Nanoparticles for drug delivery to the brain

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is not yet a truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, particularly neuropeptides, are a few examples of molecules that cannot pass the BBB alone.[1] With the aid of nanoparticle delivery systems, however, studies have shown that certain drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function.[2] In addition, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis.[3] Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Background

The first successful delivery of a drug across the BBB occurred in 1995. The drug used was hexapeptide dalargin, an anti-nociceptive peptide that cannot cross the BBB alone.[4] It was encapsulated in polysorbate 80 coated nanoparticles and intravenously injected.[5] This was a huge breakthrough in the nanoparticle drug delivery field, and it helped advance research and development toward clinical trials of nanoparticle delivery systems. Nanoparticles range in size from 10 - 1000 nm (or 1 µm) and they can be made from natural or artificial polymers, lipids, dendrimers, and micelles.[1][5] The majority of polymers used for nanoparticle drug delivery systems are natural, biocompatible, biodegradable polymers that help to prevent contamination in the CNS. Several current methods for drug delivery to the brain include the use of liposomes, prodrugs, and carrier-mediated transporters. Many different delivery methods exist to transport these drugs into the body, such as peroral delivery, intranasal delivery, intravenous injections, and intracranial delivery. For nanoparticles the majority of studies have shown increasing progression with intravenous delivery specifically. In addition to delivery and transport methods, there are several means of functionalizing, or activating, the nanoparticle carriers. These means include dissolving or absorbing the drug throughout the nanoparticle, encapsulating the drug inside the particle, and attaching the drug on the surface of the particle.[2]

Types of nanoparticles for CNS drug delivery

Lipid based nanoparticles

Diagram of liposome showing a phospholipid bilayer surrounding an aqueous interior.

One particular type of nanoparticle involves the use of liposomes as drug molecule carriers. The diagram on the right shows a standard liposome. It has a phospholipid bilayer separating the interior from the exterior of the cell.

Liposomes are composed of vesicular bilayers, lamellae, made of biocompatible and biodegradable lipids such as sphingomyelin, phosphatidylcholine, and glycerophospholipids.[6] Cholesterol, a particular type of lipid, is also often incorporated in the lipid-nanoparticle formulation. Cholesterol can increase stability of the liposome as well as prevent leakage of the bilayer because its hydroxyl group is able to interact with the polar heads of the bilayer phospholipids. Liposomes have the potential to protect the drug from degradation, target sites for action, and reduce toxicity and adverse effects.[7] Lipid nanoparticles can be manufactured by high pressure homogenization, a current method used to produce parenteral emulsions. This process is ultimately able to create a uniform dispersion of small droplets in a fluid substance by subdividing particles until the desired consistency is acquired. [8] This manufacturing process is already scaled and in use in the food industry, which therefore makes it more appealing for researchers and for the drug delivery industry.

Liposomes can also be functionalized by attaching various ligands on the surface to enhance brain-targeted delivery.

Cationic liposomes

Another type of lipid-nanoparticle that can be used for drug delivery to the brain is a cationic liposome. Cationic liposomes are lipid molecules that are positively charged.[6] One example of cationic liposomes uses bolaamphiphiles, which contain hydrophilic groups surrounding a hydrophobic chain to strengthen the boundary of the nano-vesicle containing the drug. Bolaamphiphile nano-vesicles can cross the BBB, and they allow controlled release of the drug to target sites.[5] Lipoplexes can also be formed from cationic liposomes and DNA solutions, to yield transfection agents.[6] Cationic liposomes cross the BBB through adsorptive-mediated endocytosis followed by internalization in the endosomes of the endothelial cells. By transfection of endothelial cells through the use of lipoplexes, physical alterations in the cells could be made. These physical changes, could potentially improve how certain nanoparticle drug-carriers cross the BBB.

Solid lipid nanoparticles

Diagram displays a solid lipid nanoparticle (SLN). There is only one phospholipid layer because the interior of the particle is solid. Molecules such as antibodies, targeting peptides, and drug molecules can be bound to the surface of the SLN.

In addition, solid lipid nanoparticles (SLNs) are lipid nanoparticles with a solid interior as shown in the diagram on the right. SLNs can be made by replacing the liquid lipid oil used in the emulsion process with a solid lipid. In solid lipid nanoparticles, the drug molecules are dissolved in the particle's solid hydrophobic lipid core, this is called the drug payload, and it is surrounded by an aqueous solution.[6] Many SLNs are developed from triglycerides, fatty acids, and waxes. High-pressure homogenization or micro-emulsification can be used for manufacturing. In addition, functionalizing the surface of solid lipid nanoparticles with polyethylene glycol (PEG) can result in increased BBB permeability.[9]

Nanoemulsions

Another form for nanoparticle delivery systems is oil-in-water emulsions done on a nano-scale.[9] This process uses common biocompatible oils such as triglycerides and fatty acids, and combines them with water and surface-coating surfactants. Oils rich in omega-3 fatty acids, particularly, contain important factors that aid in penetrating the tight junctions of the BBB.[9]

Polymer based nanoparticles

Other nanoparticles are polymer-based, meaning they are made from a natural polymer such as polylactic acid (PLA), poly D,L-glycolide (PLG), polylactide-co-glycolide (PLGA), and polycyanoacrylate (PCA).[7] Some studies have found that polymeric nanoparticles may actually provide better results for drug delivery compared with lipid-based nanoparticles because they may increase the stability of the drugs or proteins being transported. Polymeric nanoparticles may also contain beneficial control release mechanisms.

Polymer Branch

Nanoparticles made from natural polymers that are biodegradable have the ability to target specific organs and tissues in the body. They also have the ability to carry DNA for gene therapy, and they have the ability to deliver larger molecules such as proteins, peptides, and even genes.[7] In order to manufacture these polymeric nanoparticles, the drug molecules are first dissolved and then encapsulated or attached to a polymer nanoparticle matrix. Three different structures can then be obtained from this process; nanoparticles, nanocapsules (in which the drug is encapsulated and surrounded by the polymer matrix), and nanospheres (in which the drug is dispersed throughout the polymeric matrix in a spherical form).[7]

One of the most important characteristics for nanoparticle delivery systems is that they must be biodegradable on the scale of a few days.[2] A few common polymer materials used for drug delivery studies are polybutyl cyanoacrylate (PBCA), poly(isohexyl cyanoacrylate) (PIHCA), polylactic acid (PLA), or polylactide-co-glycolide (PLGA). Human serum albumin (HSA) and chitosan are also materials of interest. PBCA undergoes degradation through enzymatic cleavage of its ester bond on the alkyl side chain to produce water-soluble byproducts. PBCA also proves to be the fastest biodegradable material, with studies showing 80% reduction after 24 hours post intravenous injection.[2] PIHCA, however, was recently found to display an even lower degradation rate, which in turn further decreases toxicity. PIHCA, due to this slight advantage, is currently undergoing phase III clinical trials for transporting the drug doxorubicin as a treatment for hepatocellular carcinomas.

Coating these polymeric nanoparticle devices with different surfactants can also aid BBB crossing and uptake in the brain. Surfactants such as Polysorbate 80, 20, 40, and 60 as well as polaxamer 188 demonstrated positive drug delivery through the blood brain barrier, whereas other surfactants did not yield the same results.[2] It has also been shown that functionalizing the surface of nanoparticles with polyethylene glycol (PEG), can induce the "stealth effect", allowing the drug-loaded nanoparticle to circulate throughout the body for prolonged periods of time.[10] In addition, the "stealth effect", caused in part by the hydrophilic and flexible properties of the PEG chains, facilitates an increase in localization of the drug at target sites in tissues and organs.[10][11]

Mechanisms for delivery

Liposome delivery

A mechanism for liposome transport across the BBB is lipid-mediated free diffusion, a type of facilitated diffusion, or lipid-mediated endocytosis.[9] There exist many lipoprotein receptors which bind lipoproteins to form complexes that in turn transport the liposome nano-delivery system across the BBB. Apoliproprotein E (apoE) is a protein that facilitates transportation of lipids and cholesterol.[9] ApoE constituents bind to nanoparticles, and then this complex binds to a low-density lipoprotein receptor (LDLR) in the BBB and allows for transportation to occur.

This diagram shows several ways in which transport across the BBB works. For nanoparticle delivery across the BBB, the most common mechanisms are receptor-mediated transcytosis and adsorptive transcytosis

Polymeric nanoparticle delivery

The mechanism for the transport of polymer-based nanoparticles across the BBB has been characterized as receptor-mediated endocytosis by the brain capillary endothelial cells.[2] Transcytosis then occurs to transport the nanoparticles across the tight junction of endothelial cells and into the brain. Surface coating of the nanoparticles with surfactants such as Polysorbate 80 or Poloxamer 188 were shown to increase uptake of the drug into the brain as well.[2] This mechanism also relies on certain receptors located on the luminal surface of endothelial cells of the BBB.[6] Ligands coated on the nanoparticle's surface bind to specific receptors to cause a conformational change. Once bound to these receptors, transcytosis can commence, and this involves the formation of vesicles from the plasma membrane pinching off the nanoparticle system after internalization.

Additional receptors identified for receptor-mediated endocytosis of nanoparticle delivery systems are the scavenger receptor class B type I (SR-BI), LDL receptor (LRP1), transferrin receptor, and insulin receptor.[2] As long as a receptor exists on the endothelial surface of the BBB, any ligand can be attached to the nanoparticle's surface to functionalize it so that it can bind and undergo endocytosis.

Another mechanism is adsorptive-mediated transcytosis, where electrostatic interactions are involved in mediating nanoparticle crossing of the BBB.[6] Cationic nanoparticles (including cationic liposomes as well) are of interest for this mechanism, because their positive charges assist binding on the brain's endothelial cells. Utilizing TAT-peptides, a cell-penetrating peptide, to functionalize the surface of cationic nanoparticles can additionally improve drug insertion into the brain.

Toxicity

A study was performed to assess the toxicity effects of doxorubicin-loaded polymeric nanoparticle systems.[2] It was found that doses up to 400 mg/kg of PBCA nanoparticles alone did not cause any toxic effects on the organism. These low toxicity effects can most likely be attributed to the controlled release and modified biodistribution of the drug due to the characteristics of the nanoparticle delivery system itself.[2] Toxicity is an extremely important factor and limitation of drug delivery studies, and it is a major area of interest in research on nanoparticle delivery to the brain.

Research

There is extensive research currently being done in the field of nanoparticle drug delivery systems to the brain. One of the popular diseases being studied in neuroscience today is Alzheimer's disease. Many studies have been done to show how nanoparticles can be used as a platform for delivering therapeutic drugs to these patients suffering from the disease. A few Alzheimer's drugs that have been studied in particular are rivastigmine, tacrine, quinoline, piperine, and curcumin.[2] PBCA, chitosan, and PLGA nanoparticles were used as delivery systems for these drugs. Overall, the results from each drug injection with these particular nanoparticles showed remarkable improvements in the effects of the drug when compared with non-nanoparticle delivery systems. This possibly suggests that nanoparticles could provide a promising solution to how these drugs could cross the BBB. One factor though that still must be considered and accounted for is nanoparticle accumulation in the body. With long-term and frequent injections that are often required to treat chronic diseases such as Alzheimer's disease, polymeric nanoparticles could potentially build up in the body, causing undesirable effects. This area for concern would have to be further assessed to analyze these possible effects as well as to improve them.[2]

References

  1. 1 2 Kreuter, Jörg (2001). "Nanoparticulate systems for brain delivery of drugs". Advanced Drug Delivery Reviews 47 (1): 65–81. doi:10.1016/S0169-409X(00)00122-8. PMID 11251246.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Kreuter, Jörg (2013). "Drug delivery to the central nervous system by polymeric nanoparticles: What do we know?". Advanced Drug Delivery Reviews 0: 2–14. doi:10.1016/j.addr.2013.08.008.
  3. ↑ Lo EH, Singhal AB, Torchilin VP, Abbott NJ (2001). "Drug delivery to damaged brain". Brain Res. Brain Res. Rev. 38 (1-2): 140–8. doi:10.1016/S0165-0173(01)00083-2. PMID 11750930.
  4. ↑ Das, Debanjan; Lin, Senshang (June 2005). "Double-coated poly (butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration". Journal of Pharmaceutical Sciences 94 (6): 1343–1353. doi:10.1002/jps.20357. PMID 15858853.
  5. 1 2 3 Hwang, Seung Rim; Kim, Kwangmeyung (2013). "Nano-enabled delivery systems across the blood-brain barrier". Archives of Pharmacal Research: 1–7.
  6. 1 2 3 4 5 6 Masserini, Massimo (2013). "Nanoparticles for Brain Delivery". ISRN Biochemistry 2013: 18. doi:10.1155/2013/238428.
  7. 1 2 3 4 Soppimath, Kumaresh S.; Aminabhavi, Tejraj M.; Kulkarni, Anandrao R.; Rudzinski, Walter E. (2001). "Biodegradable polymeric nanoparticles as drug delivery devices". Journal of Controlled Release 70 (1–2): 1–20. doi:10.1016/S0168-3659(00)00339-4. PMID 11166403.
  8. ↑ Blasi P, Schoubben A, Traina G, Manfroni G, Barberini L, Alberti PF, Cirotto C, Ricci M (2013). "Lipid nanoparticles for brain targeting III. Long-term stability and in vivo toxicity". Int J Pharm 454 (1): 316–23. doi:10.1016/j.ijpharm.2013.06.037. PMID 23832009.
  9. 1 2 3 4 5 Amiji, Mansoor; Shah, Lipa; Yadav, Sunita (2013). "Nanotechnology for CNS delivery of bio-therapeutic agents". Drug Delivery and Translational Research 3 (4).
  10. 1 2 Carstens, Myrra G.; Romberg, Birgit; Oussoren, Christien; Storm, Gert; Laverman, Peter; Boerman, Otto C. (2006). "5". Observations on the Disappearance of the Stealth Property of PEGylated Liposomes: Effects of Lipid Dose and Dosing Frequency (3rd ed.). Liposome Technology. pp. 79–94.
  11. ↑ Salmaso, Stefano; Caliceti, Paolo (2013). "Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers". Journal of Drug Delivery 2013: 1–19. doi:10.1155/2013/374252.

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