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Nanotechnology has emerged as one of the very advancing fields of biomedical research in the last few decades. Drug delivery is one of most important part of nanotechnology in which remarkable progress has been made in last decades. Nanotechnology provides opportunities to manipulate and organize matter systematically at the nanometer scale. Controlled release devices are used for drug delivery. Drug delivery systems can be controlled according to the composition, shape, size and morphology. Their surface properties can be manipulated to augment solubility, immuno-compatibility and cellular uptake. The limitations of current drug delivery systems include lower bioavailability, limited specific targeting, cytotoxicity and pathogenicity. Versatile nano-sized drug delivery systems include nanotubes, nanoparticles, nanocapsules, nanogels and dendrimers. Nanocrystals engaged with nanocomposites has been shown to elicit active bone growth. Both the drug-delivery vehicles and bioengineering technology should be biocompatible and biodegradable. The biological functions of encapsulated drugs and cells can be dramatically enhanced by designing biomaterials on basis of shape and conjugate linkages at nanoscale levels. 
Nanotechnology includes nanoparticles and nanoscale devices are helping for diagnosis, treatment and diseases surveillance. It is an integration of engineering science with pharmaceutical and medical sciences. Drug delivery is one of the most important fields of nanotechnology. Nanotechnology typically uses particles in range of 1nm -100 nm. The interdisciplinary field of nanobiotechnology, which combines chemistry, biology, Quantum physics and medicine, is aiding the development of drug delivery systems and devices. Advanced materials and formulations are enabling the site-specific targeting and controlled release of traditional pharmaceutical agents, recombinant proteins, vaccines and nucleic acids. Nanodrug delivery systems can be devised to tune medicine release kinetics, regulate biodistribution of drugs and minimize toxic effects, thereby enhancing the therapeutic index of a given drug .
Drug delivery focuses on maximizing bioavailability at specific sites in the body and over duration of time. This can be achieved by molecular drug targeting with help of nanoengineered devices. It involves in targeting the molecules and delivering drugs with cell precision. More than $65 billion are wasted each year due to poor bioavailability. Drug delivery systems involving lipid ligand or polymer nanoparticles can be designed to improve the pharmacological and therapeutic properties of drugs. Alteration in the pharmacokinetics and biodistribution of the drug increases the efficacy of drug delivery systems. Cells take up the nanoparticles because of their compatible size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm. Efficiency is important because many diseases depend upon processes within the cell and can only be penetrated by drugs entry into the cell. 
The surface can be modified for specific cell interactions for better drug delivery to target cells and generating therapeutic effects more selectively. Active drug molecule is sealed in the nanoparticle and then releasing it on the target, thus controlling separately biodisribution and pharmacokinetics. As in conventional drugs and conjugates, these two can not be separated from end point activity. 
Different methods of drug delivery systems are used from organic to inorganic and bacteria and fungi. There is list of formulations used as nanomedicine delivery according to increasing order of complexity; Nanocrystals, Albumin based particles, Colloids (polymers, lipids), emulsions(polymers, solid lipids), Gels, Nanodiamonds, nanofibers, Nanotubes(Carbon), Dendrimers, Polymer conjugates, Polymeric micelles, Liposomes, Polymersomes, Nanocapsules, viral Capsids, Nanocapsules with active elements.
Polymer therapeutics constitutes macromolecular drugs, polymer-drug and polymer-protein conjugates and polymeric micelles. Polymers offer effectively unlimited diversity in chemistry, dimensions and topology, thus suitable for applications in nanomedicine delivery systems. Polymer architecture can be as significant to the effectiveness of drug delivery devices as chemical composition in form of polyester, polyanhydride, polyamide molecules, and stability in terms of biodegradable or non-biodegradable and water solubility properties of hydrophilic or hydrophobic nature.
Drugs can be physically entangled within polymer shells and matrices. These can be attached to the polymer backbone via covalent bonding. Polymer drug conjugates containing a systemically stable; bioresponsive polymer drug linker can change the pharmacokinetics of the drug by increasing the ffective molecular weight of drug. The linker enables the prodrug inactive in circulation and liberated at specific target site by specific enzyme or related pH. Polydispersity having important biological properties are molecular weight related. Polymers are often internalized by cells thus biocompatibility is an important field to consider. Poly-cations are mostly cytotoxic, hemolytic and complement responsive, while poly-anions are less cytotoxic but can induce anticoagulant activity and cytokine secretion .
This section refers specifically to polymer based matrix particulate systems. Nanoparticles have been defined as "submicron polymeric colloidal particles with a therapeutic agent of interest encapsulated within their polymeric matrix or adsorbed or conjugated onto the surface" .
Size variation strongly affects bioavailability and blood circulation time. The particles in systemic system with diameters less than 10 nm are rapidly removed by renal clearance activity and extravasation process. The particles diameters range of 10 to 70 nm can penetrate even very small capillaries and particles of diameters 70 to 200 nm shows prolonged circulation times. Particles diameters more than 200 nm are usually sequestered by spleen and finally removed by phagocytes .
The size of nanoparticles is comparable to size of the common biomolecule (not more than 50 nm). This property is used for cell marking and for bioconjugate applications such as antibody targeting. Their surfaces can be changed to improve aqueous solubility, biocompatibility with substances and biorecognition of nanoparticles. Gold nanoparticles and silver particles possess optical properties which are dependent on size and dimension of particle. Nanoparticles linked to biomolecules to form sensitive probes can be used in identification and isolation processes. 
Nanoparticles for drug delivery Applications. (Arruebo et al.2007)
Nanoscale drug delivery systems can be manufactured to combine biological and synthetic modules for various applications including implants, inhalants, injectables, oral, topical and transdermal drug delivery. Many properties of nanodrug delivery system can be fabricated for specific applications e.g;
Solubility can be varied with inherent hydrophilic behavior and solubilizing moiety.
Biodistribution can be tailored according to molecular weight, addition of targeting group. Biocompatibility can be achieved with manipulation of electrical charge and bioinert behavior. Biodegradability can be modulated with spacer changes. Drug release is facilitated with changes in physical and chemical interaction between drug, carrier and covalent spacer. Physical interaction between drug and carrier involves drug encapsulation. Shape is fabricated with variations in materials and chemistry of substances. 
In general, drug-delivery systems can be improvised as locally or systemically, possibly the attachment of targeting moieties. The drug device can be released near or within the target cells. Smaller drug-delivery systems can be endocytosed by endosomes. Some nanoparticles are transported to secondary endosomes/lysosomes, and then go to cytoplasm to serve as intracellular drug storage pool. Smaller particle sizes facilitate deeper penetration into capillaries and through fenestrations, so enhanced cellular uptake. Indeed, 100 nm size particles exhibit in situ uptake efficiencies 15-250 fold of those of small microparticles (1 to10 Î¼m). Nanoparticles have even been shown to cross the blood-brain barrier. More than 80% efficiencies can be achieved with poly D, L-lacticcoglycolic acid (PLGA) when sonication is used for both emulsification steps in the water-oil--water emulsion method, without considering of the length and intensity of mixing. PLGA shows best loading because of its more molecular weight, high hydrophilicity and free carboxylate end-groups. Factors increase the drug entrapping efficiency are low drug loading, a large volume of the inner and the use of methylene chloride as the organic solvent; entrapment efficiency can be made to approach 100%. Methylene chloride increases the mean particle size substantially, as does increasing the polymer concentration in the organic phase. Targeted drug delivery system involves Polymer micelles. Self assembly of amphiphilic part or graft copolymers in aqueous media leads to nanoparticles with hydrophobic inner part for encapsulation of drug and hydrophilic outer parts for stabilization and specific cell targeting. Targeting ligands can be used to increase the drug's effective concentration at a desired site. Thus, targeting can be achieved via enhanced permeation and retention (passive) and via the conjugation of molecular homing devices (Active) .
Lipid and polymeric nanocapsules are nanodrug-delivery systems that can provide controlled release and efficient targeting. The composition of the outer coating particularly depicts dispersion stability and the primary physiological response. The fabrication of nanocapsules can be accomplished by interfacial deposition, interfacial polymerization, interfacial precipitation, layer-by-layer deposition and self-assembly procedures. Important factors include capsule size, radius distribution, capsule thickness, membrane decomposition and surfactant type.
Lipid-based nanocapsules can be modified to change cell membrane permeability via channel insertion and to target specific cells via antibody attachment. Cisplatin nanocapsules display good cisplatin to lipid molar ratio and shows improved cytotoxicity against tumor in vitro relative to drugs used via conventional therapy. Lipids can be limited by their instability in biological media and by their sensitivity to changes in the temperature and osmotic pressure. The stability of lipidic nanocapsules can be improved by synthesizing lipid-polymer-conjugate nanocapsules. Strategies include polymerizing a 2D mesh in the hydrophobic core of membrane, adding surface-active polymers to create complex vesicular structures and coating the liposome with a polyelectrolyte shell.
Polyelectrolyte shells created by layer-by-layer deposition include control of surface properties, membrane thickness and nanodrug release kinetics. As change in temperature and pH parameters, various materials can be readily loaded and released like nanodrugs, active enzymes, ribonucleic acids and biodyes. A recent advance in the pursuit of a biocompatible nanocapsule has been the use of "the vault", a natural cellular nanoparticl. The internal cavity of these 13-MDa ribonucleoprotein entities can accommodate hundreds of protein molecules. Attaching a vault targeting peptide to any protein of affiliation sequesters the protein within the vault cavity, enabling the engineering of vault particles with contrived properties and functionalities .
Due to resemblance with drinking straws, these tubes have advantages over spherical nanoparticles for some applications. Small biomolecules or proteins can be filled in their cavity. Inner and outer surfaces of specific types of nanotubes are distinct in nature; they can be made to encapsulate specific drugs internally and to produce immunogenic response externally. Open mouthed structure of nanotubes aid in better interactions.
Self-assembly or deposition are used for nanotube fabrication. Like fullerene carbon nanotubes, carbon nanotubes, cyclic peptide nanotubes and template-synthesized nanotubes. Polymerization and Semiconductor deposition are used to make Polymer and Semiconductor nanotubes respectively. Inorganic nanotubes can be manufactured by sol-gel chemistry.
For nanotube fabrication, we use template approach by depositing the nanomaterial (polymer, semiconductor, metal, or carbon) within the cylindrical pores of a solid surface. Diameter of the template and deposition time correlates with outer and inner diameters respectively. This method may be used for production of concentric tubular nanocomopsite structures and segmented nanowires. Advancement in nanotubes efficency for control drug release is regulatory control over Nanotube Cap.Use of nickel embedded nanotubes to penetrate cell membranes in conjunction with magnetic field manipulation for delivering immobilized macromolecules on nanotubes cause high cell viability and transfection efficiency in the primary neurons and B Cells. This mechanism causes increased control, efficiency and decreased toxicity as compared to conventional transfection reagents. By changing magnetic field strength, nanotube speed and duration of spearing, we can alter the penetration efficiency. At low concentrations of less than 10 Î¼M carbon nanotube cause less cytotoxicity and less perturbation than larger mechanical drug delivery system. DNA payload does not depend on lysosomal activity, we can pore DNA directly into nucleus, and nanotube spearing is more efficient transduction method rather than standard endocytosis. Nanotube spearing works optimally at only 100 fM nanotubes, is more related to biochemical assays than other membrane penetration tools. An atomic force microscope having nanoneedle attached tip is able to deliver macromolecules to a single target cell, it is not suitable for gene therapy applications in the body .
Hydrogel matrices structures having high biocompatibility are used in drug delivery systems due to prevention of aggregation. Hydrogels as drug carrier can be manufacuterd in the absence of drugs thus improving drug delivery. Nanomedicine is loaded via self assembly processes on the basis of non-covalent interactions. Hydrogel networks can uptake charged and hydrophobic biomolecules. By varying polymerization factors of hydrogels, size of colloidal material can be varied. Hydrophobic inner part solubilizes lipidophilic molecule and hydrophilic corona helps in avoiding aggregation, protein adsorption and immunocytogenic response. New colloidal nanodrug delivery systems can be made by using amphiphilic precursors. 
The architecture of dendrimers is controlled by producing defining shapes, sizes, branching length and density and surface functionality. The drugs can be physically entangled within the structure or chemically attached to the surface of dendrimers. Dendrimers are characterized by high density surface groups thus improving targeting and biocompatibility of drug. Dendrimer synthesis is done by divergent or convergent mechanisms called repectively lego and click approach. These produce purified and environmentally friendly byproducts. The first route requires only one step per generation and second route is based on the Cu (I) catalyzed synthesis of 1,2,3-triazoles from alkynes and azides, producing dendrimers with good surface groups in high purity .
Ocular drug delivery System
Nanoparticles, liposomes and dendrimers are used to improve ocular drug delivery. Prolonged stay time at the ocular surface is achieved due to simpler eye drop drug inoculation avoiding the eye washing mechanism. Controlled drug delivery devices used with improved ocular formulations provide drug concentrations for an augmented period of time at target site. This reduces the dose administered and frequency. Intraocular drug delivery systems can be used to protect and release of drug in a controlled way to decrease injections frequency. 
Advantages of Nanobiotechnology
Nanotechnology may help in increasing the solubility & bioavailability of drugs, new dosage formulations and better exploration of novel drug administration routes for efficient therapies. Nanoparticles with less than 200nm diameter are not passed out of circulation by liver and spleen. 
Nanotechnology is suited for better drugs delivery to small regions within the human body as nanodrugs can cross biological membranes easily. Liposomes are effectively used for drug targeting by chemotherapeutics. Applications of nanotechnology include intracellular drugs delivery through carbon nanotubes, lipid complexes for intravenous administration of antifungal drugs, triglyceride emulsions for parenteral nutrition, silver nanoparticle antimicrobials dressings to agument wound healing. Viva-Gel is an antiHIV drug based on dendrimer formulation technology. Nanospheres of poly acrylic acid can absorb excessive nanodrug concentrations in overdosage. Nanospheres can be used as antidote reducing mortalities due to over dose drug admininstration.
Drug Delivery Systems
Current drug delivery systems include microchips, microneedle based, subdermal treatment systems, layer folding assembly systems and various microparticles produced by ink jet technology. The future of nanodrug delivery systems is to develop nanodevices manufacturing mechanisms can be employed in nanodrug delivery systems. Fabrication and manufacturing of engineering materials at the nanoscale is advanced enough to develop nanoscale processes for producing products other than semiconductors .
Soft gelatin capsules are manufactured at the nanoscale as scientists fabricating nanodevices in drug delivery systems to manufacture clinically useful nano drug formulations. Clinically useful drug delivery of certain drug can be therapeutically effective and extended over period of time. These requirements achieved by microscale drug delivery systems manufactured by nanotechnology. The current methods of preparing nano or micro particles are mainly based on double emulsion methods or solvent exchange technique .
Major problems of current methods are low drug uptake capacity, low efficiency and poor ability to control size and distribution into system. Utilizing nanotechnologies, such as nanopatterning, could allow manufacturing of nano and microparticles with high loading efficiency and highly homogeneous particle sizes. 
Formation of prodrug involves covalent linkage between drug and carrier. The type of linkage that is formed between drug and carrier would decide the triggering mechanism for the release of drug in colon of body. 
Nanoparticles, products of nanotechnology, are of increasing interest to the pharmaceutical community. They can increase solubility of drug, bioavailability and allow tissue targeting which producing decreased side-effects and improved therapeutic efficacy. Presenting the most pertinent and practical issues in the manufacturing and biological application of nanoparticles fostering state of the art scientific contributions.12]
There are many new research direction efforts for drug delivery system. The design and development of nanoparticles with multiple functions helps in detection, diagnosis, imaging, transport and controlled release of drug. Efficacy is improved with usage of lower doses of drugs. Type of design of nanoparticles aids in attaching specific receptors which allow endocytosis of nanoparticles. Nanomolecule profiling and nanotyping for clinical therapeutics is important to predict behavior, clinical outcome, and treatment response. Investigating nanoparticles distribution, metabolism, excretion, pharmacodynamics, pharmacokinetics and potential long-term toxicity is essential to monitor effects in body.