Nanoneuroscience and Nanoneuropharmacology

Nanoneuroscience and Nanoneuropharmacology, Volume 180
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An immunohistochemical analysis of the spinal cord tissue was performed at the end of the experiment and this proved a significant preservation of the white matter tissue, a reduced area of glial scaring and a higher amount of newly sprouted axons in the nanocurcumin treated group. Nanocurcumin preserved damaged white matter and downsized the glial scar.

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Current Neuropharmacology

Search for books, journals or webpages All Pages Books Journals. View on ScienceDirect. Editors: Hari Sharma. Hardcover ISBN: Imprint: Elsevier Science. Published Date: 21st December Page Count: The size of dendrimers can be carefully controlled during the process of synthesis of dendrimers. Scientists are focusing on newer approaches for speeding up the synthesis process by preassembly of oligomeric branches which can be linked together to reduce the number of synthesis steps involved and also increase the dendrimer yield [ 28 ].

Dendrimers are popularly used for transfer of genetic materials in cancer therapy or other viral diseases in different organs because of their monodisperisity, high density of functional groups, well-defined shape and multivalency. Some other types of dendrimers are peptide dendrimers, glycodendrimers, polypropilimine dendrimers, Polyethyleneimine PEI dendrimers etc.

Nanoshells nm may be used for drug carrier of both imaging and therapy. Nanoshells consist of nanoparticles with a core of silica and a coating of thin metallic shell [ 29 ]. They can be targeted to a tissue by using immunological methods. Nanoshells can also be embedded in a hydrogel polymer [ 30 ]. Nanoshells are currently being investigated for prevention of micrometastasis of tumors and also for the treatment of diabetes.

Nanoshells are useful for diagnostic purposes in whole blood immunoassays [ 31 ]. Fullerenes composed of carbon in the form of a hollow sphere or ellipsoid tube. Fullerenes are being investigated for drug transport of antiviral drugs, antibiotics and anticancer agents [ 32 ]. Fullerenes have the potential to stimulate host immune response and productions of fullerene specific antibodies.

Soluble derivatives of fullerenes such as C60 have shown great utility as pharmaceutical agents. Nanotubes are nanometer scale tube like structure and they are of different types like carbon nanotube, inorganic nanotube, DNA nanotube, membrane nanotube etc. Carbon nanotubes can be made more soluble by incorporation of carboxylic or ammonium groups to their structures and can be used for the transport of peptides, nucleic acids and other drug molecules. The ability of nanotubes to transport DNA across cell membrane is used in studies involving gene therapy.

DNA can be attached to the tips of nanotubes or can be incorporated within the tubes [ 34 ]. Nanopores 20 nm in diameter consist of wafers with high density of pores which allow entry of oxygen, glucose and other chemicals such as insulin to pass through. Nanopores can be used as devices to protect transplanted tissues from the host immune system, at the same time, utilizing the benefit of transplantation [ 35 ].

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Nanopores can also be employed in DNA sequencing. Nanopores are also being developed with an ability to differentiate purines from pyrimidines [ 36 ]. Quantum dots QD are tiny semiconductor nanocrystals type of particles generally no larger than 10 nanometers that can be made to fluoresce in different colours when stimulated by light. The biomolecule conjugation of the QD can be modulated to target various biomarkers [ 37 ]. They can be tagged with biomolecules and used as highly sensitive probes. QD can also be used for imaging of sentinel node in cancer patients for tumour staging and planning of therapy.

This technology also outlines some early success in the detection and treatment of breast cancer [ 38 ].

Progress in Brain Research

QD may provide new insights into understanding the pathophysiology of cancer and real time imaging and screening of tumors. Bioconjugated QD are collections of variable sizes of nanoparticles embedded in tiny beads made of polymer material. The new class of quantum dot conjugate contains an amphiphilic triblock copolymer layer for in vivo protection and multiple PEG molecules for improved biocompatibility and circulation, making it highly stable and able to produce bright signals.

Another advantage is that quantum dot probes emitting at different wavelengths can be used together for imaging and tracking multiple tumor markers simultaneously, potentially increasing the specificity and sensitivity of cancer detection [ 40 ]. Recent progress in the surface chemistry of QD has expanded their use in biological applications, reduced their cytotoxicity and rendered quantum dots a powerful tool for the investigation of dinstinct cellular processes, like uptake, receptor trafficking and intracellular delivery.

Another application of QD is for viral diagnosis. Rapid and sensitive diagnosis of Respiratory Syncytial Virus RSV is important for infection control and development of antiviral drugs. Antibody-conjugated nanoparticles rapidly and sensitively detect RSV and estimate relative levels of surface protein expression.

A major development is the use of dual-colour QD or fluorescence energy transfer nanobeads that can be simultaneously excited with a single light source [ 41 ]. QD linked to biological molecules, such as antibodies, have shown promise as a new tool for detecting and quantifying a wide variety of cancer-associated molecules. In the field of nanomedicine, QD can make a worthy contribution to the development of new diagnostic and delivery systems as they offer unique optical properties for highly sensitive detection and they are well defined in size and shape and can be modified with various targeting principles.

The blood brain barrier BBB is a structure formed by a complex system of endothelial cells, astroglia, pericytes, and perivascular mast cells, preventing the passage of most circulating cells and molecules [ 42 ]. The tightness of the BBB is attributed mainly to the vascular layer of brain capillary endothelial cells which are interconnected side-by-side by tight and adherens junctions.

Among the different nanodevices, nanosize drug delivery systems between 1 and nm work as a whole unit in terms of transport to cross BBB [ 43 ]. Nanosize brain drug delivery systems may promote the targeting ability of drug in brain and at the same time enhance the permeability of molecules through BBB.

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However crossing of BBB by the nano drug carriers will depend completely on the physicochemical and biomimetic features and does not depend on the chemical structure of drug, inside the nanoparticles [ 44 ]. Drug loaded nanoparticles with favourable biological properties include prolonging the residence time, decreasing toxicity and high ability of drug penetration into the deeper layers of the ocular structure and minimizing precorneal drug loss by the rapid tear fluid turnover [ 46 ].

Nanoparticles could target at cornea, retina and choroid by surficial applications and intravitreal injection. Nanocarrier based drug delivery is suitable in the case of the retina, as it has no lymph system, hence retinal neovascularisation and choroidal neovascularization have similar environments to that of solid tumors, and the EPR effect as available for solid nanoparticles in case of solid tumor may be also available for drug delivery targeted to eyes by nanoparticles [ 47 ].

Nanoparticles can deliver ocular drugs to the target sites for the treatment of various diseases such as glaucoma, corneal diseases, diabetic retinopathy etc. The uses of nanotechnology based drug delivery systems like nanosuspensions, SLNs and nanoliposomes have greater effect for ocular therapeutic efficacy [ 48 ].

Nanotechnology-based drug delivery is also very efficient in crossing membrane barriers, such as the blood retinal barrier in the eye. Contact lenses loaded with nanoparticles can be effective for topical administration of ophthalmic drugs.

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Drug loaded contact lenses can also provide continuous drug release because of slow diffusion of the drug molecules through the lens matrix. The soaked contact lenses also delivered drugs only for a period of few hours for some typical drugs [ 49 ]. The duration of drug delivery from contact lenses can be significantly increased if the drug is first entrapped in nanoformulations, such as nanoliposomes, nanoparticles, or microemulsions.

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Such drug nanocarriers can then be dispersed throughout the contact lens material. The entrapment of drug in nanocarriers also prevents the interaction of drug with the polymerization mixture. This provides additional resistance to drug release, as the drug must first diffuse through the nanocarriers and penetrate the drug carrier surface to reach the contact lens matrix [ 50 ]. The ocular biodistribution of nanoparticles can provide insights into the bioavailability, cellular uptake, duration of drug action and toxicity.

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Factors such as particle size, composition, surface charge and mode of administration influence the biodistribution in the retinal structures and also their drainage from the ocular tissues [ 51 ]. The surface chemistry can also affect nanoparticle distribution. Positively charged nanoparticles can adhere to the anionic vitreous network components and aggregate within the vitreous network. Posively charged nanoparticles can adhere to the anionic vitreous network components and aggregate within the vitreous humor [ 53 ].

Anionic nanoparticles were found to diffuse through the vitreous humor and could even penetrate the retinal layers to be taken up by Muller Cells [ 54 ]. Vitreous humor is regarded as the barrier for non-viral ocular gene therapy because of the strong interaction of conventional cationic nature of non-viral gene vectors with the anionic vitreous humor [ 53 ].

The cationic PEI nanoparticles aggregated within vitreous humor and were prevented from distributing to the retina by the vitreal barrier. Cancer cells are more vulnerable than normal cells to the effect of chemotherapeutic agents and the most of the anticancer drugs can cause injury to the normal cells. Optimum dose and frequency are both important factors in the persistence of cancer cells during cancer chemotherapy [ 56 ]. Now attempts are focused on efforts to kill cancer cells by more specific targeting while sparing the normal cells. Nanoparticulate delivery systems in cancer therapies provide better penetration of therapeutic and diagnostic substances within the cancerous tissue in comparison to conventional cancer therapies [ 57 ].

Nanoparticles are constructed to take advantages of fundamental cancer morphology and modes of development such as rapid proliferation of cells, antigen expression, and leaky tumor vasculature. Nanoparticulate drug delivery systems are being developed to deliver smaller doses of chemotherapeutic agents in an effective form and control drug distribution within the body [ 58 ]. Nanocarriers can offer many advantages over free drugs in cancer chemotherapy such as they protect the drug from premature degradation, prevent drugs from prematurely interacting with the biological environment, enhance absorption of the drugs into a selected tissue solid tumour , control the pharmacokinetic and drug tissue distribution profile and improve intracellular penetration [ 59 ].

Nanoparticulate delivery systems utilize specific targeting agents for cancer cells minimizing the uptake of the anticancer agent by normal cells and enhance the entry and retention of the agent in tumor cells Figure 3 [ 60 ]. Nanocarriers may actively bind to the specific cancer cells by attaching targeting agents with the help of ligand molecules to the surface of the nanocarriers that bind to specific receptor antigens on the cell surface.

Nanocarriers will recognize and bind to target cells through ligand receptor interactions. It is even possible to increase the drug targeting efficacy with the help of antibodies by conjugating a therapeutic agent directly to it for targeted delivery [ 61 ]. Like receptor targeting, targeting of angiogenic factors also takes advantage of properties unique to cancer cells.

Anti-angiogenic treatment is the use of drugs or other substances to stop tumors from developing new blood vessels. In a study nanoparticles were formulated comprising a water-based core of Vickers microhardness sodium alginate, cellulose sulphate, and anti-angiogenic factors such as thrombospondin TSP -1 or TSP, crosslinked with dextran polyaldehyde with calcium chloride or conjugated to heparin sulphate with sodium chloride. In addition bioluminescent agent, luciferase, or contrast agent, polymeric gadolinium was located within the polyanionic core [ 62 ] for drug targeting and detection.

Similarly, many efforts are on for cancer cell targeting specifically with drug nanocarriers.. Thus the drug nanocarriers are of great hope for future cancer therapy.

Schematic diagram of nanoparticle permeation and retention effect in normal and tumour tissues. Normal tissue vasculatures are lined by tight endothelial cells, hereby preventing nanoparticulate drug delivery system from escaping, whereas tumor tissue vasculatures are leaky and hyperpermeable allowing preferential accumulation of nanoparticles or nanoliposomes in the tumor interstial space by passive targeting. Transfer of genetic material in nanocarriers may be an approach for the treatment of various genetic disorders such as diabetes mellitus, cystic fibrosis, alpha 1 antitrypsin deficiency and may more.

A number of systemic diseases are caused by lack of enzymes factors that are due to missing or defective genes [ 63 ]. Previously gene therapy which was used to treat genetic disorders nowadays being contemplated as carrier systems which could be implanted for combating diseases other than genetic disorder like malignant form of cancer, heart diseases and nervous diseases [ 64 ].

Nanoliposomes can be used to deliver genetic materials into cells. Nanoliposomes incorporated with PEG and galactose target liver cells effectively due to their rapid uptake by liver Kupffer cells. Cationic nanoliposomes have been considered as potential non-viral human gene delivery system [ 65 ]. Also mixing cationic lipids with plasmid DNA leads to the formation of lipoplexes where the process is driven by electrostatic interactions [ 66 ]. The negatively charged genetic material e.

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Plasmid liposome complexes can enter the disease cells by infusion with the plasma or endosome membrane. Allovectin-7 gene transfer product is composed of a plasmid containing the gene for the major histocompatibility complex antigene HLA-B7 with B2 microglobulin formulated with the cytofectin [ 67 ]. The nature of a composed lipid decides the unloading of the gene from nanoliposomes which enables control over the mode of release, doping of nanoliposomes with neutral lipids such as 1,2-Dioleoyl-sn-glycerophosphoethanolamine DOPE which helps in endosomal membrane fusion by recognizing and destabilizing the phospholipids in a flip flop manner which paves way for the liposomes to integrate in the membrane with the dissociation of nucleic acid into the cytoplasm [ 64 ].

Viral system based gene carrier had the ability to overcome the biological barriers in the body and then access to the host nucleus replicative machinery which resulted in the exploitations of the system for drug delivery using nanotechnology [ 64 ]. The development of a non-viral method for in vivo gene transfer was designed where the vector was packed into compact nanoparticles by successive additions of oppositely charged polyelectrolytes including an incorporation of ligands into the DNA-polyelectrolyte shells which were mixed with Pluronic F gel serving as a biodegradable adhesive to keep shells in contact with the targeted vessel [ 68 ].

A novel method of gene delivery is with viruses such as adeno associated virus AAV which have their virulent genes removed with lentiviruses, clearly showing their efficiency [ 64 ]. The viral nanoparticles VNPs consist of protein core which ranges in complexity from small capsid-protein homomers to larger protein-based heteromers capable of internalizing oligonucleotides and being enveloped by lipids.

Chemical modification process and genetic mutation provide the viral coat proteins with receptor binding domain that helps in cell specific targeting of VNPs [ 69 ]. VNPs can be genetically engineered by inserting amino acids for bioconjugation, peptide based affinity tags and peptides as targeting ligands for stimulation of immune response. High sequence variability due to the influence of the immune system in viral life-cycles is often seen on the surface loops of viral capsid proteins.

This variability makes the loops highly susceptible to insertion of foreign sequences.