2. Nanocrystalline silicon
Nanocrystalline silicon
(nc-Si) - an allotropic form of silicon - is similar to amorphous silicon (a-Si), in that it has an amorphous phase. Where they differ, however, is that nc-Si has small grains of crystalline silicon within the amorphous phase. This is in contrast to polycrystalline silicon (poly-Si) which consists solely of crystalline silicon grains, separated by grain boundaries. nc-Si is sometimes also known as microcrystalline silicon (µc-Si) The difference comes solely from the grain size of the crystalline grains. Most materials with grains in the micrometre range are actually fine-grained polysilicon, so nanocrystalline silicon is a better term.

3. Photonic crystal
Photonic crystals are periodic dielectric or metallo-dielectric (nano) structures that are designed to affect the propagation of electromagnetic waves (EM) in the same way as the periodic potential in a semiconductor crystal affects the electron motion by defining allowed and forbidden electronic energy bands.

Since the basic physical phenomenon is based on diffraction, the periodicity of the photonic crystal structure has to be in the same length-scale as half the wavelength of the EM waves i.e. ~300 nm for photonic crystals operating in the visible part of the spectrum. This makes the synthesis cumbersome and complex. To circumvent nanotechnological methods with their big and complex machinery, different approaches have been followed to grow photonic crystals as self-assembled structures from colloidal crystals.

Photonic crystals are attractive optical materials for controlling and manipulating the flow of light. They are of great interest for both fundamental and applied research, and are expected to find commercial applications soon.

4. Liposomes
A liposome is a spherical vesicle with a membrane composed of a phospholipid bilayer used to deliver drugs or genetic material into a cell. Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains (like egg, phosphatidylethanolamine), or of pure components like DOPE (dioleolylphosphatidylethanolamine).

The lipid bilayer can fuse with other bilayers (e.g., the cell membrane), thus delivering the liposome contents. By making liposomes in a solution of DNA or drugs,(which would normally be unable to diffuse through the membrane), they can be (indiscriminately) delivered past the lipid bilayer.

5. Gliadin nanoparticles
In an effort to improve bioavailability anti-H.pylori effects of antibiotics, mucoadhesive gliadin nanoparticles (GNP) which have the ability to deliver the antibiotics at the sites of infection were prepared. GNP bearing clarithromycin(CGNP) and omeprazole(OGNP) were prepared by desolvation method.

In vivo gastric mucoadhesive studies confirmed the strong mucoadhesive propensity and specificity and specificity of gliadin nanoparticles towards stomach. Gliadin nanoparticles show a higher tropism for the gastrointestinal regions and their presence in other intestinal regions is very low. This high capacity to interact with the mucosa may be explained by gliadin composition.

In fact, this protein is rich in neutral and lipophilic residues. Neutral amino acid can promote hydrogen bonding interaction with the mucosa whereas the lipophilic components can interact within biological tissue by hydrophilic interaction. The related protein gliadin possessing an amino and disulphide groups on the side chain has a good probability of developing bonds with mucin gel.

6. Polymeric Nanoparticles
Polymeric nanoparticles have been invented by Speiser et al. They represent interesting alternative as drug delivery systems to liposomes. They usually exhibit a long shelf life and a good stability on storage.

These are superior to liposomes in targeting them to specific organs or tissues by adsorbing and coating their surface with different substances.

Nanoparticles can be prepared either from preformed polymers, such as polyesters (i.e. polylactic acid), or from a monomer during its polymerization, as in the case of alkyl-cyanoacrylates.

Most of the methods based on the polymerization of monomers consists in adding a monomer into the dispersed phase of an emulsion, an inverse microemulsion, or dissolved in a non-solvent of the polymer.

7. Solid Lipid Nanoparticles (SLN)
Solid lipid nanoparticles have been developed as alternative delivery system to conventional polymeric nanoparticles.SLNs are sub-micron colloidal carriers (50-1000nm) which are composed of physiological lipid, dispersed in water or in an aqueous surfactant solution.

SLNs combine advantages of polymeric nanoparticles, fat emulsions and liposomes, but avoid some of their disadvantages.They are biodegradable, biocompatible and non-toxic.

8. Others:
nanoparticles stabilized by thiol functionality are extraordinarily stable and therefore are a great system for studying nanostructure formation. They have many applications. Because gold nanoparticles are so easy to synthesize they have been studied intensely in recent years.

A common synthesis involves the reduction of a gold salt in the presence of capping agent molecules such as thiols, citrates or phosphines. The functionalities of these capping agents can be altered to yield various chemical properties. (5)

Mechanisms of cellular targeting

1. Nanoparticle uptake by tissues
A succession of several membrane layers provides an obstacle for therapeutic agents attempting to target intracellular structures. During this process, compound is lost due to ineffective partitioning across biological membranes. The extent of partition across a membrane is related directly to the polarity of a molecule; nonpolar or lipophilic molecules easily bypass this obstacle with greater membrane penetration, generally via diffusion. However, the situation is much more complicated, as a myriad of other cellular processes directly affect the intracellular concentrations and effectiveness of the therapeutic agent. Variable efficiencies of endocytosis mechanisms, intracellular trafficking, release of the therapeutic agent into the cytoplasm, diffusion and translocation of the therapeutic agent to its susceptible target, and partition into the nucleus or other organelles alter the actual activity of the therapeutic agent. Nanoparticles present an interesting opportunity for eliminating much of this ‘waste’ due to masking of the therapeutic agent from its biological environment; this effectively limits the influence of a compound’s physical properties on intracellular drug concentrations. Instead, the properties and surface characteristics of the nanoparticle play a greater role in compound delivery and resulting intracellular drug concentrations. Nanoparticles may be ingested and ‘sampled’ by curious cells.

Endocytosis encompasses the process of membrane manipulation to envelope and absorb materials and includes three subtypes: phagocytosis, pinocytosis, and receptor-mediated endocytosis. Phagocytosis involves the ingestion of materials up to 10 lm in diameter,and can be accomplished by fairly few cell types of the reticuloendothelial system, such as macrophages, neutrophils, and dendritic cells. Pinocytosis is an uptake mechanism that can be conducted by virtually all cell types, and normally involves ingestion of sub-micron material and substances in solution. Larger microparticles provide selective access to phagocytic cells, while smaller nanoparticles provide access to virtually all cell types.

2. Cellular phagocytosis/endocytosis
Receptor-mediated endocytosis affords the potential for even greater selectivity in cellular targeting. The cellular membrane is dotted with a myriad of receptors, which upon extracellular binding to their respective ligands (or to nanoparticles whose surface is functionalized with ligands), transduce a signal to the intracellular space. This signal can trigger a multitude of biochemical pathways; however it may also cause internalization of the ligand and its appended nanoparticle via endocytosis. Caveolin- and clathrincoated pits provide an illustration of receptor-mediated endocytosis. Typically, clathrin coats generate a membrane indentation with a radius of curvature as small as approximately 50 nm,and invaginate further upon binding of the ligand. Cross-linking of receptors via ligands attached to nanoparticles results in a more pronounced membrane crater with subsequent enfolding and reunification of the cellular membrane to form an endosome. It has been shown that nanoparticle sizes between 25 and 50 nm are a requisite for optimal endocytosis and intracellular localization.

Steps detailing the cytosolic delivery of therapeutic agents via nanoparticle carriers. (1) Cellular association of nanoparticles, (2) internalization of nanoparticles via endocytosis, (3) endosomal escape of nanoparticles or (4) lysosomal degradation of nanoparticle, (5) therapeutic agent freely diffuses into cytoplasm, (6) cytoplasmic transport of therapeutic agent to target organelle, (7) exocytosis of nanoparticles.(6)

Nanoparticle drug delivery for human therapeutics
Nanoparticles have found widespread use in drug delivery, counting more than a dozen FDA-approved variants with indications ranging from cancer to infection.

1. Neurological cancers (glioblastoma multiforme)
The central nervous system represents a formidable challenge for the delivery of therapeutic agents due to the blood-brain barrier (BBB). This physical barrier limits the brain uptake of the vast majority of neurotherapeutics and neuroimaging contrast agents. The anatomical and cellular morphology of neurovascular capillary endothelial cells, including limited pinocytosis and tight junctions, produces this unique central nervous system manifestation.The brain microvasculature involves four types of cells: endothelial cells, pericytes, astrocyte foot processes, and nerve endings. Endothelial cells share the capillary basement membrane with pericytes that participate in immune surveillance. The other side of this basement membrane is almost entirely surrounded by astrocyte foot processes. Brain capillary endothelial cells are cemented together by tight junctions; this is associated with a 100-fold reduction of pinocytosis across the endothelium .Therefore, substances may gain access to the central nervous system by lipid- mediated free diffusion or potentially by receptor-mediated endocytosis of nanoparticles. Nanotechnology may provide an effective means for circumventing this delivery issue past the BBB. Glioblastoma multiforme (GBM) is among the most devastating and lethal of neoplasms, often claiming the lives of patients within a median of one year following diagnosis. The treatment is multidisciplinary, including radiotherapy, chemotherapy, and surgery.Transport of many chemotherapeutic agents past the BBB has proven difficult. Recently, however, a series of discoveries have been made. In particular, low-density lipoprotein receptors (LDLR) are upregulated on GBM cellular surfaces to between 128,000 and 950,000 receptors per tumor cell.In contrast, average neurons have comparatively lower LDLR numbers, as evidenced by examining normal rat and monkey brain tissue.Thus, targeting LDLR may offer the opportunity for potential therapeutic selectivity in chemotherapeutic drug delivery. Previous studies have investigated the use of lowdensity lipoproteins (LDL). Natural LDL particles are roughly 22– 27 nm in diameter with a core of lipids primarily composed of cholesteryl esters with small amounts of triglyceride. Initial studies used plasma-derived LDL as delivery agent to GBM tumors.

However, due to the difficulty of isolating natural LDL, reconstituted and synthetic versions have become desirable.Synthetic LDL nanoparticles have been shown to effectively deliver a toxic payload of paclitaxel to GBM tumor cells, and this cytotoxic effect is overturned upon treatment with the LDL receptor inhibitor suramin.

Anatomy of BBB


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