Document Type : Editorial

Authors

1 Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

2 Department of Biotechnology, School of pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

3 Department of Medical chemistry, School of pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

Abstract

Introduction: Central Nervous System (CNS) is one of the most important organs which is managing so many functions in human body. So, impairment of its function may results in several disorders in body, or CNS diseases, which are considered very important. CNS diseases are divided into many different groups and each group is treated with its own related medication. Some drugs that are used for treating CNS impairments have disadvantages like short length effect, renal and digestive toxicities and restrictions in pharmaceutical form. Some other drugs may cause complications worse than disease itself so the scientist shouls find the ways to solve these problems.
Methods: first “Scopus”, “PubMed”, and “ScienceDirect” were searched with the keywords “CNS”. “CNS diseases” and “lipid based nanoparticles” and the whole articles were collected; then the most irrelevant and inappropriate articles was removed and 105 articles were remained; at the last section of article selection the best articles was selected from the 105 articles that were remained and the finally selected articles were reviewed and this article was written.
Results: The review of many important articles and summarizing them was shown that the scientists and drug designers have used many ways to overcome all or some of the disadvantages of the CNS drug delivery (as mentioned above) and they found that one of the best ways to fix these bugs is using lipid-based nanoparticles in nanotechnology field.

Keywords

INTRODUCTION

CNS, abbreviation of Central Nervous System, is one the most important body organs due to its functions and duties, and thereby each malfunctioning in CNS can cause some consequences; that is why each type of CNS disorders should quickly diagnose and treat. CNS diseases are divided into different categories including neurodegenerative diseases, part of them are related to many different factors such as oxidative stress and glutamate,apoptosis, aging, and etc. This kind of diseases cover many CNS diseases, among them Alzheimer, Parkinson and Huntington will be discussed in this article. The next group is infectious diseases, causing overwhelming inflammation in brain and other parts of CNS. One of the most important diseases in this group is cerebral malaria resulting to unpleasant complications and even death, especially in children. Traumatic disorders, brain cancers and tumors, autoimmune-based CNS disorders and immunodeficiency are other types of CNS diseases that are caused by traumas (especially child hood traumas), genetic disorder, some types of viruses, and more other causes. There are many ways to cure these disorders, but each of them has its own disadvantages. So, researchers are trying to find new ways to overcome these disadvantages; among them nanoparticles may be desirable, 1,2 covering a broad range of applications in treatment of many kinds of CNS disorders, from cerebral malaria 3 to AIDS. The nanoparticles that are used in CNS disorders treatment, have a huge variation and only the Lipid-Based Nanoparticles (LBN), including NLC, SLN, and LB nanoemultions will be discussed in this article.

Lipid based nanoparticles

Different types of nanoparticles have different applications spectrum, from using as silver nanoparticles for antimicrobial coating to using as tattoo inks!.4 In his regard, one of the newest types of nanoparticles are lipid-based nanoparticles that have been used for a variety of purposes, some of which are discussed in the following.

SLNs

Solid Lipid Nanoparticles (SLNs) have discovered in the late years of the last century to overcome the shortage of previous nanoparticles like polymeric nanoparticles, liposomes and etc. This kind of nanoparticles are made of solid lipids at ordinary temperature. SLNs have a solid core coated with monolayer phospholipids and the drugs are entrapped in solid core. These nanoparticles are used in many different medical purposes such as controlled drug delivery, cosmetic, dermatologic preparations and etc.

NLCs

Nanostructured Lipid Carriers (NLCs) are a kind of lipid-based nanoparticles that are very similar to SLNs with similar applications. The most significant difference between NLCs and SLNs is that NLCs are made by mixing of solid lipids and liquid lipids, resulting to improved drug loading, particle capacity and release properties.

Micro and nanoemulsions

These kinds of lipid-based nanoparticles are the mixture of oil, surfactants and water, making it one of the best choices for hydrophobic drugs delivery.These kind of nanoparticles are used in several cases, some of them will be discussed in this article.

Liposomes

Bilayer vesicle with empty middle, this is the liposomes definition,6 the nanoparticles that are used for medical usages like targeted drug delivery with properties including enhanced drug uptake and prolonged drug circulation in blood and also the capacity to gene transfer.

CNS diseases and lipid based nanoparticles

Using nanoparticles is one of the newest methods for treating CNS diseases and there has been many research on this method, among which some cases using lipid particles will be discussed at the following.

CNS infectious diseases

Infectious diseases can be caused by a large variety of organisms, from simple viruses to complex organisms like malarial parasites. The efficacy of lipid-based nanoparticles for treating this kind of CNS diseases has been shown successfully.7, 8

Malaria is a parasitic disease in the category of CNS infections. A study investigated the effect of Artemether (ARM) + Lumefantrine (LFN) carried by Nanostructured lipid carriers (NLC) made by oleic acid+glycerylin. In vitro In vivo tests were performed in PBS buffer on Swiss Albino mice, C57BL/6 mice and albino Wistar rats. The experimental results in the buffer environment showed that both drugs were amorphous and had sustained release. The presence of NLCs increased the stability up to 6 months at various temperatures and humanity, and for 1 year at stable temperature. The use of NLC loaded by ARM and LFN as an intravenous injection in Swiss albino mice indicated that the time life after infection increased by 45 days. On the other hand, the mice were treated by 1/100 of oral ARM-LFN NLC combination. In the study, treatment of C57BL/6 mice had successful outcome, with the results such as complete resolution of symptoms, rectal normal temperature restoration in the 4th treating day, and finally no toxicity and side effects were observed in albino Wistar rats in 14 days of treatment.9

Brain cancers & tumors

Cancers can happen by genetic failures; these failures can be the congenital malformation or the result of some other reasons, smoking, some kinds of infections and viruses.10

CNS Histone Hyperacetylation is one of the subsets of brain cancer and in a study the results of examining the curcumin-NLC on PBS and Male CD1 mice was indicated. NLC particles were made by Glyceryl palmitostearate as solid and Capric triglycerides as liquid lipid. Initial burst effect for the first 4–5 h and sustained release of drug for the remaining time of monitoring were shown in PBS and decreasing CNS histone acetylation in CD1 mice.11 Examining the effects of Tripalmitin + oleic acid-made NLCs that were loaded by curcumin (Cur) in in vitro studies on human brain cancer cells showed that both Cur and NLC-Cur caused increasing in ROS at 20 mg/mL concentration and NLC-Cur can do it at lower concentration (10 mg/ml) too. By the way, the apoptotic induction effect of Curcumin becomes better by using this formulation. In vivo studies on female BALB-C mice showed that the growth of mice bearing A172 xenografts was inhibited by Curcumin loaded NLCs.12 In another study, two carriers, NLC and SLN, were examined to increase the effect of Ferulic Acid (FA) & Idebenone (IDE) in glioblastoma, disease from the category of brain cancer and tumors which is one of the most dangerous brain tumors that is hard to cure and is most fatal brain tumors exactly in elder patients13. Cellulose membranes which are made of Franz diaphragm diffusion cells was examined invitro and it is observed that FA release was better when carried by more oil containing NLC formulations than when carried by SLNs. Experiments on human U87MG cells had acceptable results with no cytotoxic effects; it was proved that treatment with IDE or IDE-loaded NLCs have lower effect than FA or NLCs loaded with FA and it was showed that FA-NLC could be a potential treatment for glioblastoma.14 A review of paclitaxel-loaded NLCs in in vitro environment showed that the drug loading of NLCs ranged between 4.3 and 9.8% and empty NLCs were less toxic than free paclitaxel and anzatax® and also anzatax® was more toxic than paclitaxel. Also, it was realized that the inhibiting activity of transferrin-conjugated paclitaxel NLCs (Tf-PTX-NLCs) was improved by increasing the PTX concentration. NLCs, in this study, were made by triolein(liquid) and Cholestrol (solid).15

Autoimmune based CNS disorders

Autoimmunity includes a group of diseases that are caused by an impairment of the immune system like some kinds of cancers and multiple sclerosis (MS) with very serious complications in patients.

Amyotrophic lateral sclerosis (ALS) is a disease that can be caused by gene mutations and often called Lou Gehrig,s disease. This illness can cause unbearable disabilities by destroying nerve cells. 16 A research on ALS with minocycline loaded nanoliposomes showed that using nano liposomes resulted in improvement of minocycline delivery to Cu/Zn superoxide dismutase gene,17 the gene that its mutation refers to familial ALS.

Immunodeficiency

One of the most important causes of immunodeficiency is human immunodeficiency virus (HIV) with various types like cyanovirin-N. It was discovered that at 1981 for the first time at USA, 18 this virus cause a venereal disease (AIDS) which is transmitted from sex with an infected person.

The in vitro study of Efavirenz (Efa) with NLC & SLN in PBS environment showed 92.45% of drug releasing at 24 hours. Study on blank brain tissue showed that Efa-NLC had no damage on the brain tissue on low and medium dose repeated administration and caused no toxic effects in these doses. On the other side, administration of formulation through intra nasal route caused significant drug concentration in the cerebrospinal fluid (CSF) by passing through the Blood Brain Barrier in male Wistar rats in vivo.19

Neuro degenerative disorders

Neurodegeneration can cause by loss of neuron structure or function of like neurons death and etc.

and this category includes many kind of diseases like Parkinson, Alzheimer and Huntington.20,21

A study tried to investigate the effect of an encapsulated Brain-derived neurotrophic factor (BDNF) with nanoscale carriers on Huntington’s disease. In an in vivo analysis, it was found that the strategic therapeutic effect of this method is important.17 A study examined the encapsulation of Aripiprazole with Nano-emulsions and its effect on schizophrenia. In vivo results indicated that the needed dose and the side effects were reduced because of the improvement of drug’s bioavailability, solubility and BBB penetration;17 Another study proved that the effect of curcumin carried by Nanostructured Lipid Carriers (NLCs) was evaluated on Alzheimer disease. In vitro studies on 1% (w/v) tween 80 in Physiological saline 181, found that the drug release from NLCs was decreased by Lactoferine (Lf) adsorption, and in vivo studies on Brain capillary endothelial cells (BCECs) showed that empty NLCs and Lf-modified NLCs caused no toxicity on BCECs. On the other hand, curcumin-NLCs were examined on Sprague-Dawley (SD) rats & ICR mice and showed that the flexible drug delivery platform can be registered because of Lf-mNLC successful BBB crossing during the brain targeting.22 In a study, intranasally administering of Nile Red and DiR carried by chitosan coated NLCs (Miglyol + Precirol ATO5) was evaluated in Neurodegenerative disorders therapy. In this study, in vitro experiments on human bronchial epithelial (16HBE14o-) cell line showed effective delivery to the brain and in in vivo studies on C57 mice showed no inflammatory, fibrosis and atopic tissue formation.23 One of the important choices of Parkinson’s disease treatment is L-dopa (LD). However one of the most important complication of long-term LD therapy is due to its metabolism. In vitro studies showed that Levodopa loaded NLCs needed less prescribed dose. It was because of several reasons: its solubility was improved, NLC formulations protected LD from metabolism and especially from esterase enzymes of plasma, which could increase the drug’s half-life and it is necessary to ensure that the effect of lipases is so similar in PDB and PDC NLCs.24 Bromocriptine (BC) is a agonist of dopamine receptors with a wide therapeutic potential in neurodegenerative disorders. In vivo studies proved that the effect of BC loaded NLCs had longer lasting therapeutic benefit than free BC after administration in male Sprague-Dawley rats in Parkinson’s disease therapy. Both formulations elevated the effect at first half an hour after administration. The effect of free BC disappeared after 3 h, while the effect of NLC-BC continued by 3-5 hours after administration. Both formulations significantly showed a reduction in akinesia at the first half an hour after administration and also BC could reduce the immobility time. Also, both free BC and NLC-BC formulations proved to reduce the immobility time.25 Alzheimer is another neurodegenerative disorder. Gastrointestinal side effects of current Alzheimer’s FDA approved drugs lead to drug therapy discontinuation and different studies evaluated the using of nanotechnology in drug delivery of Alzheimer’s therapy. It was reported that intravenous administration of nano encapsulated ferulic acid lead to increased bioavailability. In an in vivo study, galantaminehydrobromide SLNs was administered orally in cognitive deficit rats. This formulation enhanced bioavailability up to 100%, compared to free galantamine and significantly showed capability of memory restoration.26 In another research, the inhibitory effect of galantamine on acetylcholine esterase was greatly enhanced by galantamine flexible liposomes intranasal administration, and the cytotoxicity was significantly reduced.27 An in vitro study used SLNs loaded with lipoyl-memantine as a co-drug in mouse N2a neuroblastoma; This study proved safety of the formulation from toxicological point of view and suggested its potential for in vivo investigations.28 In another study, Rivastigmine-loaded liposomes was used for intranasal application. The average SLN rivastigmine concentration was significantly higher compared to free rivastigmine in hippocampus and cortex of ret models with AD.29 Also, using Rivastigmine-microemulsion as an intranasal administration for nasal ciliotoxicity was stable for three months.30 Intranasal administration of donepozil loaded nanoliposomes increased the bioavailability of donepezil in healthy male wistar rats and furthermore the safety of formulations was approved.31 In a study, conjugated monoclonal antibodies (mAbs) with liposomes was used to targeted drug delivery across the BBB, Curcumin-conjugated mAbs-nanoliposomes was injected into the transgenic mice’s neocortex and hippocampus of and showed the specific binding to Aβ deposits.32, 33 In an in vitro investigation, using apolipoprotein peptide analog, TAT peptides and anti-transferrin receptor antibody in hCMEC/D3 cells, showed higher permeability across the barrier model. These formulations were used for in vivo studies on APP/PS1 mice and showed increased plasma level of Aβ.34, 35 Also, curcumin nanoemulsion was investigated in sheep nasal mucusa as an in vitro study which proved the safety and highest flux of formulation across mucosa.36 In another in vivo study, Albino rats were received the nanoemulsion of curcumin and resveratrol. The toxicity results showed the lining epithelium of nasal cavity doesn’t damaged with repeated administration of both formulations and in addition both of them can reach the therapeutic concentration in the brain.37 Centellaasiatica plant extract was used to prepare a nanoemulsion for intranasally delivery and showed ex vivo permeation and also in vivo antioxidant property.38 In this article, a bioadhesive microemulsion-based patch loaded with huperazine A and ligustrazine phosphate (LP) was used for transdermal drug delivery. In vivo studies on male Spargue-Dawley rats showed reduced progression of Alzheimer disease because of improved cerebral cholinergic function and oxidative system. In scopolamine-induced amnesia rats all of these effects were visible.39,40

Other CNS diseases

Some types of CNS diseases cannot be categorized in the categories that were said above, like insomnia, the diseases caused by some drugs age-related diseases, and schizophrenia, which all have many reasones.

Schizophrenia is caused by genetic and environmental factors41 and the most important symptoms of this disorder are hallucination (especially vocal illusions), delusion and disorganizing in thinking and speech. So, many drugs are used for treating schizophrenia and using nanotechnology can improve their effect. In a study, it was shown that treating with Olanzapine- and Simvastatine-loaded NLCs in PBS causes gradual release up to 48 hours and skin permeation was observed on newborn pig’s skin. In vivo examination of this nanoparticles on rats showed equal permeation of both drugs. Also, it was proved that conventional NLCs have higher mean particle size, lower polydispersity and similar Ȥ-potential compared to combo-NLCs. Olanzapine was more soluble in Oleic acid (liquid part of NLCs), while Simvastatin was more soluble in Tripalmitin (solid part of NLCs) and the releasing extent of Simvastatin is lower than Olanzapine.42 Other In vivo research on treating insomnia showed that nasal delivery of Zaleplon with nanoemulsion gelscauses enhanced tissue permeation and bioavailability.17

CONCLUSION

In general it can be concluded that lipid-based nanoparticles can be introduced as one of the best types of nanoparticles for using in the treatment of CNS disorders through solving many problems such as passing medications from BBB, drugs instability in Gastro Intestinal tract, Protect drugs from unwanted metabolisms and etc.

ACKNOWLEDGEMENT

We thanks Dr.Somayeh Sadighian for her a lot and important helps to us in writing this paper and exactly we thanks Dr. Narges Forouzideh and our edition team.

CONFLICT OF INTERESTS

No conflict of interests was not reported by the authors.

FUNDING SOURCES

Costs associated with this process were supported by the writers themselves and the internet and web features was supported by Zanjan University of Medical Sciences.

AUTHORS CONTRIBUTIONS

All of the authors involved in all sections of the paper (from A to Z) and therefor, they will contribute to all rights and results of the publication of the article.

 

 

1. Kanazawa T, Akiyama F, Kakizaki S, Takashima Y, Seta Y. Corrigendum to ‘Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles’ [Biomaterials 34 (2013) 9220–9226]. Biomaterials. 2014;35(13):4247.

2. Hwang SR, Kim K. Nano-enabled delivery systems across the blood–brain barrier. Archives of Pharmacal Research. 2013;37(1):24-30.

3. Waknine-Grinberg JH, Even-Chen S, Avichzer J, Turjeman K, Bentura-Marciano A, Haynes RK, et al. Glucocorticosteroids in Nano-Sterically Stabilized Liposomes Are Efficacious for Elimination of the Acute Symptoms of Experimental Cerebral Malaria. PLoS ONE. 2013;8(8):e72722.

4. Høgsberg T, Loeschner K, Löf D, Serup J. Tattoo inks in general usage contain nanoparticles. British Journal of Dermatology. 2011;165(6):1210-8.

5. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Advanced Drug Delivery Reviews. 2012;64:175-93.

6. Patil YP, Jadhav S. Novel methods for liposome preparation. Chemistry and Physics of Lipids. 2014;177:8-18.

7. Santos-Magalhães NS, Mosqueira VCF. Nanotechnology applied to the treatment of malaria. Advanced Drug Delivery Reviews. 2010;62(4-5):560-75.

8. Nayak AP, Tiyaboonchai W, Patankar S, Madhusudhan B, Souto EB. Curcuminoids-loaded lipid nanoparticles: Novel approach towards malaria treatment. Colloids and Surfaces B: Biointerfaces. 2010;81(1):263-73.

9. Prabhu P, Suryavanshi S, Pathak S, Patra A, Sharma S, Patravale V. Nanostructured lipid carriers of artemether–lumefantrine combination for intravenous therapy of cerebral malaria. International Journal of Pharmaceutics. 2016;513(1-2):504-17.

10. Control CfD, Prevention. Human papillomavirus-associated cancers-United States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012; 61: 258.

11. Puglia C, Frasca G, Musumeci T, Rizza L, Puglisi G, Bonina F, et al. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice. European Journal of Pharmaceutics and Biopharmaceutics. 2012;81(2):288-93.

12. Chen Y, Pan L, Jiang M, Li D, Jin L. Nanostructured lipid carriers enhance the bioavailability and brain cancer inhibitory efficacy of curcumin bothin vitroandin vivo. Drug Delivery. 2015:1-10.

13. Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. Journal of Neuro-Oncology. 2012;108(1):11-27.

14. Carbone C, Campisi A, Musumeci T, Raciti G, Bonfanti R, Puglisi G. FA-loaded lipid drug delivery systems: Preparation, characterization and biological studies. European Journal of Pharmaceutical Sciences. 2014;52:12-20.

15. Emami J, Rezazadeh M, Sadeghi H, Khadivar K. Development and optimization of transferrin-conjugated nanostructured lipid carriers for brain delivery of paclitaxel using Box–Behnken design. Pharmaceutical Development and Technology. 2016;22(3):370-82.

16. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet Journal of Rare Diseases. 2009;4(1):3.

17. Hassanzadeh P, Atyabi F, Dinarvand R. Application of modelling and nanotechnology-based approaches: The emergence of breakthroughs in theranostics of central nervous system disorders. Life Sciences. 2017;182:93-103.

18. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases E-Book: Elsevier Health Sciences; 2014.

19. Pokharkar V, Patil-Gadhe A, Palla P. Efavirenz loaded nanostructured lipid carrier engineered for brain targeting through intranasal route: In-vivo pharmacokinetic and toxicity study. Biomedicine & Pharmacotherapy. 2017;94:150-64.

20. del Campo M, Mollenhauer B, Bertolotto A, Engelborghs S, Hampel H, Simonsen AH, et al. Recommendations to standardize preanalytical confounding factors in Alzheimer’s and Parkinson’s disease cerebrospinal fluid biomarkers: an update. Biomarkers in Medicine. 2012;6(4):419-30.

21. Alzheimer’s A. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 2015; 11: 332-84. doi:10.1016/j.jalz.2015.02.003.

22. Meng F, Asghar S, Gao S, Su Z, Song J, Huo M, et al. A novel LDL-mimic nanocarrier for the targeted delivery of curcumin into the brain to treat Alzheimer’s disease. Colloids and Surfaces B: Biointerfaces. 2015;134:88-97.

23. Gartziandia O, Herran E, Pedraz JL, Carro E, Igartua M, Hernandez RM. Chitosan coated nanostructured lipid carriers for brain delivery of proteins by intranasal administration. Colloids and Surfaces B: Biointerfaces. 2015;134:304-13.

24. Cortesi R, Esposito E, Drechsler M, Pavoni G, Cacciatore I, Sguizzato M, et al. L-dopa co-drugs in nanostructured lipid carriers: A comparative study. Materials Science and Engineering: C. 2017;72:168-76.

25. Esposito E, Mariani P, Ravani L, Contado C, Volta M, Bido S, et al. Nanoparticulate lipid dispersions for bromocriptine delivery: Characterization and in vivo study. European Journal of Pharmaceutics and Biopharmaceutics. 2012;80(2):306-14.

26. Misra S, Chopra K, Sinha VR, Medhi B. Galantamine-loaded solid–lipid nanoparticles for enhanced brain delivery: preparation, characterization,in vitroandin vivoevaluations. Drug Delivery. 2015;23(4):1434-43.

27. Li W, Zhou Y, Zhao N, Hao B, Wang X, Kong P. Pharmacokinetic behavior and efficiency of acetylcholinesterase inhibition in rat brain after intranasal administration of galanthamine hydrobromide loaded flexible liposomes. Environmental Toxicology and Pharmacology. 2012;34(2):272-9.

28. Laserra S, Basit A, Sozio P, Marinelli L, Fornasari E, Cacciatore I, et al. Solid lipid nanoparticles loaded with lipoyl–memantine codrug: Preparation and characterization. International Journal of Pharmaceutics. 2015;485(1-2):183-91.

29. Yang Z-Z, Zhang Y-Q, Wang Z-Z, Wu K, Lou J-N, Qi X-R. Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration. International Journal of Pharmaceutics. 2013;452(1-2):344-54.

30. Shah BM, Misra M, Shishoo CJ, Padh H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation andex-vivocharacterization. Drug Delivery. 2014;22(7):918-30.

31. Ullah Z, Al-Asmari A, Tariq M, Fatani A. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil. Drug Design, Development and Therapy. 2016:205.

32. Mourtas S, Canovi M, Zona C, Aurilia D, Niarakis A, La Ferla B, et al. Curcumin-decorated nanoliposomes with very high affinity for amyloid-β1-42 peptide. Biomaterials. 2011;32(6):1635-45.

33. Mourtas S, Lazar AN, Markoutsa E, Duyckaerts C, Antimisiaris SG. Multifunctional nanoliposomes with curcumin–lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. European Journal of Medicinal Chemistry. 2014;80:175-83.

34. Markoutsa E, Papadia K, Giannou AD, Spella M, Cagnotto A, Salmona M, et al. Mono and Dually Decorated Nanoliposomes for Brain Targeting, In Vitro and In Vivo Studies. Pharmaceutical Research. 2013;31(5):1275-89.

35. Mancini S, Minniti S, Gregori M, Sancini G, Cagnotto A, Couraud P-O, et al. The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease. Nanomedicine: Nanotechnology, Biology and Medicine. 2016;12(1):43-52.

36. Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids and Surfaces B: Biointerfaces. 2014;113:330-7.

37. Nasr M. Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery. Drug Delivery. 2015;23(4):1444-52.

38. Jaiswal M, Kumar A, Sharma S. Nanoemulsions loaded Carbopol® 934 based gel for intranasal delivery of neuroprotective Centella asiatica extract: in–vitro and ex–vivo permeation study. Journal of Pharmaceutical Investigation. 2016;46(1):79-89.

39. Shi J, Cong W, Wang Y, Liu Q, Luo G. Microemulsion-based patch for transdermal delivery of huperzine A and ligustrazine phosphate in treatment of Alzheimer’s disease. Drug Development and Industrial Pharmacy. 2011;38(6):752-61.

40. Wen MM, El-Salamouni NS, El-Refaie WM, Hazzah HA, Ali MM, Tosi G, et al. Nanotechnology-based drug delivery systems for Alzheimer’s disease management: Technical, industrial, and clinical challenges. Journal of Controlled Release. 2017;245:95-107.

41. Epstein GB. Toxoplasma gondii as a Risk Factor for Schizophrenia and Psychosis: University of Maryland, Baltimore County; 2016.

42. Vitorino C, Almeida A, Sousa J, Lamarche I, Gobin P, Marchand S, et al. Passive and active strategies for transdermal delivery using co-encapsulating nanostructured lipid carriers: In vitro vs. in vivo studies. European Journal of Pharmaceutics and Biopharmaceutics. 2014;86(2):133-44.