain barrier (BBB), after he and his colleagues had carried out some experiments to demonstrate that some drugs were neurotoxic when injected directly into the brain and not into the vascular system.3 It was just in the late 1960s that Reese and Karnovsky visualized the fact that the barrier was localized to the endothelium by electron-microscopy studies.4
The BBB is composed of polarized endothelial cells connected by tight junctions of the cerebral capillary endothelium and a variety of transporters (Figure 1), which are responsible for its extremely low permeability, limiting the delivery of drugs to the central nervous system (CNS).5,6 BBB functionality is dynamically regulated by an ensemble of different cell types, such as astrocytes, pericytes, and neurons (Figure 1A).7–9 Endothelial cells are surrounded by a basal lamina, which is generally rich in laminin, fibronectin, type IV collagen, and heparin sulfate,5,7–9 which may represent an interesting targeting for drug transport and provides a negatively charged interface.10,11
Aimed at the development of more efficient therapies for neurological disorders, extensive research is being done into the molecular and cell biology of many of these disorders. To date, human genetic mutations and defective cell-signaling pathways linked to a disease have been identified, and may contribute to the development of mechanism-based therapies and biomarkers for affected patients at early stages in the disease.12,13 Moreover, pharmaceutical companies have spent billions of dollars in the hope that their scientists could develop drugs to defeat the brain disorders, eg, a drug that helps brain-cell growth, repairs damage, or slows down tumor progress, something that is not available now. However, obstacles to effective therapy delivery remain, and one of the most notable obstacles for drugs to penetrate the brain effectively is the BBB.14,15
How to circumvent the blood–brain barrier?
Based on better knowledge of BBB biology, several different strategies for delivering molecules across the barrier have been developed for treating CNS diseases, and can be broadly classified as invasive, pharmacological, and physiological approaches.15–19 The invasive method is based on direct delivery of drugs into the brain tissue through varying techniques, such as the use of polymers or microchip systems, stereotactically guided drug insertion through a catheter, and transient disruption of the BBB. However, these approaches are invasive, leading to risks of infection, damage to brain tissue, and toxicity. Furthermore, invasive approaches are costly and require hospitalization.20–22
The pharmacological method for crossing the BBB is based on modifying, through medicinal chemistry, a drug molecule to enable BBB permeability and making it insusceptible to drug-efflux pumps, such as P-glycoprotein (PgP).17 One early strategy was based on the development of highly lipophilic and small drugs, allowing them to diffuse successfully through the brain’s endothelial cells (Figure 1B). Unfortunately, synthesizing drugs that fulfill this condition eliminate a vast number of potentially useful polar molecules that could be used to treat CNS disorders. A second possibility is to use small water-soluble drugs to facilitate traversal of the BBB by the paracellular hydrophilic diffusion pathway (Figure 1B), though the majority of these molecules are just able to penetrate the interendothelial space of the cerebral vasculature up to the tight junctions, and not beyond. Moreover, modifications to drug structure often result in loss of the drug’s biological activity.23
Among all the approaches employed in drug delivery to the brain tissues, the physiological method is the most advantageous, as it takes advantage of the transcytosis capacity of specific transporting receptors expressed at the BBB surface in order to penetrate the barrier (Figure 1B). For example, the occurrence of low-density lipoprotein receptor-related protein on the BBB is of critical importance for therapeutic proteins or peptides to glial cells or neurons across the whole CNS.24–26 Another method consists in the use of receptor-mediated endocytosis by conjugation of drug molecules to ligands, such as antibodies and peptides, against receptors that are expressed on the surface of endothelial cells of the barrier,6 allowing the drug to be transported into the brain (Figure 1B). In addition, cationic compounds are able to bind to the negatively charged plasma membrane of the endothelial cells by electrostatic interactions.10,11 Therefore, the cationic substance crosses the BBB by adsorption-mediated transcytosis or endocytosis (Figure 1B). However, a low rate of drug dissociation from the ligands, nonspecific drug–receptor interactions, and the limited concentration of cationic substances in the brain are disadvantages for this kind of approach.
Undoubtedly, all three of these approaches have strong disadvantages that limit the successful treatment of neurological diseases. In response to this insufficiency in methods to transport therapeutic drugs across the BBB, aggressive research efforts into the use of nanotechnology to deliver drugs effectively across the BBB without altering their effect is being done. For this purpose, a broad range of nanoparticles with different sizes, architectures, and surface properties have been engineered for brain drug delivery.27,28 These include liposomes,29,30 polymeric nanoparticles,31,32 carbon nanotubes,33,34 nanofibers,35,36 dendrimers,37,38 micelles,39 inorganic nanoparticles made of iron oxide,40 and gold nanoparticles.41 Unfortunately, it is beyond the scope of this article to review potential advantages – or disadvantages – of each of these nanocarriers in the imaging and/or therapy of the brain. For a more detailed overview of nanotechnology-based systems on drug delivery to the CNS, we refer the reader to Vlieghe and Khrestchatisky.27 Here we focus on the one of most promising approaches aimed at improving brain drug targeting and delivery: liposomes and molecules that can selectively target brain tissues. In fact, liposomes are at present the nanoparticle type with the most studies that have been published for delivery to the brain, representing in this way the most advanced material and thus with the highest potential for clinical applications.
Why use liposomes for treating neurological disorders?
Common diseases of the CNS, such as neurodegeneration, multiple sclerosis, stroke, and brain tumors, represent a huge medical need. According to a World Health Organization report, about 1.5 billion people globally are suffering from neurological diseases.42 The prevalence of neurological disorders is expected to have a significant increase in the next decade, as the aging population is highly increasing and living longer. Drug therapies to the brain have been particularly inefficient, especially due to the BBB, as discussed earlier. It would be thus be desirable to gain a better understanding of the molecular mechanism of the disease and the development of improved diagnostic devices and treatments. In this way, liposomes have emerged as promising carriers for CNS delivery.
Liposomes are roughly nano- or microsize vesicles consisting of one or more lipid bilayers surrounding an aqueous compartment. The potential use of these vesicles as a carrier system for therapeutically active compounds was recognized soon after its discovery in the early 1960s. In recent years, liposomes have been explored as carriers of therapeutic drugs, imaging agents, and genes, in particular for treatment and/or diagnosis of neurological diseases.29,43–45 Due to their unique physicochemical characteristics, liposomes are able to incorporate hydrophilic, lipophilic, and hydrophobic therapeutic agents. Hydrophilic compounds may either be entrapped into the aqueous core of the liposomes or be located at the interface between the lipid bilayer and the external water phase. Lipophilic or hydrophobic drugs are generally entrapped almost completely in the hydrophobic core of the lipid bilayers of the liposomes. In addition, the use of cationic lipids allows the adsorption of polyanions, such as DNA and RNA (Figure 2). They also have the advantage of presenting good biocompatibility and biodegradability, low toxicity, drug-targeted delivery, and controlled drug release.46,47 In order to improve blood circulation and brain-specific delivery, the liposome surface can be further modified by the inclusion of macromolecules, such as polymers, polysaccharides, peptides, antibodies, or aptamers (Figure 2). Unfortunately, efficient brain-specific drug delivery by liposomes is not in clinical practice. However, several liposomal drugs are either approved for clinical use or in clinical trial studies (Table 1).48–59
Figure 2 Schematic representation of the main liposomal drugs and targeting agents that improve liposome affinity and selectivity for brain delivery.
Optimizing the ideal liposome for crossing the BBB has important implications for the treatment of neurological diseases. Different liposomal formulations and strategies have been developed for enhancing drug delivery across the BBB. The following examples illustrate current strategies using liposomes as brain vectors (Table 2).60–69 Cationic liposomes are successfully used as carriers for the delivery of therapeutic drugs and genes.70–72 Several studies have shown that these cationic nanocarriers are more efficient vehicles for drug delivery to the brain than conventional, neutral, or anionic liposomes, possibly due to the electrostatic interactions between the cationic liposomes and the negatively charged cell membranes, enhancing nanoparticle uptake by adsorptive-mediated endocytosis.60–62 But there is a major drawback to the use of cationic nanocarriers for brain delivery: due to nonspecific uptake by peripheral tissues and their binding to serum proteins that attenuates their surface charge, large amounts of these nanocarriers will be required to reach therapeutic efficacy, and those carriers are potentially cytotoxic. Therefore, there is a need for the development of liposomes that efficiently target diseased areas in the brain.
Table 2 Means by which liposomes can penetrate the BBB
Surface-functionalization methodologies improve, at least in part, the pharmacokinetics and biodistribution of liposomes into the brain. For example, the addition of polyethylene glycol (PEG) or polysaccharides forms a protective layer over the surface of liposomes and protects the vehicle from the binding of plasma proteins, preventing the opsonization process and subsequent clearance of liposomes. Even though the PEGylation of liposomes prolongs their circulation time in the body, it does allow liposomes to cross the BBB. Therefore, their functionalization with biologically active ligands, such as peptides, antibodies, aptamers, and others, which specifically bind to receptors that are expressed on the surface of the brain endothelial cells, facilitates their binding and transport across the BBB.73,74
Although actively targeted brain drug delivery has improved the crossing of nanoparticles into the brain, additional properties can be included in liposomal systems to enhance the delivery of drugs at the targeted site in response to specific stimuli, such as variations in temperature, magnetic field, ultrasound intensity, or changes in pH. For example, recent reports introduced the concept of magnetic liposomes as a targeting moiety for delivering of therapeutic molecules across the BBB. In one example, one or more drug molecules could be reversibly bound to the surface of iron oxide nanoparticles, and when encapsulated within the core of liposomes, bypassed an established in vitro model of the BBB by action of an external magnetic field.67 Furthermore, it has been shown that magnetic liposomes can also be taken up into human monocytes, followed by the entry of nonmagnetic monocytes into the brain.67 Although this approach has not been largely explored for brain delivery, this may become a good strategy for effective drug delivery by stimuli-responsive liposomes.
Furthermore, multifunctional liposomes can be engineered into a single structure, providing a powerful approach to improve disease-specific detection, treatment, and follow-up monitoring.30 The term “theranostic” is used for nanoparticles that incorporate both therapeutic and diagnostic agents onto the same system.75 One example of theranostic agent for brain delivery was described by Wen et al,76 using quantum dots and apomorphine liposomally encapsulated for both brain therapy and imaging. The results showed that theranostic liposomes were transported across the BBB, providing a new and exciting strategy for brain-cancer imaging and therapy.76
It is worth mentioning that various routes of administration have been tested to access the brain for therapeutic purposes. For the delivery of liposomes to the CNS, intravenous injection seems to be the preferred route. The possibility of choosing between alternative routes of administration (oral, ocular, or mucosal) has been largely explored for bypassing the BBB, but it is beyond the scope of this article. For example, intranasal administration provides a practical and noninvasive approach to deliver drugs to the brain, allowing in this way an increase in the amount of drugs delivered across the barrier.77–79 It was shown that a liposomal formulation of rivastigmine was able to prevent degradation of the drug in the nasal cavity and to carry it through the mucosal barriers.80 Furthermore, the ability of cationic liposomes to delivering proteins to the brain via the intranasal route has also been demonstrated.81
In this review, a search of the literature was undertaken to investigate whether the use of liposomes offered any additional benefit than the therapeutic drug alone to treat most significant neurological diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, stroke, and brain cancer, and discuss its advantages and limitations. As a vast majority of CNS drugs have limited brain uptake, they may benefit from the use of liposomes as a drug-delivery vehicle into the brain. Moreover, liposomes have been widely explored as drug-delivery carriers to increase uptake of such drugs into the CNS. Therefore, there appears to be an obvious need for establishing CNS-penetrant and specific therapeutics to overcome the BBB and to do this in a controlled manner.
Materials and methods
A PubMed and Web of Science search was conducted to identify all known published articles on liposomes in drug development focused on the treatment of neurological disorders up to May 2016.
Initially, articles were identified using a combination of the following keywords: 1) “liposomes” and “Alzheimer”; 2) “liposomes” and “Parkinson”; 3) “liposomes” and “Huntington”; 4) “liposomes” and “stroke” or “cerebral ischemia”; and 5) “liposomes” and “glioma”. Reviews, patents, editorial materials, book chapters, conference publications, and articles not published in English were excluded from the literature search. Based on titles/abstracts, only studies that described in vivo experiments were selected for review. The final decision to include/exclude studies was based on full copies of articles.
In vivo studies with liposomes have been performed in most species, including mice, rats, dogs, monkeys, and humans. As in vivo study interpretation of results deserves attention, especially because of the biological differences between species, this was the parameter used to group the studies. Also, the following parameters of the liposome formulation were compared: 1) route of administration, 2) time points, 3) liposome composition, 4) ligands, 5) drug or imaging agent, and 6) particle size. Lately, biological outcome into the CNS has also been reported.
Results and discussion
AD, PD, and Huntington’s disease were grouped together in this topic, because a growing number of studies indicates that these disorders share in common some features, such as the accumulation of intracellular or extracellular protein aggregates, selective degeneration of neurons, inclusion-body formation, and inflammation in particular brain regions.82 However, the search for reports on the use of liposomes for delivery of active or imaging compounds against neurological diseases was done individually. A flowchart of the literature search is shown in Figure 3. An initial search yielded a total of 319 articles for AD, 141 articles for PD, and 59 articles for Huntington’s, after excluding duplicate articles found in the PubMed and Web of Science databases. For AD, 26 full-text article reviews were performed, and 12 studies were included for their fulfillment of inclusion criteria (Figure 3, Table 3).80,83–95 For PD, 19 full-text articles were reviewed, and eight articles had all the requisites to be considered here (Figure 3, Table 3).96–103 Unfortunately, for Huntington’s disease, just one full article was analyzed and this article did not show any outcome of interest for this disease, and for this reason was not included here (Figure 3).
Figure 3 Flow diagram of studies that were identified based on the search terms described in the body of this article.
Liposomes in the treatment of Alzheimer’s disease
AD is a progressive and irreversible disease of the brain, affecting mainly people aged over 65 years. The neuropathogenesis of AD is a critical unsolved question. Progressive production and accumulation of insoluble protein aggregates, such as neurofibrillary tangles of hyperphosphorylated tau and amyloid-β (Aβ) plaques are thought to underlie the neuropathology of AD, leading to brain atrophy and neurodegeneration.104 In addition, some studies have also suggested that deficits in cholinergic neurotransmitter systems and increased levels of free radicals or proinflammatory cytokines might be involved in AD neuropathogenesis.105–108 More recently, a new potential cause for AD has been found in the behavior of certain immune cells that normally protect the brain instead beginning to consume a vital nutrient: the amino acid arginine.109 This new discovery has implications not only in a new potential cause of the disease but also as a new strategy for targeting disease.
To date, the US Food and Drug Administration (FDA) has approved three acetylcholinesterase inhibitors – rivastigmine, galantamine, and donepezil – for the treatment of AD, which lead to an increase in central cholinergic action in the brain areas affected by the disease.110 However, the administration of these inhibitors is associated with some severe side effects. It would thus be desirable to develop new formulations to avoid these side effects, and all studies proved that the use of liposomes was a good strategy in the treatment of AD.80,86,90–92,111 Intranasal delivery of rivastigmine or galantamine liposomes has been shown to be a viable and effective route to improve drug bioavailability for brain drug targeting.80,90,92 Intranasal delivery was also used as a successful approach for delivery of liposomes containing quercetin, which has antioxidant properties. As oxidative stress plays a very important role in the neuropathogenesis of AD, the use of quercetin liposomes has been shown to decrease neuronal oxidative stress.93–95
Moreover, there have been several studies exploring different strategies to block the effects of Aβ and tau proteins that constitute major hallmarks of AD.84–87,91 Once encapsulated into liposomes, the H102 peptide, a β-sheet breaker, was able to block the early steps of aggregation and misfolding of the soluble Aβ, improving the spatial memory impairment of AD in rats.112 α-Mangostin is a polyphenolic xanthone that exhibits pharmacological effects, such as anti-inflammation, antioxidant, and antitumor effects. When administered intravenously, α-mangostin liposomes have been shown to protect and improve the neurons against Aβ-oligomer toxicity in rats.88
Methoxy-XO4, a highly specific Aβ plaque ligand with the dual role of targeting moiety and fluorescent marker, has been conjugated to liposomes. When administered intravenously, these liposomes were able to cross the BBB in vivo and specifically bind to Aβ-plaque deposits, labeling vascular and parenchymal amyloid deposits in brain tissue.87 For example, glutathione PEGylated liposomes demonstrated efficient encapsulation of an antiamyloid single-domain antibody fragment (VHH-pa2H), increasing its transport from blood into the brain.83 It has also been demonstrated that bifunctionalized liposomes decorated with phosphatidic acid and a modified ApoE-derived peptide are able to cross the BBB in vivo and destabilize Aβ aggregates, suggesting that this approach is a good option for AD treatment.84,85
Although the scope of this review is on liposome-strategies with the aim of facilitating BBB crossing, it is important to mention that other strategies have been developed for the use of liposomes for AD treatment.89,113–116 Curcumin is a natural compound extract from the plant Curcuma longa, and has been reported to be a fluorescent molecule with high affinity for the Aβ peptide and able to reduce Aβ aggregation. In this way, intracranial injection of liposomes encapsulating curcumin efficiently labeled Aβ deposits in both human and mice tissues, proving to be an effective formulation for diagnosis and treatment of AD.113 Also, intraperitoneal injection of liposomes containing phosphatidic acid or cardiolipin was able to reduce Aβ peptides in the plasma and shifted the equilibrium that exists between brain and blood Aβ peptides, slightly affecting the plaques in the brain.89 Lastly, different liposome-based vaccines were developed and directed toward Aβ plaques115,116 and tau.114
Liposomes in the treatment of Parkinson’s disease
PD affects 4 million people worldwide.117 The neuropathogenesis of PD is characterized by motor symptoms, such as tremor, rigidity, slowness of movement, difficulty with walking, and problems with gait. These motor symptoms result primarily from the death of dopamine-generating neurons in an area of the brain called the substantia nigra, leading to the decreasing of dopamine levels.118 Also, misfolding and intracellular aggregation of α-synuclein fibrils, also known as Lewy bodies, are pivotal to PD neuropathogenesis.117,118 Mitochondrial dysfunction and oxidative stress may also be implicated in PD neurodegeneration.118 However, the mechanisms underlying PD pathogenesis have not been fully elucidated.
Currently, available therapies for PD are essentially symptom-directed, having no effect on the disease progression. To date, the natural precursor of dopamine, levodopa or L-dopa, has been used in the clinic for several years.119 However, levodopa cannot be administered alone, since it is converted to dopamine via peripheral dopamine-decarboxylase enzyme and causes such side effects as sleepiness, nausea, and dyskinesia.120 A recently reported study overcame this problem, developing liposomes for site-specific delivery of levodopa into the CNS.96 Chlorotoxin-modified stealth liposomes encapsulating levodopa proved to be an efficient nanocarrier, increasing levodopa concentration into the substantia nigra and striatum.96 In the same way, it was also observed that intraperitoneal injection of liposome formulations encapsulating anti-PD drugs could improve the release of dopamine in the striatum region.96–99,102,103
Also, there are ongoing studies showing that GDNF is able to promote growth, regeneration, and survival of substantia nigra dopamine neurons, preventing the progression of PD if administered in the early stages of the disease.121–124 Recently, a very promising study showed neurotrophic and neuroprotective effects of GDNF protein into the rat brain.100 Although the liposomal preparation of GDNF offered no significant advantage of GDNF alone after intranasal injection, the liposomal formulation might have a protective effect on the protein, preventing it from degradation.100 Another example that demonstrated the improvement of the treatment of the disease with GDNF is reported in Xia et al.101 In this study, intravenous administration of OX26-targeted PEGylated liposomes was used as a nonviral gene-delivery system to deliver GDNF plasmid into the CNS. The expression of GDNF genes, under the influence of a rat tyrosine hydroxylase promoter, was observed in organs where the TH gene is highly expressed, including the substantia nigra, adrenal gland, and liver. Sustained therapeutic delivery was achieved at the neurons of the nigrostriatal tract in experimental PD.101 Lastly, novel liposomal formulations have been characterized and efficacy in PD rats reported after intracerebral injection.125–130 As the injection was at the local site of the disease and did not show any evidence of transposing the BBB, they were not considered in this review article.
Stroke or cerebral ischemia
Unlike the other neurological disorders described so far, stroke has high incidence, disability, and mortality rates in a modern society.131 An ischemic stroke is characterized by the sudden reduction of brain blood flow due to obstruction of cerebral vasculature, damaging the neural tissue (ischemic penumbra zone).132 Unfortunately, the treatment for stroke has its limitations, due to the poor ability to deliver therapeutic agents across the BBB. Therefore, efforts have been made to identify and develop drug-delivery systems to the brain. Liposomes are described as a possible valuable system to achieve better therapeutic effects in the treatment of stroke. The search for reports on the use of liposomes as drug-delivery nanocarriers for the treatment and/or diagnosis of stroke is shown in Figure 3. An initial search yielded a total of 365 articles after excluding duplicate articles found in the PubMed and Web of Science databases. In total, 62 articles were eligible.133–194 Although all articles described new nanocarriers for the delivery of therapeutic molecules into the brain, only 57 studies are included in Table 4, because the full text of five articles139,173,182,183,189 was not available to access.
The initial treatment for acute ischemic stroke consists in the administration of the FDA-approved tissue plasminogen activator (tPA), which is effective within the first 3 hours after the event occurs. This drug works on quickly dissolving the blood clot to restore brain perfusion.195 However, its use is limited, due to elevated risk of cerebral hemorrhage, most probably due to the generation of free radicals posttreatment.196 Because oxidative damage is an important aspect of the pathology of stroke and involved in vascular cell-membrane damage, researchers considered the possibility of developing a novel system to deliver tPA efficiently to the ischemic penumbra area in the brain. Actin is already known to be able to bind to antigens present at the surface of cells with damaged membranes. Therefore, actin-targeted liposomes for tPA delivery were developed, and this new drug-delivery system was in fact very efficient in delivering tPA within the brain, reducing hemorrhagic transformation in rats after focal embolic stroke.173 Furthermore, the enzyme SOD was demonstrated to be an excellent biological natural free radical scavenger, and its ability as a neuroprotectant agent was tested. As free enzymes possess no BBB-penetration capacity and degrade rapidly in the serum, SOD encapsulation in liposomes was needed. In vivo experiments demonstrated the efficacy of SOD-loading liposomes to get into the brain, providing significant protection against free radicals.136,139,185,186,189,192
Moreover, a wide debate is ongoing in the literature about new strategies to treat this disease. Neuroprotective and neuroreparative drugs (for example, citicoline) are under development.197 Citicoline, an exogenous form of cytidine-5′-diphosphocholine, is a key intermediate in the biosynthesis of phosphatidylcholine, the primary neuronal membrane phospholipid that is degraded during brain ischemia to free radicals and fatty acids. In addition, citicoline restored Na+/K+ ATPase, inhibited activation of phospholipase A2, and accelerated cerebral edema reabsorption.198 Therefore, citicoline was considered a good candidate for molecular therapy for stroke, since its acts at several points on the ischemic pathway. Unfortunately, due to the drug’s polar nature, crossing the BBB was far lower than desired. It has been observed that liposome-encapsulated citicoline increases its bioavailability within the brain parenchyma and improves its therapeutic efficacy for the treatment of stroke in animals.142,155,159,169,177,179–182
Besides damaged blood vessels in cerebral ischemia, another important process that occurs in stroke is neovascularization or angiogenesis. This is the physiological process of forming new blood vessels from the existing vasculature in healthy brain tissue into areas of ischemic penumbra.199 The outermost cells in the zone of ischemic penumbra slightly restore their metabolism activities, since they have more blood supply when compared to cells more centrally located in the ischemic area. At this site, where blood supply is limited, there is rapid consumption of ATP, due to low levels of oxygen. Therefore, the delivery of exogenous ATP by liposomes could restore the metabolism of ischemic cells and reduce the area of injury.135,137,138,183,184,187,188
As mentioned earlier, cells within the infarcted area of ischemic tissue do not receive enough oxygen or nutrients to generate ATP. For this purpose, liposome-encapsulated hemoglobin (Hb) was engineered as a pharmacological agent able to deliver oxygen for the treatment of ischemic diseases. Several studies reported in the literature suggest the efficacy of Hb liposomes in the treatment of stroke by enhancing the biodistribution of Hb liposomes within the ischemic area in the brain.144,145,147,160–164,167,171,191,193,194 In the same way, liposomes for the delivery of angiogenic peptides140 and VEGF157 to promote angiogenesis in ischemic tissue were developed, and both formulations effectively promoted vascular regeneration.140,157
Over the years, many liposomal formulations have been developed for the treatment of stroke. Moreover, when liposomes were associated with contrast agents, researchers observed that they quickly accumulated in the ischemic zone.134,143,148,152,190 Some formulations have demonstrated their ability to improve in vivo activity of drugs, such as chrysophanol,133 dexamethasone phosphate,154 nerve growth factor,170 Xe,150,158 FK506,149 isopropylidene–shikimic acid,151 asialo-erythropoietin,153 antisense oligonucleotides,165 plasmids,174 quercetin,166,168 fasudil,176 nitric oxide,146 N-acetyl-leucyl-leucyl-norleucine amide,178 and a combination of synergistic drugs.156,175 Very recently, a promising uncoupling new drug – ZL006 (5-(3, 5-dichloro-2-hydroxybenzylamino)-2-hydroxybenzoic acid) – was developed for stroke treatment. Its mechanism of action is based on the selective blocking of the coupling of nitric oxide synthase, and it was also recognized as a neuroprotective drug. As with many other drugs, ZL006 possesses low to BBB-permeability capacity. However, its encapsulation in immunoliposomes targeted the BBB and significantly enhanced the delivery of ZL006 within the brain. A remarkable neuroprotective effect was also observed.141
Brain cancer – glioma
There are more than 100 different types of brain and CNS tumors. In this article, we focused our search on the term “glioma”, which encompasses all tumors that arise from glial cells, including astrocytomas, oligodendrogliomas, ependymomas, and glioblastomas multiforme.200 Glioblastoma multiforme is by far the most common and aggressive cancer form of the glial tumors. The current standard of care for this type of cancer includes surgery, followed by treatment with radiation and/or chemotherapeutic drugs. The current median overall survival of patients with glioblastoma multiforme is less than 15 months after surgery, followed by synergistic combination of radiotherapy and chemotherapy with the anticancer drug temozolomide.201 Treatment for this type of cancer has its limitations, due to the poor ability to deliver therapeutic agents across the two unique barriers present in the brain: the BBB and the blood–brain tumor barrier (BBTB). Moreover, the low accumulation of nanoparticles into brain tumors by the enhanced permeability and retention (EPR) effect should be also taken into account.202 Therefore, efforts have been made to identify and develop drug-delivery systems for the brain. Liposomes are described as a possible valuable system to achieve better therapeutic effects in the treatment of gliomas, since several targeting strategies have been reported showing ability to reach the brain and to target the tumor. The search for reports on the use of liposomes as drug-delivery nanocarriers for the treatment and/or diagnosis of gliomas is shown in Figure 3. An initial search yielded a total of 448 articles after exclusion of duplicate articles found in the PubMed and Web of Science databases. In total, 80 articles were eligible.60,64,65,203–283 Although all described new nanocarriers for the delivery of therapeutic molecules into the brain, only 77 studies are included in Table 5, because the full text of seven articles212,217,230,246,254,255,265 was not available to access.
Design of liposomal drug-delivery systems for glioma diagnosis
One of the most challenging problems in therapy of gliomas is their detection in the earliest stages of development. Like many tumor types, early detection correlates with successful therapy. Therefore, both new diagnostic and therapeutic approaches need to be developed for glioma-imaging oncology. For this purpose, a huge variety of contrast agents have been encapsulated into liposomes. These new nanomaterials may provide new opportunities for biomedical imaging, due to their unique magnetic, optical, and/or chemical properties, leading to the creation of better contrast-enhancement agents and increasing the sensitivity of techniques clinically available for diagnosis of brain tumors.284
Modern imaging techniques, such as magnetic resonance imaging (MRI), optical imaging, ultrasound, and single-photon-emission computed tomography (SPECT), are rapidly emerging as noninvasive modalities for detection and follow-up posttreatment of gliomas.285,286 MRI is the preferred approach for glioma imaging, since it provides high-spatial-resolution anatomic images of this tumor type.287 Optical imaging applied to glioma therapy has the potential to localize and identify intrinsic brain tumors for removal during surgery.288 Ultrasound, unlike MRI, defines tumor volume and provides intraoperative localization of tumor tissue, although its use is limited by the presence of the skull.285 SPECT yields growth rate and gives information about the heterogeneity of gliomas, but provides low-spatial-resolution images.289 Positron-emission tomography (PET) provides functional information, since this technique is highly sensitive for measurements of biological processes, such as cell proliferation, angiogenesis, and glucose consumption.290
Paramagnetic contrast agents are the most widely used agents to enhance the visibility of gliomas in MRI images. Gadolinium (Gd)-based compounds, such as Gd–diethylenetriaminepentaacetic acid, gadodiamide, and gadoteridol, are effective contrast agents, owing to their seven unpaired electrons. Although Gd-based compounds are able to cross the BBB, a key advantage of using liposomes as Gd carriers is preferential localization at the tumor site through the EPR effect. In this way, it was shown that Gd liposomes with prolonged blood-circulation time tend to accumulate in the intratumoral extravascular space after moving across the tumor’s leaky vasculature.208,254 Moreover, a recent advance was reported in the design of a pH-responsive Gd liposome that was able to release the imaging agent into a cerebral glioma rodent model, detecting with 0.2 pH precision the mildly acid tumor microenvironment.208
Methods for optical imaging of glioma are based on fluorescence. The lipid-binding fluorescent carbocyanine dyes DiD (4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, disodium salt), DiO (3,3′-dioctadecyloxacarbocyanine perchlorate), and DiI (1,1′-dioctadecyl-3,3,3,′3,′-tetramethylinocarbocyanine perchlorate) are widely used for imaging studies. The characteristics of aqueous-insolubility ease of aggregate formation and the fact that these dyes do not readily cross the BBB suggest that it would be desirable to develop a liposome-based system. In this way, the carbocyanine dyes have been encapsulated into liposomes with the ability to demarcate tumors.60,256,269 The results of these studies suggest that those formulations, independent of the mode of administration, stained the tumor tissue and increased their bioavailability.60,256,269 However, the use of these fluorescent probes has the disadvantage of requiring low-light conditions for the visualization of tumors in vivo, which is not useful in a surgical environment. It was recently reported that Evans blue liposomally encapsulated was able to demarcate visually the margins of invasive gliomas, which may not significantly change the surgical conditions for the resection of this type of tumor.232
Also, studies reported in Table 5 suggest that the use of MRI or optical imaging alone in the imaging of gliomas is not enough for their classification and grading, optimal treatment, and follow-up after treatment,261,273 since each imaging technique is associated with individual advantages and limitations. Furthermore, it is generally observed that the presence of targeting ligands over the liposome surface improves the uptake of vesicles by target cancer cells and increases their retention time within tumors.231,233,239,247,253 In gliomas, angiogenesis seems to be the preferable target area for diagnosis of this cancer. Angiogenesis, the formation of new vessels, is a key process for glioma survival and growth.291 From the literature search, two molecules were identified for angiogenic cells: endoglin, also known as CD105, and the Ala-Pro-Arg-Pro-Gly peptide. MRI of endoglin-target liposomes was able to demonstrate tumor angiogenesis253 and delineate tumor margins, showing correlation between endoglin-associated neovasculature and tumor infiltration.231 In the same way, PET of Ala-Pro-Arg-Pro-Gly peptide-targeted liposomes was able specifically to image the different structure of glioma vessels.247 Also, liposome-targeted delivery of contrast agents containing antibodies to GFAP and the extracellular loop of Cx43 on its surface that selectively bound to brain-reactive astrocytes and faster-migrating glioma cells has been developed.239 Also developed have been PEGylated liposomes containing VEGF antibody on the surface, increasing the distribution and efficacy of the delivery of liposomes to glioma.233 However, it is still unclear if any of the strategies described could enhance detection of the earliest stage of tumors.
Design of liposomal drug-delivery systems for glioma therapy
Glioma therapy consists of surgery followed by radiotherapy, chemotherapy, or photodynamic therapy (PDT). Moreover, the stage and type of glioma often determines whether monotherapy or combined therapies are needed. Radiation therapy is a very common option for the treatment of gliomas, and has a variety of modalities, including external beam and brachytherapy.292 External beam radiotherapy, the most common approach in the clinic, uses ionizing radiation to kill cancer cells, but its application is limited by doses lower than 80 Gy due to toxicity.293 Brachytherapy or internal therapy uses a radioactive source that is delivered into or near the tumor itself, making it possible to deliver high radiation to the tumor and harming as few normal cells as possible.294 In this way, recent studies suggest that brachytherapy with liposomally encapsulated 186Re or 188Re isotopes holds significant promise for glioma therapy.229,242,245 These studies demonstrated that animals treated with 186Re or 188Re liposomes had significantly prolonged survival, independent of the route of administration.229,242 Also, 188Re liposomes have been explored for diagnostic evaluation, revealing the potential of these liposomes as a future theranostic agent for brain gliomas.245
A wide variety of liposome-encapsulated anticancer drugs have also been developed for both experimental and clinical oncology. By virtue of their unique physicochemical characteristics, liposomes have mainly shown improvement in the therapeutic index of chemotherapeutic drugs by enhancing their efficacy against aggressive and chemoresistant glioma cells and/or lowering drug side effects in the body. Antitumor antibiotics include doxorubicin (DOX), daunorubicin (DNR), and bleomycin. DOX, an anthracycline antibiotic, damages DNA by intercalation, inhibiting DNA synthesis or poisoning of topoisomerase II, by alteration of membrane function, or by generation of free radicals.295,296 DNR, also an anthracycline antibiotic similar in its chemical structure to DOX, acts through intercalation into DNA, metal ion chelation, and/or by free radical formation.296 Bleomycin, a polypeptide antibiotic, exerts its action by breaking the DNA double helix.297
Furthermore, antitumor antibiotics are among the most widely used and studied chemotherapeutic drugs. They are currently available in the market as free drugs (Adriamycin®, Cerubidine®, and Blenoxane®, trade names for DOX, DNR, and bleomycin, respectively), encapsulated in PEGylated liposomes (Doxil® [PEGylated form of liposomal DOX]), and encapsulated in conventional liposomes (Myocet® and DaunoXome® [liposomal DOX and DNR, respectively]). Although the anticancer activity of free drugs has been reported to be effective against gliomas cells in vitro, they present very poor efficacy in vivo, because these antibiotics do not readily cross the BBB.298 In a rat brain-glioma model, prolonged survival of the animals was observed when PEGylated liposomes were used to deliver DOX.267 In contrast, in a cohort of patients with brain cancer, liposomal DOX, DNR, or bleomycin was found moderately effective against glioma.275,278,279,281–283
Based on the moderate efficacy of liposomal formulations against brain tumors, it is clear that more effective drug-delivery strategies are needed. One promising alternative strategy involves the combination of ultrasound and microbubbles to induce BBB opening for local and transient delivery of drugs into the brain, leading to improvement in chemotherapy treatment.226,228,243,265 Moreover, as Doxil has been already clinically approved for the treatment of some types of cancer, these results suggest that the use of ultrasonic microbubbles for glioma chemotherapy is highly clinically relevant.228,243 Other alternative strategies were found in this search. Researchers developed stimuli-responsive liposomes that were able to release DOX in a controlled manner in response to an external low-power radio frequency field209 or local temperature rise.218 Both strategies showed an improvement of DOX delivery across the BBB and prolonged survival time of animals.
In fact, over the years many liposomal formulations have been developed for the treatment of gliomas. Some formulations demonstrated their ability to improve activity of anticancer drugs in vivo, such as topotecan,220 irinotecan,214,230,235,259 arsenic trioxide,255 cisplatin,237,240,268 and oxaliplatin,237 and codelivery of synergistic two-drug combinations257,258 into brain tumor-bearing animal models. Other formulations demonstrated increased bioavailability of the bioactive compound celastrol,217 carriage of small molecules241 and large payloads,225,270 and enabled efficient gene therapy.271,274,276,277 Additionally, the design of liposomes that simultaneously carry imaging and therapeutic agents is promising for glioma therapy, since it allows the opportunity for real-time visualization of drug localization, drug delivery, and monitoring the tumor-therapy response.252,260,262,272,280 However, although passively targeting liposomes are the only ones used in clinical therapy, they suffer several limitations, such as low EPR effect within the brain, nonspecific uptake, and the crossing of both barriers. Therefore, methods for enhancing the targeting of liposomes to brain tumors were developed.
According to our search, liposomes actively targeting strategies for CNS delivery of anticancer drugs across the BBB are basically divided into adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). AMT is trigged by electrostatic interactions between the negatively charged surface of brain endothelial cells and the positively charged moieties of macromolecules. AMT-based drug delivery for glioma therapy was performed using the cationic cell-penetrating TAT peptide to functionalize the surface of liposomally encapsulated DOX.248 The authors demonstrated that the TAT peptide could penetrate the BBB, since DOX was efficiently delivered to brain tumor-bearing rats.248 However, this cationization strategy suffers from several limitations, such as instability of the system in the serum, nonspecific interactions, immunogenicity, and toxicity.202,299
RMT-based drug delivery has been widely explored for liposome targeting to the brain. This strategy relies on liposomal ligand interaction with the very specific receptor-mediated transport system in the BBB. In fact, there are several kinds of receptors that are expressed on the surface of endothelial cells of the barrier, such as transferrin and lactoferrin, that have been explored to facilitate the crossing of liposomes into the brain. Transferrin liposomes have been reported to be able to deliver borocaptate (BSH) and small interfering RNA (siRNA) into the CNS, which is highly significant, because these compounds do not readily cross the BBB.224,246,263 In the same way, the covalent binding of lactoferrin to the liposome surface proved to be an effective strategy for the treatment of brain tumors.244
In glioma therapy, similarly to the BBB, the BBTB also represents a challenge for glioma-targeted delivery.300 Fortunately, many kinds of receptors are highly expressed in the BBTB (tumor vessels and/or glioma cells), and these receptors have been explored for the design of actively targeting liposomes for brain delivery of anticancer drugs across the BBTB. For example, such ligands as chlorotoxin,206,215,221 TR peptide,205 RGERPPR peptides,216 folate,64,65 anti-EGFR antibody,222 and IL-13,223 have been successfully attached to the surface of liposomes. As a result, these decorated liposomes were able selectively to bind, target, and enhance uptake by glioma cells. In the same way, hemagglutinating virus of Japan liposomes have successfully delivered foreign genes into murine glioma cells, representing a good system for gene delivery.227
More recently, researchers have developed liposomes that can penetrate the BBB and targeting brain-cancer cells. This new system, known as dual-targeting liposomes, was produced to deliver DOX,211,213,238 DNR,250 epirubicin,249 topotecan,251 plasmids,236 and siRNA,212 and for codelivery of synergistic two-drug combinations.203,210 All of these dual-targeting liposomes proved to be effective in crossing the BBB and targeting glioma cells. It was also demonstrated that just angiopep-2 peptide was able to target BBB and glioma cells at the same time,219 and RGD peptide targeted both BBTB and tumor cells.204,207,209
PDT uses photosensitizing agents, such as Photofrin, for brain tumors, along with light of appropriated wavelength to kill glioma cells. The PDT cell-killing mechanism is directly related to the production of reactive oxygen species, which leads to cell apoptosis, with minimal side effects.301 Unfortunately, the efficiency of this therapy for gliomas is limited by the BBB. Just like for chemotherapy, the efficacy of PDT for the treatment of brain tumors was greatly improved when Photofrin was encapsulated into liposomes, since the photosensitizing agent was efficiently delivered within brain tumors.264,266 Finally, it is worth mentioning here that although the preferred route for delivery of liposomes seems to be intravenous injection, alternative routes of administration, such as convection-enhanced delivery and intracranial, intracarotid, and intraperitoneal injections, have been also considered.
The BBB is the most important obstacle to effective brain drug delivery. There has been great interest in this area, especially in the development of targeted liposomes to cross the BBB and to deliver therapeutic molecules only to the disease site within the brain. From the reported articles, we could see that liposomes can get into the brain via different mechanisms. Examples of these mechanisms are: 1) transport of liposomes via RMT, followed by their internalization by neurons or glial cells and release of therapeutic molecules within those cells; 2) adsorption of cationic liposomes in the endothelial cells, which enhanced the concentration of therapeutic molecules within the brain cells; 3) antibody- or peptide-conjugated liposomes used to transport and target encapsulated drugs into the brain via transcytotic pathways; 4) inhibition of efflux transporters, such as PgP, by coating liposomes with transporter-inhibitory substances; and 5) disruption of the BBB. In fact, liposomes have the potential to revolutionize drug development for therapy and/or diagnosis of neurological diseases. By their unique physicochemical properties, liposomes have shown great ability to compartmentalize and solubilize hydrophilic and hydrophobic drugs (Figure 4). Furthermore, liposomes are biocompatible and biodegradable systems, which make them suitable for neuromedicine.
Also, the functionalization of liposomes surface modified with antibodies, peptides, aptamers, and other small molecules has shown promise in delivering a huge range of therapeutic molecules to targeted sites in the body (Figure 4). Liposomes usually improve the therapeutic index of new or established drugs by prolonging biological half-life and reducing their side effects. More importantly, liposomes may provide an excellent therapeutic tool for treatment or diagnosis of neurological disorders, due to their ability to cross the BBB and efficiently deliver drugs and/or contrast agents into the CNS, as discussed in this article. Additionally, theranostic liposomes have been developed, allowing real-time therapeutic efficacy. Also, high efficacy in using liposomes to deliver a drug in a spatial and temporal manner has been demonstrated (Figure 4), which we believe may be critical for the success of more effective therapy for neurological diseases.
Unfortunately, most advances and breakthroughs in liposome-based approaches have just happened for glioma therapy. The development of effective therapy for AD, PD, and stroke has been largely constrained. This might be due to our deficiency in understanding the neurological mechanisms and pathogenesis of these disorders. Increasing our comprehension about these diseases will contribute to the development of novel potential therapeutic strategies. This is essential, since we are living in a modern aging society and an effective spectrum of treatments is urgently needed.
By crossing the BBB, achieving efficient drug delivery into the brain is possible, which leads to an intensive search for alternative administration routes for liposomes. In this review, various studies used different administration routes to access the brain for the therapeutic delivery of liposomes (Figure 4). Intravenous injection of liposomes was the preferred route in the majority of the works cited here. Alternatively, intranasal injections offered a direct mode of drug delivery into the brain for AD and PD. Convection-enhanced delivery provided interesting results for efficient delivery of liposomes for drug delivery to tumor-bearing animal models (Tables 3–5). Administration of liposomal formulation via nonparenteral routes is highly desirable, since effective strategies for crossing the BBB are urgently needed.
The authors report no conflicts of interest in this work.
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