Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease

Journal of Controlled Release 260 (2017) 61–77

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Review article

Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease

MARK

Mukta Agrawala, Ajazuddina, Dulal K. Tripathia, Swarnlata Sarafb, Shailendra Sarafb, Sophia G. Antimisiarisc,d, Spyridon Mourtasc, Margareta Hammarlund-Udenaese, Amit Alexandera,⁎ a

Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud Road, Bhilai 490024, Chhattisgarh, India University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492010, Chhattisgarh, India c Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, Rio 26510, Greece d FORTH/ICE-HT, Institute of Chemical Engineering, Rio, 25104 Patras, Greece e Department of Pharmaceutical Biosciences, Translational PKPD Research Group, Uppsala University, Uppsala, Sweden b

A R T I C L E I N F O

A B S T R A C T

Keywords: Alzheimer β amyloid Liposome Lactoferrin Transferrin Glutathione

In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.

1. Introduction With changes in modern lifestyle, the busy lifestyle also brings some disorders associated with increasing age of the human being. One such epidemic condition considered worldwide as the reason of death is Alzheimer disease [1]. As per the World Alzheimer report 2016, now around 47 million peoples, all over the world suffering from dementia which is estimated to increase by 131 million till 2050 [2,3]. Alzheimer or dementia is a neurodegenerative disorder [3–5] which directly and severely affect the functioning of central nervous system triggering memory impairment, progressive cognitive neuronal dysfunctioning, thinking and behavioral disturbance and much more similar problems

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1

Corresponding author. E-mail address: [email protected] (A. Alexander). Apolipoprotein E

http://dx.doi.org/10.1016/j.jconrel.2017.05.019 Received 2 April 2017; Received in revised form 12 May 2017; Accepted 13 May 2017 Available online 24 May 2017 0168-3659/ © 2017 Elsevier B.V. All rights reserved.

uproar in the daily life of the patient [6]. The exact cause of Alzheimer is not yet identified but some factors considered to be more responsible for the dementia are aging, genetic mutation, and family background. The people with age > 65 years are more likely to be susceptible for the Alzheimer's, as the frequency of neuronal degeneration increases with increasing age factor. Genetically, the gene APOE1-e4 is responsible for the incidence of this brain disorder [7–10]. The symptoms of Alzheimer's initially involves the loss of memory followed by decreasing ability of the person to recognize the relatives, friends, children's, spouse's further leading to interruption in daily routine activity like walking, eating, dressing etc. and finally the patient become bed ridden in last stages, ultimately fatal [11]. The histopathology of Alzheimer

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include the formation of neurofibrillary tangles and accumulation of β amyloid plaque [12] accompanying with neuronal inflammation, increased oxidative stress and reduced level of neurotransmitters (ACh2, BuCh3) [11]. The formation of β amyloid plaque in the neuronal extracellular space is considered the major cause of neurodegeneration and memory impairment [13]. Normally, a protein APP4, present on the surface of the neuron, is cleaved from a proteolytic enzyme β secretase, results in the formation of small fragments of β amyloid peptide [14]. These fragments have a tendency to normally get dissolved and eliminated from the brain but in elderly peoples or person with some abnormalities, this peptide gets accumulated and forms a large aggregate that causes nerve degeneration and may lead to Alzheimer disease [15]. The major obstacle encountered in the treatment of Alzheimer's and other brain disorders is BBB5, that prevent the transfer of most of the drug, peptides and large molecules across the endothelial cell lining [16–18] to protect the brain from undesirable side effects of the same [19]. The BBB structurally composed of BCECs6, astrocytes, pericytes, neuronal cells, basement membrane etc. [20,21]. The BCECs closely attached to each other through tight junction that confines paracellular transfer of small drug molecules and the presence of degrading enzyme limits the transport of various molecules from the periphery to the brain [22]. All such arrangements have been made to maintain the homeostasis inside the brain and keep it unaffected from the harmful stimuli of drug and toxic compounds. But there are some provisions like paracellular diffusion for hydrophilic substances, the transcellular pathway for small lipoidal molecules and although some other mechanisms like carrier-mediated transcytosis, receptor-mediated transport, cell-mediated endocytosis, adsorptive transcytosis etc. [23] that helps in transfer of essential components through specific mechanisms to the brain [24,25]. The BBB creates major hurdle in the effective treatment of various CNS7 disorders. All over the world, the researchers are trying to make attempts to formulate a drug molecule and delivery system, which can able to deliver the drug into the brain by crossing the BBB and maintain the higher concentration inside the brain. In this track, various novel drug delivery systems like nanoparticle, liposome, dendrimers etc. offers good stratagem due to their unique capability to target BBB [26]. Drug delivery to the brain is a very complex phenomenon that can be done by three major routes like, injecting/inserting drug via intracerebral or intracerebroventricular injection (invasive approach), systemic administration via oral or i.v.8 and intranasal administration of the active compounds. The first approach is invasive, painful and causes patient inconvenient hence, used in very severe condition or only when the patient is hospitalized. While the rest two approaches are very popular, among which the systemic drug delivery encounters the interruption through BBB that limits the drug concentration, bioavailability, and effectiveness of drug and also increases the systemic side effect. To overcome such problems various novel approaches such as nanocarriers are used to enhance the drug property and pharmacokinetic behavior. The last approach as mentioned above i.e. i.n.9 administration offers a distinct and attractive approach that bypasses the BBB and directly deliver the drug to the brain via olfactory region thereby enhancing the drug bioavailability and activity. Hence, become popular among researchers for the treatment of CNS disorders like Alzheimer's, Parkinson's disease etc. Another factor to be taken into account for the delivery of drugs to

the brain systemically is the development of several types of NCs10 to assist their translocation across the blood-brain-barrier, the basic barrier between blood circulation and CNS. The most commonly developed types of nanocarriers, for such applications, are liposomes, solid lipid nanoparticles, albumin nanoparticles and polymeric nanoparticles [27–35]. In general, NC-assisted drug delivery possesses many advantages; increased drug bioavailability and stability and at the same time decreased peripheral toxicity. Between the different types of NCs, the ones that have easily modified by its surfaces, such as liposomes, hold an additional advantage since they may be modified in order to efficiently target a particular site of interest (e.g. BBB). Thus, targeted liposomal NCs are considered to have great future perspectives for the diagnosis and treatment of brain located diseases. Several types of liposome formulations have been developed up-to-date, as systems to facilitate the translocation of drugs across the BBB, by employing a number of different strategies. The possible mechanism for the transportation of drug across the BBB is due to the phospholipid bilayer of liposome facilitating the permeation of drug across various biological membranes. However, it does not allow to cross BBB. Hence, various surface modifications have been made to that enables the transfer of liposomal carrier via BBB [36]. There are a number of receptors present on the surface of BBB, particularly for different proteins, peptides, antibodies etc. Such molecules are used as surface-active ligands and assist the translocation via receptor-mediated transcytosis. At the same time, the cationic liposomes cross the BBB via absorption mediated transcytosis. One more strategy is carrier mediated transcytosis that utilizes some nutrients like glucose; glutathione etc. binds to the surface of liposome and facilitate its translocation [37,38]. Once the liposome enters into the brain it releases the entrapped drug to the target site initially through passive diffusion where the drug release is triggered by general passive efflux [37]. This does not control the release rate hence, some more progressive approaches have been developed that responds to the changes in the physiological environment and release the drug in a controlled manner. In such system, the drug release from the liposomal vesicle is triggered by a change in pH, enzymatic stimulus or change in the level of some redox agents like glutathione [39–42]. In the case of Alzheimer's disease, once the drug release it performs its particular function like disaggregation of β amyloid plaque by binding with the β amyloid peptides, increases the ACh in the brain, reduces inflammatory reaction in the brain, promotes neuronal health depending upon the nature of drug and thereby treat Alzheimer's disease. Among all the modification in the liposomes, one strategy applies cationic liposomal drug vehicles that would be able to take advantage of the BBB's negative charge, and consequently trigger the cell internalization processes through electrostatic interactions [43–45]. However, major drawbacks of this strategy are the nonspecific uptake of cationic NCs by peripheral tissues, together with their binding to serum proteins, which result in the requirement for administration of high doses of NCs to reach therapeutic efficacy; such doses cannot be administered in most cases, due to toxicity. Another strategy to target BBB includes the surface functionalization of liposomes with PEG11 or polysaccharides, as a method to improve their pharmacokinetic profile, allowing longer time-periods in circulation and increased distribution of such “stealth” liposomes into the brain (by preventing their fast clearance through the RES12). However, although succeeding to dramatically improve liposome circulation time, the strategy of “stealth” liposomes does not provide any certainty that liposomes will be transcytosed across the BBB. To provide such additional properties to (“stealth”) liposomes, several modern methods for functionalization of the liposomal surface with biologically active ligands, such as peptides,

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Acetylcholinesterase Butyl cholinesterase 4 Amyloid precursor protein 5 Blood brain barrier 6 Brain capillary endothelial cells 7 Central nervous system 8 Intravenous 9 Intranasal 3

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Nanocarriers Polyethylene glycol 12 Reticuloendothelial system 11

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2.1. Stealth liposome

antibodies or small molecules, which specifically bind to receptors or target transporters overexpressed on brain endothelial cells, have been engineered. It has been observed that due to the specificity of the interaction between receptors and ligands, receptor-mediated transcytosis is the most successful and commonly used strategy for liposome delivery to the brain. The TfR13, a transmembrane glycoprotein overexpressed on brain endothelial cells, is the most commonly targeted receptor. Tf14-functionalized liposomes have been used for BBB targeting, however, endogenous Tf inhibits their binding to the TfR [46], a problem solved by using antibodies against TfR (which binds the receptors at different sites), to avoid ligand competition [47–49]. Similarly, lactoferrin, a mammalian cationic iron-binding glycoprotein that binds to Lf15 receptors, also overexpressed on the BBB, has also been used for liposome functionalization. Lactoferrin-modified liposomes have been developed as functionalized NCs to cross the BBB via receptor-mediated transcytosis [50,51]. Carrier-mediated transcytosis is another major mechanism for transport across the BBB. Most nutrients are transported from blood to brain by BBB selective transporters, such as hexose, amino acid or monocarboxylate transporters, overexpressed on the BBB. The strategy to mediate the delivery of liposomes into the brain by such transporters has also been used. As examples: (i) glucose modified liposomes have been developed as a strategy to enhance liposome transcytosis into the brain since glucose transporters are predominant on the human BBB [52–54]. (ii) Another case is the so-called G-Technology® which applies the strategy of liposome modification with glutathione to target the glutathione transporter (highly expressed on the BBB) and deliver drugs into the brain [18,48,55,56]. In addition, the strategy of decorating liposome surface with more than one targeting ligands has also been successfully applied for delivery to the brain. Such bifunctional liposomes demonstrated increased BBB targeting capability, compared to liposomes with one ligand, mainly because they overcome the drawback of receptor (or transporter) saturation [57]. Multifunctional liposomes, bearing bifunctional BBB targeting species and other small molecules with high affinity towards amyloid species (such as curcumin), are also described in this review [47–49,58–60]. As far as the regulatory aspects are concerned, the most popular carrier system available for the loading of the drug is non-other than liposomes, according to the increased number of Investigational New Drug (IND) application submissions. In addition, a huge number (500) of liposome submission into FDA database based was found as of February 18, 2016 [61]. Interestingly, the numbers of submission were more in the year 1998 just after the approval of Doxil®, AmBisome® and DaunoXome®. Among them, the intravenous route of the administration of liposomes was more preferred over the inhalation route [62]. In the present review, we have emphasized the role of liposomal carrier system along with various strategies, established for the delivery of an anti-Alzheimer drug across the BBB into the brain.

Stealth liposome is an advancement in liposomal formulation that enhances the circulation period of liposome in blood and suppresses the phagocytic uptake thereby boost up the targeting efficiency of the carrier [13]. Working in this area, [63] synthesized a lipid conjugate targeting to β amyloid plaque fused in a stealth liposomal system to target the BBB and tested its efficacy in transgenic AD mouse model. The author has prepared the liposomal system with the objective to test the localization of liposome into plaque after intravenous injection [63]. According to the author, firstly a DSPE16-PEG-XO4 lipid conjugate was prepared with a targeting ligand methoxy-XO4 and PEG-3400 and incorporated to the liposome, share the surface phenomenon. Here the liposome was prepared by DPPC17, cholesterol, DPSE-mPEG-2000 and the conjugate (Fig. 1). Finally, the drug rhodamine was encapsulated in the aqueous core. The surface active ligand on liposomal preparation contains methoxy-XO4 as a targeting ligand, which also acts as a fluorescent biomarker; provide ease of identification during analysis. The particle size of liposomes was analyzed by TEM18, at the range of 150–170 nm. Further, analysis by atomic emission spectroscopy showed a greater number of targeting ligand at the liposomal surface ensuring specific binding with β amyloid plaque while the stealth liposome assures the maximum concentration of liposome inside the brain. The targeting ability and plaque binding ability of liposomal system were investigated in APP/PSEN1 transgenic mice. The confocal microscopic study shows the presence of liposome in the brain by detecting XO4 labeled liposome in brain tissues (olfactory, cortex and hippocampus). The liposomes were tested for its ability to bind with the β amyloid plaque in the brain and the studies showed selective binding of targeted liposome to the aggregates in the brain. Both the targeted and non-targeted liposomal systems were administered into transgenic mice as well as non-transgenic mice (7 and 12-month-old) through intravenous injection and the concentration of liposome in the brain was tested by confocal microscopic imaging. The images showed higher binding of targeted liposome throughout the brain of transgenic mice while no traces in other. After that, the animal was sacrificed to detect the rhodamine concentration in brain and it was found that the drug concentration enhanced at a satisfactory level when administered through the targeting liposome. The author worked on the hypothesis, β amyloid aggregated when defragmented into small fibrils, get easily cleared from the brain by either of two mechanisms; perivascular transfer or receptor-mediated transcytosis [64,65]. The fluorescence in the images assures the binding of the liposome as well drug to the aggregates which cause defragmentation of plaque and facilitates its easy removal. 2.2. Transferrin-modified liposome BBB is a major challenge in brain drug delivery that limits approximately all the drug to enter the brain [66]. Some transport mechanisms are present in the brain endothelial cells and astrocytes [67] that facilitate drug transfer across the brain, among which most common one is receptor-mediated transport, used in most of the novel technologies to deliver the drug in the brain [68–73]. Transferrin protein is commonly used ligand for targeting of the drug to BBB [74,75] and efficiently promotes the drug accumulation in the brain [76].

2. Surface modified liposome As discussed above, liposome offers surface modification with various active agents or ligands to target specific sites and facilitate site-specific delivery. To achieve this, various studies are focused on targeting BBB and β amyloid plaque via various ligands to assist the availability of drug inside the brain. In this section, we have highlighted such modification made to the surface of the liposomes to increase the bioavailability of drug in brain region.

2.2.1. Transferrin-modified α-M loaded liposome By using this phenomenon Lan Chen et al. [81], have prepared transferrin-modified liposome for efficient delivery of a polyphenolic

13

16

14

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1,2-distearoyl-sn-glycero-3-phosphoethanolamine 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 18 Transmission electron microscopy

Transferrin receptor Transferrin 15 Lactoferrin

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Fig. 1. Aβ targeted stealth liposome with XO4 labeled PEGylated binding ligand. [Adopted and modified from Eric et al. [63]].

xanthone α-M19 [77]. α-M is act as a neuroprotective against amyloidogenesis, used in the treatment of Alzheimer disease that slow down the cerebral neuronal degeneration [78,79]. Liposomes were prepared as blank, α-M and transferrin-modified α-M, by thin-film hydration method. Transferrin was covalently linked with α-M liposome through PEG linker and the prepared liposomes were further characterized and evaluated for brain uptake and pharmacokinetic behavior. The formulations prepared were further characterized using appropriate methodologies and it was found that all the formulations were within the appropriate size range (< 200 nm). On the other hand, zeta potential was less than − 25 mV with PDI (0.2). This reflects the stability of the formulation throughout the study tenure. With this strategy, it was well observed by the authors that the entrapment efficiency was significantly increased up to 90%. In addition, the in vitro drug release study shows a good sustained release profile. The brain targeting was confirmed by in vitro uptake study, performed by using an advanced BBB model (bEnd3 cells and astrocytes) that gives more accurate result [80]. The study confirms that Tf-α-M20liposome effectively crosses the BBB through a receptor (transferrin receptor) mediated transcytosis as compared to the free α-M solution. In vivo brain uptake and Pharmacokinetic studies were performed by using groups of SD21 rats. The drug concentration was tested in the brain as well in peripheral organ with respect to time. The data reveals that drug accumulation in the brain is higher in Tf-α-M-liposome as compared to αM solution and α-M-liposome (Fig. 2). The transferrin-modified formulation also increases the t1/2, AUC and MRT22 of the drug. Therefore, this strategy proves that transferrin-modified liposomes provide an efficient carrier system for brain drug delivery that offers easy transfer of drug across BBB without altering drug integrity [81].

of NGF followed by cross-linking with RMP-7 and transferrin (Fig. 3). PEGylation improves the stability of liposome inside the biological medium by protecting them from degradation of systemic enzymes [83–87] and prolongs the circulation period of the liposome in blood so that it can be easily represented to BBB to a greater extent. Further, the addition of cholesterol takes part in offering a rigid configuration to the liposomal vesicle [88]. In addition, the RMP-7 was added due to its selective binding ability bradykinin receptor of BBB [89]. It possesses greater half-life and considered safer for therapeutic application [90]. At the same time, the transferrin also shows specific binding to transferrin receptor of brain endothelial cells [91]. Bothe the approaches adopted for drug targeting work synergistically and provide an effective drug targeting through transcytosis. The prepared liposomes were further evaluated and it was found that the particle size increases with increased amount of targeting ligands as the particle size may range from 152.3 to 189.1 nm with an increase of 0 to 30 μg/ml of RMP-7 concentration. At the same time, the effect of these ligands on the zeta potential was controversial to each other i.e. RMP-7 slightly increases the zeta potential with increasing concentration while Tf reduces (− 5.5 to − 5.8). The in vitro study was performed on HBMECs and SK-N-MC cells to check the permeability across the cell linings and viability of the SK-N-MC cells (mimic neuronal phenotype characteristics). The results ensure that the RMP7/Tf/NGF-liposome effectively crosses BBB and able to reduce the neurotoxicity due to cell apoptosis of SK-N-MC cells. Hence, offers a potential drug carrier system for effective brain delivery of NGF. 2.3. Lactoferrin modified liposomes Lactoferrin is a glycoprotein generally present in mammalian brain cells [92,93] having the ability to bind to the lactoferrin receptor at BBB firstly and thereafter getting converted to a positively charged group which bind to negatively charged BBB at physiological condition [94].

2.2.2. Transferrin-modified NGF loaded liposome Using the similar approach, Kuo et al. [82,104] prepared an RMP723/Tf-modified liposome for brain delivery of NGF for the treatment of AD. The study was performed with an objective to ensures the brain targeting ability as well as the ability of carrier system to inhibit the apoptosis of SK-N-MC cells [82]. The liposomal system was prepared with a combination of lipid phase (PC24 and DPPC), cholesterol, DSPEPEG-2000-CA25 and DSPE-PEG-200026 furthermore the encapsulation

2.3.1. Lactoferrin modified procationic liposome In context to modified liposome, Chen et al. [50] adopted another strategy lactoferrin modified procationic liposome. A procationic liposome is a formulation that is initially negative or non-ionic in nature and gets turned into cationic form when entering into the brain [95]. They have prepared a procationic liposome modified by binding with lactoferrin that has high affinity to bind with lactoferrin receptor present in BCEC of BBB and can easily cross the BBB [96,97]. The prepared liposomes were further considered for cytotoxic evaluation as well drug distribution efficiency. They have prepared such novel technology to enhance the brain delivery of drug for treatment of Alzheimer's disease. The procationic liposome was prepared with

α-Mangostin Transferrin modified α-M liposome 21 Sprague Dawley 22 Mean residence time 23 Cereport 24 Phosphotidylcholin 25 1,2-dipalmitoyl-sn-glycero-3-phosphoethanol-amine-N-[carboxy-PEG-2000] 26 1,2-dipalmitoyl-sn-glycero-3-phosphoethanol-amine-N-[methoxy-PEG-2000] 19 20

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Fig. 2. Drug concentration in the brain of the α-M solution, α-M liposome, and Tf-(α-M) liposome groups at different time points. Data are presented as the mean ± standard deviation (SD). n = 6, *P < 0.05, **P < 0.01. [Adopted with permission from Lan Chen et al. [81]].

Fig. 3. Reaction mechanism of cross-linking RMP-7 and Tf on NGF-liposomes. [Adopted and modified from Kuo et al. [82,104]].

transport which depends upon concentration as well as time. Such transfer is also referred as active transport [98]. In vivo pharmacokinetic investigation of the various prepared liposomal formulation was performed using Kunming mice and newborn Sprague–Dawley rats were used to evaluate the brain targeting ability as well the drug releasing behavior of liposomes. The formulation was intravenously injected to the group of mice/rat and the blood serum and brain were investigated for half-life, tmax, Cmax and AUC31 of coumarin 6. The result shows Lf-PLC-8 gives maximum AUC (1041.793 ± 33.772 μg/L·h) in the brain as compared to conventional and PLC. Similarly, Lf-PLC-8 shows maximum Cmax (160.878 ± 14.335 μg/L) of coumarin-6 at tmax 0.5 h is observed in the brain than the other formulations (Fig. 4) while low in the blood. This result confirms the Lf-PLC-8 as the most prominent candidate for brain drug delivery as compared to conventional liposome and PCL. These studies further confirm lactoferrin modified the procationic liposomal delivery system as a promising carrier for effective and targeted drug delivery to the brain for Alzheimer's disease [50].

bovine lactoferrin as a surface ligand for drug targeting, coumarin-6 as a fluorescent dye, CHETA27, and an endothelial cell growth supplement. Firstly, different types of liposome i.e. CL28, PCL29, Lf-PCL30 and coumarin loaded PCL, Lf-PCL were prepared by thin film solvent evaporation method thereafter lactoferrin was added to the prepared liposome in 7.4 EDTA buffer at a different ratio with CHETA. The prepared formulations were then characterized and evaluated for various criteria and compared with conventional liposomal preparations. The author reported that the size of lactoferrin loaded liposome was found to be < 130 nm which is nearly similar to the coumarin loaded liposome. On the other hand, zeta potential estimation suggested an interaction between lactoferrin and PCL. The drug encapsulation efficiency study was conducted by using coumarin 6 as a model drug that shows higher encapsulation in the case of PCL and Lf-PCL, than the conventional one. The in vitro uptake study was conducted to estimate the ability of the liposomal system to cross the BBB by culturing BCECs and ACs in the laboratory and the result demonstrates that liposomal formulation crosses the BBB through receptor-mediated

27

Cholest-5-en-3-ol-(3)-[2-[[4-[(carboxymethyl) carbamate 28 Cationic liposome 29 Procationic liposome 30 Lactoferrin loaded procationic liposome

2.3.2. Lactoferrin modified NGF32 loaded liposome The Alzheimer's brain is characterized by neurodegeneration due to

dithio]-1-iminobutyl]amino]ethyl]

31 32

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Area under curve Neuronal growth factor

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Fig. 5. A schematic representation of a Lf/NGF-liposome. [Adopted by permission from Kuo et al. [82,104]]. Fig. 4. Concentration of Coumarin-6 in the brain after 0.5, 1 and 2 h of intravenous injection of the conventional liposome, PCL, and Lf-PCL. [Adopted with permission from Chen et al. [50]].

the cell viability of SK-N-MC cell. So, the study proves that the Lf-NGFliposome offers a promising delivery system that improves neuronal health by protecting the neurons from the degenerative effect of Aβ plaques and this approach can be further tested for clinical studies to provide better treatment to the Alzheimer's disease [104].

the accumulation of senile plaque and tau protein. Various approaches have been adopted in order to reduce the plaque formation as well as dissolve the already prepared plaque and improve the neuronal health. One promising approach in this sequence is the delivery of NGF, a compound that enhances the neuronal cell viability or life span by protecting the neurons from the degenerative effect of amyloid β plaque [99,100]. To study the effect of NGF in the treatment of Alzheimer's disease Kuo et al. [82,104] has prepared a lactoferrin modified NGF loaded liposome for efficient delivery of NGF to the brain. Due to the high molecular weight and polar nature, it is difficult for NGF to cross the BBB [101] hence, it is delivered by associating with a liposomal system with enhanced BBB crossing ability since the presence of lactoferrin on the surface of the liposome. The liposome is prepared with a combination of different lipid phase like cholesterol, DPPC, PEPEG-200033, and DPSE-PEG-200034 in a varying ratio of cholesterol there after NGF were loaded to the liposome and surface modified with lactoferrin (Fig. 5). The effect of varying ratio of cholesterol and lactoferrin on the physicochemical behavior and drug release profile was further studied. The particle size measurement study showed an increase in particle size with increased amount of cholesterol. This is because of cholesterol increases the rigidity of vesicle as well as reduces the phase transition temperature so the gelation of lipid and hence responsible for larger particle size [102]. At the same time, the lactoferrin also increases particle size and surface thickness with its increasing concentration by forming a layer on the liposomal surface [103]. A similar effect of cholesterol and lactoferrin concentration was also observed in the value of zeta potential that shows an increase with increasing amount of both the above-mentioned components. However, the increasing concentration of cholesterol retards the entrapment efficiency as well as the drug release rate because cholesterol reduces the fluidity and increases the stability of lipid membrane. The release study indicates a controlled and sustained release for 48 h without initial bursting effect. The cellular uptake, toxicity, and viability of neurons were tested in-vitro on HBMECs, HAs and SK-N-MC cells. The results demonstrate that the Lf-NGF35 liposomes increase the cell viability. Lactoferrin having an ability to accelerates the endothelial cell proliferation and enhances the drug permeability across BBB through receptor-mediated transport. At the same time, it also increases

2.4. Glucose modified liposome The major challenge for a drug used in brain disorders is to cross the BBB which is only permeable to some small molecules while impermeable for all the other [105]. BBB prevent the entry of all toxic as well drug molecules and protect the brain thereof [106]. There is a special arrangement present in BBB to facilitate transport of some essential molecules like glucose AA36, required for proper functioning of the brain. Such substances are able to cross the BBB via carrier-mediated transport [107]. This feature provides a good strategy for successful delivery of the drug into the brain. In this connection, Fulan et al. 2012, worked on the strategy for the delivery of a drug by loading with glucose modified liposome which can easily cross the BBB through glucose transporters. They have prepared a glucose modified targeting liposomal system by use of PEG with varying chain length and evaluated its distribution throughout the brain as well efficacy as a suitable candidate for the treatment of Alzheimer. PEG was added to stabilize the formulation, reduce the effect of RES system as well its accumulation in spleen and liver [53,108]. The glucose modified liposomes were prepared by using soyabean phospholipid and cholesterol as lipid phase, coumarin 6 as drug moiety and varied chain lengths of PEG as a linker between lipid phase and glucose to prepare a delayed release formulation. Cholesterol and glucose were linked covalently with different PEGs to prepare modified liposome by film hydration ultrasound method at 2:1 M ratio of phospholipid and cholesterol derivatives. Thereafter coumarin 6 was loaded to this by solvent evaporation technique. The prepared modified liposomes were characterized for their size, shape, and PDI, transmittance etc. The size of the liposomal preparation should be < 200 nm so that it can easily cross the BBB [109]. The electron microscopy studies demonstrated that the prepared liposomal formulation having a size range from 80 to 105 nm and spherical in shape. PDI of the liposome depends upon the chain length of PEG [110]. Zeta potential of the formulation lies between −20 to −30 mv as well PDI ranges from 0.15 to 0.30. The results showed that the liposomal preparations are stable enough and able to cross the BBB because of lower size. The in vitro studies have been performed by coculturing the BCEC and ACs37. To check the effect

33 1,2-dipalmitoyl-sn-glycero-3-phosphoethanol-amine-N-[methoxy(polyethylene glycol)-2000] 34 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000] 35 Lactoferrin modified neuronal growth factor loaded liposome

36 37

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of the liposomal system on BBB fluorescein sodium leakage test was performed and it was found that the integrity of BBB was not affected by the treatment. Cumulative cleared volume study demonstrated that the liposome prepared with long chain PEC, facilitate the drug transport across BBB. The brain targeting ability of formulation can be studied by NIR38 fluorescent imaging. The different liposomal formulations were injected intravenously in mice model and the drug concentration as well liposomal accumulation was studied via confocal spectroscopy and quantitative biodistribution study in the brain and another peripheral organ like liver, spleen, lung, kidney etc. after an hour of injection. The results show that glucose modified liposome with a medium chain PEG having a higher concentration in the brain while less in peripheral organs. In contrast, the liposome prepared with shorter chain PEG shows greater concentration in the periphery than brain because due to shorter chain length glucose does not represent to the surface and so the liposome unable to cross the BBB through glucose transporter. Likewise, in a longer chain, PEG shows flexibility and folding ability that also reduces the ability of liposome to cross the BBB. The studies showed the liposomal preparation with medium chain length PEG gives the best result due to its ability to cross BBB [53].

insertion method by using two different types of phospholipid DMPC43 and EYPC44 and glutathione were attached to the liposomal surface as a ligand through the PEG linker. The prepared formulations were studied in WT45 littermates and APP/PS1 transgenic mice to estimate its targeting efficiency and pharmacokinetics. The pharmacokinetic data were collected and compared for the free VHH-pa2H antibody, glutathione-PEGylated-DMPC-VHH-pa2H liposome, and glutathione-PEGylated-EYPC-VHH-pa2H liposome and the result demonstrates, rapid clearance as well as greater Vd46 in the case of free VHH-pa2H while antibody liposomal formulations show increased t1/2 (15.2 h) and AUC (293% ID/ml ∗ h). From these findings, it can be concluded that glutathione PEGylated liposome increases the drug retention time and reduce the rapid clearance of antibody thereby enhances the drug efficacy while the glutathione ligand ensures drug targeting into brain hence, the study proves G-Technology® offers an effective carrier for drug delivery into the brain [128].

2.5.2. Brain targeting of opioid peptide DAMGO One more approach in this series is effective brain delivery of an opioid peptide DAMGO (H-Tyr-D-Ala-Gly-MePhe-Gly-ol) through glutathione conjugated PEGylated liposomes. Lindqvist et al. [111] have prepared a PEGylated liposome conjugated with glutathione for improved brain targeting of DAMGO (Fig. 7) [129,130], with an objective to study the effectiveness of glutathione-conjugated drug carrier in efficient brain delivery and the pharmacokinetic and pharmacodynamic behavior of DAMGO in animal model [131,132]. Glutathione conjugation facilitates the drug transport across BBB via receptor-mediated transport [114,133,134] while PEGylation prolongs the liposomal retention time in the blood and at the same time offers a biocompatible carrier system. The liposome was prepared with EYPC, cholesterol, and mPEGDSPE as lipid phase and the drug DAMGO was encapsulated simultaneously during preparation. Thereafter, the prepared liposome was conjugated with glutathione at 1:1 ratio of DSPE-PEG-maleimide. The average particle size of GSH-PEG liposome was < 130 nm and PDI was found 0.024 which remains best brain drug delivery. The plasma protein binding ability of DAMGO was studied in vitro by equilibrium dialysis method and the portion of free drug was found 0.86. The study shows the protein binding of the drug was not concentration dependent. The in vivo pharmacokinetic behavior of the nanocarrier system was measured by administering the formulation intravenously, initially at a loading dose of 1250 μg/min/kg for 10 mins followed by a constant rate infusion of 60 μg/min/kg for 2 h. The results show that the plasma concentration of DAMGO from GSH-PEG liposome (120,000 ng/ml) was 130 times greater than free peptide infusion (980 ng/ml). Similarly, the GSH-PEG formulation also increases the brain distribution (Kp,uu) of DAMGO as 0.21 while the free drug infusion shows 0.09. The GSH-PEGylated liposomal formulation also increases the half-life, around 40 folds greater (417 min) than the free drug (9.23 min) while reduces the renal clearance from 47.3 ml/min/kg (free drug) to 0.17 ml/min/kg (liposomal formulation). The PEGylation increases the retention time of drug in the brain and prevents the drug elimination from endothelial cells [135,136]. The Vd was found 2 folds higher than the free drug. The study represents that the GSH-PEGliposomal formulation increases the brain distribution of the drug. It offers an efficient drug delivery system for brain targeting of peptide drug molecules [111]. However, the same group of author further investigated the possible faces behind improved brain uptake of drug using these strategies. In contrast to the above-mentioned findings, they observed that the

2.5. Glutathione PEGylated liposome/G-Technology® Another successful strategy in modified liposome is G-Technology® a well-established, patented, FDA39 approved technology proved to enhance the brain targeting of drug molecules [111,112]. G-Technology® includes PEGylation of liposomes with slight modification on PEG molecule that, it is combined with glutathione (an endogenous peptide with antioxidant property) [113,114] able to cross BBB via sodiumdependent transporter [115,116]. Various attempts made using this approach to target BBB have been discussing below. 2.5.1. Brain targeting of anti-amyloid single domain antibody/glutathione PEGylated By using the above-mentioned approach G-Technology®, Marteen et al. [128] have successfully prepared glutathione targeted PEGylated liposome for brain delivery of amyloid β antibody (VHH40). Some heavy chain antibodies having ability to specifically bind to the amyloid β plaque in the brain [117] and also crosses the BBB [118]. The drawback associated is they have a poor half-life and rapid clearance [119–122] when injected intravenously, this problem is overcome by PEGylation of the antibody fragment to increase its weight as well size. PEGylation prevents the glomerular filtration and thereby excretion while encapsulation of this PEGylated antibody into a suitable carrier to facilitate the entry into brain eliminates the problem of poor half-life [119,123–125]. Glutathione is a tripeptide that has antioxidant property and is able to cross the BBB through the specific receptor [113,114,126]. They encapsulated VHH into a GSH41-PEG liposome for successful delivery of VHH into the brain without affected by renal excretion. This technique is well known as G-Technique® [127]. The prepared formulation was evaluated for brain uptake and biodistribution which is tested by radiolabelling of DTPA-conjugated VHH in a transgenic mice model. The antibody VHH-pa2H was produced by subcloning of Saccharomyces cerevisiae (yeast) and the extracted antibody was then conjugated with DTPA chelator and radiolabelled with In111 (Fig. 6) for further analysis. The radiolabelled conjugate was analyzed by HPLC42 and autoradiography using human brain section to confirm the conjugation and radioactivity. Then the PEGylated glutathione liposome was prepared by the post38

Near infrared Food and drug administration 40 An amyloid β antibody 41 Glutathione 42 High performance liquid chromatography 39

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1,2-dimyristoyl-sn-glycero-3-phosphocholine Egg yolk phosphatidylcholine 45 Wild type littermates 46 Volume of distribution 44

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Fig. 6. Radiolabelling and encapsulation of VHH-pa2H (A) DTPA conjugation of VHH-pa2H (B) In111-labeling of VHH-pa2H-DTPA and (C) post-encapsulation labeling of VHH-pa2HDTPA, in which In111Cl3 diffuses over the liposomal membrane to bind to DTPA on the VHH molecule. [Adopted and modified with permission from Marteen et al. [128]].

and brain distribution ability by auto quenching of carboxyfluorescein, a fluorescent tracer material in the core of liposomal vesicle [138]. The liposome is prepared with HSPC47, cholesterol, mPEG2000DSPE and 5(6)-carboxyfluorescein by ethanol injection method followed by post inclusion of GSH and DSPE-PEG2000-maleimide micelle. The prepared liposomes having a particle size at a range of 105-108 nm and PDI around 0.049–0.065 represents the stability of the formulation. The cell uptake study was performed in vitro in RBEC48, the amount of liposome across the cellular lining was interpreted by quantifying the amount of fluorescent CF49. The results demonstrated approximately 1.8 folds higher cell uptake by the endothelial cells for GSH-PEG liposomes. The study shows a temperature-dependent uptake of the liposome that decreases with decreasing temperature. At the same time, the in vitro stability study was performed in culture media to ensure the stability of the formulation in the biological media. The brain distribution and pharmacokinetic behavior were studied in vivo, after administering the formulation through two different routes in the selected animal model (male Wistar rat) one is intravenous while the other via the intraperitoneal route. The studies show that both the route gives satisfactory drug concentration, circulation and retention time but IV50 route is more beneficial for brain uptake of the drug. The microdialysis was performed to study the free drug concentration in brain and it shows a significant increase in drug concentration with GSH-PEG liposome than the PEG-liposome. It can be concluded that GSH modification of PEGylated liposomal system (G-Technology®) offers a promising approach to target the drug molecule to the brain and protect the drug as well by providing a safe and stable homing/carrier system [126].

Fig. 7. Structure of glutathione-conjugated PEGylated liposomes. [Adopted and modified with permission from Lindqvist et al. [111]].

targeting ligand specific carrier or liposome is not necessarily required to enhance the brain uptake of DAMGO. To ensure the role of ligand (glutathione) the author have prepared three different formulations, one is a combination of empty GSH-PEG liposome with free DAMGO, second has DAMGO loaded GSH-PEG liposome and the last one is PEGylated liposome with encapsulated DAMGO and compared with the brain concentration of free DAMGO molecule. The results show, approximately double concentration in the brain when administered as DAMGO PEGylated liposome while the similar results found in DAMGO loaded GSH-PEG liposome. In contrast with the other work in G-Technology®, the present study suggests that ligand-mediated brain targeting does not inevitably need for increased brain uptake of drug substances, the non-specific PEGylated liposomes, themselves sufficient for increasing brain delivery of DAMGO. Although, this depends upon the nature of drug substances to be encapsulated and the composition of liposome [56,137].

2.6. Bifunctional liposome With a number of other benefits, a liposome offers an advantage of

2.5.3. Cargo delivery across BBB A similar piece of work has been done by Rip et al. [126], they have also prepared GSH modified PEGylated liposomes and studied its pharmacokinetic behavior, cellular uptake by brain endothelial cells

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nalized nanoliposome, surface modified with a lipid-PEG-Drug (curcumin) conjugate to identify the brain targeting ability of modified nanoliposome as well as the anti-amyloid β activity of curcumin. Curcumin, a very effective and magical phytoconstituent, having an ability to bind with the amyloid β plaque to dissolve the aggregates [140–143] and also disrupt the neurofibrillary tangles (basic cause of Alzheimer's disease) [144–146]. The major challenge associated is to deliver the drug at the desired site, across the BBB. Lipid serves as targeting ligand specific to BBB while PEG is used as a spacer between the lipidic vesicle and curcumin to make the drug easily available at the surface and to make the formulation stealth in nature i.e. long circulating. Thin film hydration is the method choice used for nanoliposome preparation. Initially, the lipid (DPS)-PEG2000-drug (curcumin) conjugate (Fig. 9) was synthesized which was further sonicated with cholesterol. PEGylation slightly affects the size of liposome which was found to 159 nm while the non-PEGylated formulation having 116 nm size. However, the PDI57 and zeta potential does not affect by the surface modification. Unlike to the other works in this field, Mourtas et al. have further performed his study on post-mortem human brain of AD58 patients than the animal model. The AD brains were obtained from the brain bank of France after fulfilling all the French bioethical laws. Different sections of isolated brain were treated with the prepared formulations and observed for labeling of senile plaque. It was found that the lipid-PEG-curcumin conjugate effectively labels the amyloid β plaques which ensures the targeting ability of formulation specifically to the amyloid β aggregates. At the same time, the study also shows that it effectively crosses the endothelial lining of BBB. The in vivo studies demonstrate a significant reduction in amyloid β plaques formation in AD brain. Overall, the study proves the multifunctionalized nanoliposome of PEGylated lipid-curcumin conjugate as an effective carrier system to target the BBB and reduce the senile plaque formation.

surface modification through various ligands and surface-active agents to enhance the efficacy and targeting ability of the carrier system. One such approach is multi-functionalized or bifunctionalized liposomes that are modified by the addition of more than one surface-active ligand; one is able to bind to the specific receptor at BBB while the other binds to the specific surface (β amyloid plaque in the case of Alzheimer's disease). 2.6.1. mApoE-PA bifunctional liposome To understand the concept of the bifunctional liposome, Balducci et al. [139] have developed a carrier system for the delivery of the bioactive across BBB [139]. In their work, they prepared a bifunctional liposome (mApoE51-PA52-Lip53) for the treatment of Alzheimer's disease to check the effective targeting ability i.e. ability to cross blood brain barrier using a receptor binding protein (mApoE). At the same time, they also looked upon the hindrance of β amyloid aggregates formation; facilitate its disruption and clearance from the brain. Extrusion is a method of choice used by Balducci for the preparation of bifunctional liposomes. The liposomal matrix was prepared with cholesterol and bovine brain sphingomyelin that is mixed with dimyristoyl phosphatidic acid and mApoE peptide on the surface, responsible for drug targeting. Sphingomyelin is distributed in the outer lipoidal membrane while the drug rhodamine B was encapsulated within the aqueous core. The prepared liposomes were characterized by using electron microscopy to check their ability to reduce the β amyloid aggregation formation. Pharmacokinetic studies were carried out on BALB/c mice subjected for various in vivo tests to check the memory improvement ability of the novel carrier system. The prepared bifunctionalized liposomes were found from 110 to 120 nm in size, about 0.15 polydispersity index as well − 25 to − 15 zeta potential that shows the stability of the formulation. It has a dually radiolabelled surface structure to confirm the drug targeting and the in vivo studies demonstrated the high percentage of liposomes in the brain as compare to another part of the body. They have used AAP54-PS155 transgenic AD56 mice for pharmacokinetic estimation of the prepared formulation. A significant reduction in β amyloid plaque has seen in the mouse treated with bifunctionalized liposome even after several months of treatment. The author worked on the hypothesis, the novel formulation crosses blood brain barrier and break the β amyloid aggregates in small fragments easily cleared from brain to blood and then excreted from liver and spleen. The theory is supported by various pharmacokinetic data. Confocal microscopy confers the higher percentage of drug in the brain. Results show the lower concentration of β amyloid in the brain (Fig. 8) as well greater in peripheral organs like liver and spleen. In addition, with the novel object recognition test shows significant memory enhancement in liposome treated mouse. This combined effect significantly reduces the severity of Alzheimer's disease as well it also reduces the β amyloid oligomer formation hence slow down the formation of the large β amyloid aggregate formation. The studies hereby prove the bifunctionalized liposome an effective delivery system to treat Alzheimer's disease but the exact cause of the excessive formation of β amyloid plaque formation is even though remains untreated that gives a huge scope of research in this field.

2.6.3. PA-peptide bifunctionalized liposome Similarly, in the sequence of multifunctional liposomes one more successful attempt has been made by Bana et al. [151]. They have prepared a liposome multifunctionalized with PA and a peptide derivative (mApoE), specific to the peptide receptor of BBB [147]. PA is responsible for amyloid β targeting [148] hence the formulation offers a multifunctional behavior that having the ability to cross the BBB by binding with the peptide bond and at the same time after entering the brain it specifically binds to the amyloid β aggregates to dissolve it. This makes it a very effective and superior approach to treating the Alzheimer's disease [149,150]. The liposome was prepared with sphingomyelin and cholesterol surface modified with PA and mApoE. The prepared liposomal formulation was further evaluated for physicochemical characteristics and it was found that the multifunctional liposome having a size of 123 nm, zeta potential − 15.2 mV and PDI < 0.1 which shows the stability of the formulation. The in-vitro cellular uptake study demonstrates that the bifunctionalized liposome more efficiently crosses the brain capillary endothelial cells by endocytosis than the monofunctional liposomes. At the same time, the binding ability of mApoE-PA-Lip was tested by SPR59 method and the results show that the mApoE-PA-Lip binds to the Aβ42 at a greater extent than the PA-Lip. In order to test the biodistribution, an in vivo study was performed on Balb/c mice and the result shows a higher concentration of bifunctional liposome in brain tissues as compared to the monofunctionalized liposome due to the affinity of specific binding ligands. Overall the study suggested that the bifunctional liposome offers various advantages over the mono-functional liposomes and effectively crosses the BBB as well as bind to the Aβ aggregates so

2.6.2. DPS-PEG2000-curcumin conjugated bifunctional nanoliposome Moving ahead in this context, a very interesting piece of work was done by Mortis and team (2014). They have prepared a multifunctio51

Modified peptide (Apo-lipo-protein) Phosphatidic acid liposome 54 Amyloid precursor protein 55 Presenilin 1 56 Alzheimer disease 52 53

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Polydispersity index Alzheimer's disease 59 Surface plasmon resonance 58

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Fig. 8. Graph showing a significant reduction in β amyloid level in the brain of mApoE-PA-LIP treated transgenic mice. [Adopted from Balducci et al. [139]].

Fig. 9. Lipid (DPS)-PEG2000-drug (curcumin) conjugate. [Adopted and modified with permission from Mourtas et al. [47]].

SPC64, PA65, Cl66 and two types of PEG derivatives by solvent evaporation method. NGF was then encapsulated in the liposome by dissolving the lipid mixture into a saline buffer containing human NGF. Thereafter the liposome was conjugated with the ApoE and APMP sequentially by suspending the liposomal particles into the buffer containing respective agents. The prepared dual targeted liposomes were further subjected to physicochemical characterization, structural behavior analysis, conjugation, cytotoxic study as well as in vitro and in vivo evaluation to confirm the safety and efficiency of the formulation. The particle size of liposome was affected by concentration and size of bioactive molecules as well as the composition of lipid component [154,155]. Stability of liposome preparation was measured by the value of zeta potential and it was found that increased APMP cause a significant decrease in the value of zeta potential while increased ApoE increases the value of zeta potential [156]. To gain the stability of liposome a PEG derivative was added that reduces the rapid elimination from the body by enhancing the half-life

inhibit the plaque formation effectively [151]. 2.6.4. Dual targeting NGF liposome Various attempts have been made and discussed earlier, in order to prevent the formation or dissociation of the β amyloid plaques in the brain. However, one more aspect of the treatment is to strengthen the weaker neurons and promoting the neuronal growth which can be regulated by NGF60 [152]. Chih Kuo and colleagues [82,104] worked on this strategy and prepared a dual BBB targeting liposome for the delivery of NGF with the aim to enhance the nerve growth by reducing the degenerative effect of β amyloid plaque and increasing the acetylcholinesterase in the brain instead of β amyloid plaque. A dual targeting liposome was prepared with ApoE and APMP61 [153] as a surface ligand that respectively targets the LDLR62 receptor and GLUT 163 and effectively crosses the BBB. The mechanism of drug transfer through BBB is either carrier-mediated transcytosis or receptormediated transcytosis. The liposome formulations were prepared by 60

Neuronal growth factor p-aminophenyl-a-D-manno-pyranoside 62 Low density lipoprotein receptor 63 Glucose transporter 1 61

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absorption of hydrophilic molecules as well as to enhance the drug targeting ability, the drug are delivered by loading in modified liposomes via intranasal route [163].

[157]. The data of conjugation efficiency reveals that the concentration of surface active ligand also alters the conjugation efficiency which was decreases with increasing concentration of APMP and ApoE. The in vitro cytotoxic study shows that the APMP-ApoE liposome was non-toxic to the neuronal cells. The biomolecules enhance the permeability of NGF through the BBB. The in vitro viability demonstrated that the prepared NGF liposomal formulation reduces the toxic effect of β amyloid on the nerve cells and enhances the cell viability. Overall, the in vitro study proves the dual-targeted NGF liposome as a safe and effective approach to treating the neurodegeneration.

3.1. Intranasal H102 peptide-loaded liposomes Zheng and co-workers, [171] have prepared a liposomal system for intranasal delivery of H102 peptide for the treatment of Alzheimer disease. H102 is a novel agent that interferes with the formation of β amyloid plaque by breaking the β sheets [164] responsible for the accumulation of β amyloid [165,166]. H102 is a synthetic oligopeptide, having specificity to β amyloid monomer thereby preventing the accumulation of β amyloid plaque by misfolding of monomers. At the same time, it also diminishes the APP level and improves the memory impairment. The problem of poor naso-mucosal retention, rapid clearance, and enzymatic degradation can be overcome by loading of drug into a liposomal system. Therefore, the formulation was targeted to the brain by administering through intranasal route which will facilitate the drug transfer across BBB via olfactory and trigeminal nerve [167–170]. Liposome was prepared with EPC69, DMPC-PEG2000, and cholesterol by thin film hydration method. The drug was added after formation of the film. The prepared liposome was further characterized and evaluated in vitro and in vivo. Morphology was done by TEM and particle size, zeta potential and PDI was measured in zeta sizer. Results show that prepared formulation having an average particle size near about 110 nm as well zeta potential and PDI confirms the stability of the formulations. Entrapment efficiency was found > 70% which was satisfactory. In vitro release study shows a sustained release for 12 h in case of H102 liposomal preparation, following first order kinetics. The circular dichroism study demonstrates that liposome protects the drug from enzymatic degradation while Calu3 cell transport experiment confirms the drug transfer through BBB. The drug absorption in the brain via nasal route was enhanced by the addition of penetration enhancer (1% chitosan). The pharmacokinetic studies were performed by using male SD rats and the results were compared with an H102 solution and liposomal preparation. The H102 solution, when administered by intranasal route attains peak plasma concentration immediately after administration and having rapid clearance. The liposomal formulation offers the sustained release of the drug, 2.7 folds higher AUC as the well higher concentration of drug in the brain and produces very less toxicity in nasal route. Morris Maze water experiment shows improvement in memory impairment in AD mouse model. Overall pharmacokinetic data reveals, liposome as a safe and effective carrier for drug delivery into the brain [171].

2.7. Phosphatidic acid and cardiolipin liposome As discussed earlier, the senile plaque deposition and formation of neurofibrillary tangles by the accumulation of tau protein in the brain are two major characteristic features of Alzheimer's disease [158]. The β amyloid is produced in the brain by cleavage of APP and normally removed via peripheral clearance [14]. This process of clearance is altered in case of Alzheimer's disease. Various approaches adopted to treat Alzheimer's disease mainly concern to prevent the formation of β amyloid plaque or cause disaggregation of plaques. BBB is a major challenge in those strategies to achieve the target [159]. To avoid this complexity, one unique approach suggested by Ordonez et al. [162] is the ‘sink effect’ [160,161]. This approach is based on sifting the β amyloid equilibrium towards the periphery. and prevent β amyloid deposition in the brain thus avoiding the Alzheimer's disease. In the present study, the author has prepared a PA-LIP67 and CL-LIP68 that specifically binds to β amyloid both in the brain and the peripheral region and facilitate its clearance. By this mechanism, it shifts the equilibrium towards the periphery and generates sink effect that triggers the outward movement of β amyloid from the brain. Small unilamellar vesicles were prepared with sphingomyelin and cholesterol by repeated extrusion method contains either CL or PA. The prepared liposomes were further evaluated for particle size, zeta potential, polydispersity index, stability etc. The in vivo study was performed in AAP/PS1 transgenic mice that mimic the pathophysiology of AD condition. Particle sizes of all the prepared formulations were found below 105 nm. The zeta potential as well polydispersity index also ensures the stability of the formulation till a sufficient period of time. The peptide binding ability of the formulation was tested by ultracentrifugation [148] and it was found that both the formulations having 25% peptide binding ability. The cell viability test shows that the liposomal preparation does not affect the cell proliferation. The efficacy of the formulation was tested in vivo in a transgenic mouse model by repeated intraperitoneal injection. The blood sample was collected and observed for free β amyloid concentration as well the concentration in the brain was observed by sacrificing the animal and extracting the brain out. The results show satisfactory reduction and clearance of circulating β amyloid in blood as a well partial reduction in β amyloid peptide in the brain. The decrease in peripheral peptide level produces sink effect that significantly reduces the β amyloid in the brain. Overall the study proves that this strategy offers an effective technique to treat Alzheimer's disease by avoiding the BBB [162].

3.2. Galantamine hydrobromide loaded flexible liposome One more approach adopted, in the series of intranasal delivery of drug-loaded liposome for the direct nose to brain delivery of the therapeutically active agent to the brain without interruption of BBB is galantamine hydrobromide loaded flexible liposome prepared by Weize Li and Co-workers [163]. The drug selected, was a plant derived phenanthridine alkaloid that has the ability to specifically and reversibly inhibit the acetylcholinesterase [172,173]. At the same time, it also possesses antioxidant activity that suppresses the degeneration occurs due to free radical and memory improvement by influencing the muscarinic transmission. The drug also offers targeting ability (allosteric potentiating ligand) specific to nicotinic acetylcholine receptor [174–177]. Supporting to all these abilities a recent study proves that the drug also has potential to reduce the formation of Aβ aggregates with very less cytotoxic effects [178,179]. On the basis of the above properties, the drug can be considered very potent for the treatment of Alzheimer's disease. Still, when administered orally or intravenously

3. Liposomes for intranasal administration The intranasal route offers an attractive and alternative approach for delivery of drug directly to the brain without any interruption of BBB. This strategy bids advantage of less enzymatic degradation, avoiding first pass metabolism, greater surface area for drug absorption and direct nose to brain administration of drug moiety through the olfactory region. However, to overcome some limitations like poor 67 68

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the drug produce systemic/GI70 side-effect, as well as some extent of the drug, get degraded by the GIT enzymes [180–182]. Hence, the drug is delivered through the intranasal route that offers an advantage of bypassing the GI effect and hence reduces the systemic side effect by directly delivering the drug to the brain (bypassing the BBB) via olfactory route [183]. At the same time, the hydrophilic drug encounters some problem in absorption through nasal mucosa so, in order to enhance the naso-mucosal absorption the drug was loaded in a novel drug carrier system that is a flexible liposome. The flexible liposome is referred to as a liposomal system with high elasticity to facilitate the drug absorption over skin and mucous membrane [184,185]. In the present study, a hydrophilic drug (galantamine hydrobromide) is loaded into the flexible liposome and delivered via the intranasal route to enhance the drug absorption, bioavailability as well as drug efficacy. The method adopted for the preparation of flexible liposome was thin film homogenization by using polyethylene glycol (approved by USFDA as a safer excipient for intranasal formulations) as an edge activator, the agent added to the liposomal formulations to enhance the elasticity and flexibility as well as the hydrophilicity of lipoidal membrane [178,186]. The average size of the prepared liposomal vesicles was about 112 nm with homogenous spherical multilamellar vesicular structure. The surface charge of the liposomal vesicles was − 49.2mv that indicates the stability of liposome. In addition, the entrapment efficiency of the liposome was significantly higher (83.6%), because of high lamellarity of liposomal vesicles. In order to check the acetylcholinesterase inhibition activity, the different groups of SD rats were treated with varying dose of the drug and the results suggest that the drug loaded in the flexible liposome shows maximum inhibition in a dose-dependent manner. These results were supported by the pharmacokinetic data that shows the drug loaded flexible liposome offer higher Cmax (13.98 μg/ml) and AUC (55.42 μg·h/ml) as shown in (fig. 10). However shorter tmax (0.75 h) than the oral and direct intranasal formulation. Also, the formulations were tested for cytotoxicity, and it was found that the drug loaded flexible liposome formulation shows minimum toxicity over the oral and intranasal drug solution. On the basis of these data, we can say that the flexible liposome for intranasal delivery offers an attractive approach to enhance the intranasal drug absorption and overall availability of the drug to the brain with improved drug efficacy [163].

Fig. 10. Graph shows mean concentration of different drug formulation in a different group of animals (group 2: oral administration of drug solution, group 3: Intranasal administration of drug solution, group 4: Intranasal administration of drug + flexible liposome and group 5: Intranasal administration of drug loaded into flexible liposome). [Adopted with permission from Li et al. [163]].

3.3. Rivastigmine loaded CPP-modified liposome

Fig. 11. Figure represents rivastigmine loaded Liposome and CPP-modified liposome. [Adopted and modified with permission from Yang et al. [190]].

The same scheme has been followed by a group of another author to enhance the pharmacological properties, drug targeting to brain whereas reducing the drug clearance by first pass metabolism and the systemic side effect [187,188] of one more potent cholinesterase inhibitor rivastigmine [189] that is able to inhibit the activity of both the acetylcholinesterase as well as butyl cholinesterase and thereby increasing the neurotransmitter level in brain and so reduces the severity of loss due to neurodegeneration. The author has selected an approach of preparing liposome and CPP-modified liposome to deliver the carrier through intranasal route in order to overcome the limitations associated with the drug molecule as discussed above [190]. CPP are considered as a kind of smaller peptide that having an ability to cross the cell membrane [191] via endocytosis and transcytosis [192]. Yang and their team have prepared two types of liposomal formulations; one is normal liposome while other is CPP-modified liposome (Fig. 11). These are prepared with EPC, cholesterol and a PEGylated derivative of CPP (DSPE-PEG-CPP) using ammonium sulfate gradient loading method. Further, the drug was loaded to the blank liposomal formulations and evaluated. It was found that all the liposomal preparation offer uniform shape and size distribution and remain unaffected by the CPP modification.

The particle size of liposome and CPP-liposome was found to be 166.33 and 178.9 nm; PDI 0.255 and 0.333; zeta potential −10.5 and − 8.6 as well as entrapment efficiency of 33.4% and 30.5%, respectively. The drug transportability of liposomal formulations across the BBB was investigated in vitro through BMVECs71 model and it was observed that the CPP loaded liposome offers an enhanced BBB permeation than the conventional liposome due to high permeability of CPP. The Pharmacokinetic study was performed on male SD rats and the drug concentration was observed in various regions of the brain as well as in peripheral organs after intranasal and IV administration of liposomal formulations. The result reveals that the maximum rivastigmine concentration was observed in the entire brain region after intranasal administration of CPP-modified liposome (Fig. 12) which retain for sufficient period of time as compared to other liposomes administered through intranasal and IV route. The study shows that the CPP-modified liposome, when administered through intranasal route, offers a promising approach to enhance the brain targeting of rivastigmine with removing all the associated side effects. Here, in the present study number of different novel approaches has been discussed to enhance the efficacy, bioavailability, and brain

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to preclinical trials and still, there is a great ray of hope in the early clinical application and trials of different liposomal formulations. With this underlined points we would definitely like to see the less expensive liposomal pharmaceuticals on the market in the near future. 4. Conclusion Liposome, a well-known and popular carrier system, among researchers to target the active compounds to their specific site of action and broadly used for brain targeting, because of its unique ability to cross BBB. Now a day, various modifications have been made in the liposomal surface to enhance its brain targeting ability. With the help of some specific ligands (glucose, lactoferrin, transferrin, specific peptides etc.), liposome efficiently crosses the BBB and able to deliver the drug at the particular site. Its application as a carrier system is well explored by the neurologists and scientists to treat AD. This advanced nanotechnological approach, proven to reduce the severity of AD and helps to regain the normal neurological functioning of the neuronal channel by preventing the plaque formation and removing the already formed amyloid deposits in preclinical studies. This area offers a very interesting and successful approach towards treatment of AD and needed further investigations in clinical studies so that such useful strategy become beneficial to the real-world patients from an assumption.

Fig. 12. Concentration of rivastigmine in a different region of the brain (olfactory, cortex and hippocampus) administered via the intranasal route. [Adopted and modified with permission from Yang et al. [190]].

targeting ability of the active molecules to ensures an effective treatment for Alzheimer's disease. Among all these, some modifications are intended for systemic administration via oral or i.v. route while some are administered through i.n. route. Most of these strategies are not practically in use till now i.e. are in clinical trial and having their own merits and demerits. The selection of a particular one depends on various factors like nature of active drug moiety, compatibility with various polymers and ligands, availability of resources, nature and severity of disease etc. the systemic route is referred as very common in clinical practices because of various well-known advantages but associated with some problems like extensive first pass metabolism, enzymatic degradation, peripheral side effects and most importantly the entrapment with BBB. Henceforth, the various surface modification has been made to overcome such issues and improves drug efficacy. At the same time, the i.n. route of drug administration is supposed to be superior over the systemic route. Studies indicate that i.n. the route offers various advantages over systemic drug administration like direct drug entry to the brain without interruption through BBB, protect the drug from the first pass metabolism as well as the enzymatic degradation, increases drug bioavailability, efficacy, reduces peripheral side effects. Additionally, it is patient convenient (self-administration, noninvasive) and cost effective approach. Despite this, the mucociliary clearance of drug limits the drug bioavailability through i.n. the route which can be overcome by using various novel drug carrier system. Hence, on the basis of various studies, the modification made on i.n. liposomal carrier system supposed to be superior to the systemic drug carrier system. Although, these advanced strategies are still not in clinical practices because of non-availability of suitable humanizes BBB model [193]. The studies are till now found successful in various in vitro and in vivo BBB model and hence, approved for clinical trial studies [38].

Conflict of interest None Acknowledgement Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing the UGC-INFLIBNET facility. The authors acknowledge Department of Science and Technology (No. SR/FST/LSI434/2010), New Delhi (SERC Division), India and UGC-SAP F.No.3-54/ 2011 (SAP II) dated March 2011, New Delhi, India for providing financial assistance under DST-FIST scheme. An author also wants to acknowledge the Science and Engineering Research Board (SERB), New Delhi for providing financial assistance under Start-Up grant scheme vide letter no. YSS/2015/001751; Dated: December 7, 2015, and SERB/ LS-368/2013, dated June 10, 2013. In the same sequence, authors also grateful to Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini-research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015, and 1115/CCOST/MRP/2015; Dated: September 4, 2015. Similarly, an author would like to acknowledge University Grant Commission (UGC), New Delhi, vide letter .no. MRP ID: MRP-MAJOR-PHAR-2013-31484 and All India Council for Technical Education (AICTE), New Delhi, vide letter.no. F. No. 8-126/RIFD/Policy-3/2013-14 dated February 4, 2014 for providing financial assistance to carry out the scientific research. References [1] M. Fazil, S. Shadab, J.K. Baboota, J. Sahni, Ali, Nanotherapeutics for Alzheimer's disease (AD): past, present and future, J. Drug Target. 20 (2012) 97–113. [2] 2015 Alzheimer's disease facts and figures, Alzheimers Dement. 11 (2015) 332–384. [3] M. Prince, A. Comas-Herrera, M. Knapp, M. Guerchet, M. Karagiannidou, Improving healthcare for people living with dementia coverage, Quality and Costs Now and in the Future, Alzheimer’s Disease International (ADI), London, 2016. [4] E. Meeuwsen, R. Melis, G. van der Aa, G. Goluke-Willemse, B. de Leest, F. van Raak, C. Scholzel-Dorenbos, D. Verheijen, F. Verhey, M. Visser, C. Wolfs, E. Adang, M. Olde Rikkert, Cost-effectiveness of one year dementia follow-up care by memory clinics or general practitioners: economic evaluation of a randomised controlled trial, PLoS One 8 (2013) e79797. [5] E.J. Meeuwsen, R.J. Melis, G.C. Van Der Aa, G.A. Goluke-Willemse, B.J. De Leest, F.H. Van Raak, C.J. Scholzel-Dorenbos, D.C. Verheijen, F.R. Verhey, M.C. Visser,

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