INTRODUCTION:

Bacterial are common infective agents producing a wide variety of diseases. Bacteria are still an important cause of morality in developed countries and the origin of massive epidemics. The search for therapeutic and prophylactic agents against these toxins is a topic of extreme importance [1-4].

The broad use and sometimes abuse of antibiotics has contributed to the appearance of bacterial resistance that has forced the biomedical researchers to look for new strategies to combat bacterial infections. One of the most attractive alternatives is the inhibition of bacterial attachment to target cells during the first stages of the infection using anti-adhesive molecules. Bacteria adhesion is mediated by specific carbohydrate-protein interactions between lectin-like proteins at the surface of bacteria and glycoconjugates (glycoprotein and glycolipids) at the surface of target cells or vice versa. Blocking this interaction should inhibit the attachment of bacteria to the target cell surface and stop the infection.

Bacteria Producing AB₅ Toxins

This is a very important group of Gram-negative bacteria which produce toxins causing thousands of deaths every year. These toxins present six subunits, one A subunit that is responsible of the infection and a homopentameric B subunits (B₅) that are required for the attachment of the toxin to the cell surface. Inhibition of the attachment of the subunits B₅ should be enough to stop the infection process. This B unit presents a carbohydrate recognition site that interacts with carbohydrates present at the cell surface in a multivalent way (five simultaneous interactions between B₅ and cell surface carbohydrates).

Cholera Toxin

Cholera toxin is an AB₅ protein secreted by Vibrio cholerae causing the disease cholera. This is an infectious intestinal disease characterized by severe diarrhea, and vomiting that if untreated may be life-threatening due to enormous loss of water and electrolytes. The B subunit is able to recognize and interact with ganglioside GM1 at the cell membrane forming a pore for subunit A that blocks GTP ase activity of G protein and results in an increase of the synthesis of cAMP. In the intestine this leads to watery, electrolyte rich diarrhea as Cl^- leaves the cells followed by Na⁺ and water.

Shiga and Vero Toxins

Shiga toxins (Stx1 and Sxt2), produced by Shigelladysenteriae and Shiga-like toxins (SLT-I and SLT-II) alsocalled Vero toxins produced by Escherichia coli O157:H7, are AB₅ toxins causing watery diarrhea or hemorrhagic colitis respectively that are particularly severe in children and elder people being responsible of millions of episodes around the world.

Heat Labile Enterotoxin

The heat labile enterotoxin (LT) of E.coli is a cholera-like enterotoxin that adheres as cholera toxin does to ganglioside GM1 and causes a somewhat less severe diarrhea due to the same mechanisms [5-8]. Based on the structural similarities between cholera toxin and heat labile toxin, the group of Schengrund has used the same type of experiments to prove the activity of oligosaccharide-derivative dendrimers for cholera toxin and heat labile toxin with similar results [9-11].

Bacterial Endotoxins

Gram-negative bacteria such as Haemophilus influenza, Escherichia coli, Salmonella enterica, Kelbsiella pneumoniae, Bordetellapertussis, Pseudomonas aeruginosa, Chlamydia psittaci, and Legionella pneumophila present at the outer leaflet of the bilayer membrane a lipo-polysaccharide (LPS) component which play a key role in septic shock (sep-sis syndrome) [12-15].

Type 1 Fimbriated Escherichia coli

Type 1 fimbriae are adhesion organelles expressed by many Gram-negative bacteria and responsible of the adherence of Escherichia coli to the urinary tract causing common urinary tract infection [16-17]. This adhesion process is governed by the interaction between type 1 fimbriae and mannose conjugates found at the bladder epithelial cell surface.

Streptococcus suis

Streptococcus suis is a Gram-positive bacteria responsible of meningitis, septicemia, and pneumonia in pigs, swine and other domestic animals and also meningitis in humans who have been in contact with pigs [18-21]. These bacteria present a galactosyl-1-4-galactose-binding adhes in implicated in the adhesion process of the bacteria to the host cells [22-23].

Staphylococcus aureus

Staphylococcus aureus (Gram-positive bacteria) remains a dangerous pathogen in humans that can cause illnesses ranging from minor skin infections to life-threatening diseases such as pneumonia, meningitis, endocarditis, Toxic shock syndrome (TSS), and septicemia [24-25].

Actinomyces naeslundii

A. naeslundii is a Gram-positive bacterium that colonizes oral cavities. During this colonization process, A. naeslundii co-aggregate with Streptococcus oralis through galactose residues present at the surface of S. oralis and an adhesin of A. naeslundii pili [26].

Fungal Infection

One of the most common infections of fungi is caused by Candida albicans. C. albicans is a normal inhabitant of the human mouth and gastrointestinal tract. Under normal circumstances, C. albicans colonizes humans with no harmful effects, although overgrowth may result in candidiasis in skin or mucosa [27]. Systemic candidiasis is often observed in immune-compromised individuals such in transplantation, malignancy or AIDS. Different forms of C.albicans are also recognized by different lectins that are expressed at the surface of target cells [28].

Prion Protein Infection

Stanley Prusiner discovered almost 25 years ago a new infective agent, a protein named prion. The prion protein is the product of a normal gene expressed mainly in neural tissue and presents several helix and few sheets in its natural configuration known as PrP^C. This protein adopts an abnormal configuration upon contact with the sheet-rich infectious form of the protein known as PrP^Sc after scrapie, an old recognized disease of sheep [29]. These types of structures are found in several neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy, etc.

Viral Infection

This is the area of application where more efforts have been done respect to develop new anti-infective agents based on dendrimers. Recently, a review describing dendrimers as antivirals has been published [30]. Here, we intend to update the information presented in that review with the most recent publications concerning dendrimers as antiviral drugs. Again, this section will be divided for each different viral agent.

HIV-1, HIV-2, AND SIV

Infection by Human Immunodeficiency Virus (HIV) is a global health problem although, especially dramatic in developing countries in sub-Saharan Africa and Asia where the vast majority of infected patients do not have access to antiretroviral drugs. Most recent research in this topic is concentrated on vaccine development and mainly on developing microbicides [31-32].

Herpes Simplex Virus (HSV) Infection

Genital human herpes virus infection is one of the most prevalent sexual transmitted diseases (STDs). HSV-1 and 2 cause muco-cutaneous infection, such as herpes labialis and herpes genitalis. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating. Currently, no cure is available [33].

Influenza Virus Infection

Influenza virus is a RNA virus that infects mainly vertebrates. There are 3 types of influenza: A, B, and C. Influenza A is the cause of all flu pandemics. This virus adheres to the target cells through the interaction of the main envelope glycoprotein: haemagglutinin (HA). HA recognizes sialic acid receptors on the host cell. It is known that monovalent sialic acid was able to prevent influenza A agglutination of chicken erythrocytes [34-36].

Food-and-Mouth Disease Virus (FMDV) Infection

Food-and-mouth disease virus infects animals through the respiratory tract or skin abrasions and it is economically the most important disease in farm animals [37]. A very interesting approach to generate a vaccine against this infection has been described by Andreu et al. [38]

Ebola Virus Infection

Ebola Virus along with Marburg virus constitutes the Filoviridae family that is responsible of sporadic outbreaks of hemorrhagic fever in Africa characterized by a high death rate [39]. There is not currently any vaccine or specific treatment available for these dangerous agents and only supportive measures can be provided for infected [40-41].

Problems Associated With Conventional Antimicrobial Therapy

Conventional antimicrobial therapy consists of chemotherapeutic agents, or antibiotics to treat the infectious diseases by either killing of the microbes, or interfering with their growth. With the commercial production of the first antibiotic penicillin in the late 1940s, use of the antibiotics to treat the infectious diseases increased and to-date many new antibiotics have been developed [42],ranging from the topical antibiotic ointments (such as neosporin) to intravenously injected antibiotic solutions. These drugs have proven to be effective in eliminating the microbial infections that arise from minor cuts and scrapes to life threatening infections. An antimicrobial drugs act on the microbes by various mechanisms such as inhibiting cell wall synthesis(e.g., β-lactam drug, vancomycin, bacitracin), inhibiting the protein synthesis (chloramphenicol, tetracyclines, aminoglycosides, macrolids), inhibiting the nucleic acid synthesis (fluoroquinolones, rifampicin), inhibiting the metabolic pathways (sulfonamides, trimethoprim), and by interfering with the membrane integrity (polymixin B) [43-45].

Types of infections

Infectious disease is a clinically obvious disorder resulting from the presence of a pathogenic agent which can either be a virus, bacterium, fungus or parasite. These diseases are also called communicable diseases due to their ability to get transferred from one person to another (malaria, tuberculosis) and also sometimes from one species to another (flu, influenza). Infectious diseases can be vastly classified as: 1) known diseases which are insistently there (e.g., dengue, malaria, tuberculosis); 2) new, previously unknown diseases (e.g., severe acute respiratory syndrome); and 3) diseases which threaten to enhance in the near future (e.g., avian influenza).

Classification of bacterial pathogens

The classification of infectious agents inregards to their infective lifestyles in the host and corresponding pathogenic indications must be precisely described [46-49].For a microbial pathogen, what matters is whether intra or extracellularityis on the basis of the in vivo life and in relationship with pathogenicity. Classically, infectious agents are indicated as extracellular and intracellular pathogens [50-53].

Extracellular pathogens

Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Escherichia coli are typical examples of bacteria which have been considered extracellular pathogens, and lesion infections, osteomyelitis, scarlet fever, specified forms of pneumonia, urinary tract infections are examples of infections caused by these pathogens [54]. To produce disease, extracellular pathogens utilize any portal of entry provided a satisfactory fluid medium be recognized at the site of lesion [55].

Intracellular pathogens

Classical examples of intracellular pathogens are Brucella abortus, Listeria monocytogenes, Mycobacterium tuberculosis, Salmonella enterica, and typical infectious diseases caused by them include brucellosis, listeriosis, tuberculosis, and salmonellosis [56-57]. Intracellular pathogenic bacteria have the ability to establish a relationship in the sensitive host which includes a stage of intracellular reproduction [58-60].

Targeted therapy of infections using Nanoparticles

The hydrophilic nature of some antibiotics prevents their capacity to penetrate the cells and, furthermore, the internalized molecules are mostly accumulated in lysosomes, where the bioactivity of the drug is low. Nanoparticles can be targeted to sites of infection passively or actively. Passively targeted nanoparticles selectively undergo extravasation at sites of infection, where inflammation has led to enhanced blood vessel porousness. Actively targeted nanoparticles contain ligands (e.g. antibodies) that bind receptors (e.g. antigens) at sites of infection [61-67].

Challenges in treating infectious diseases using nanotechnology

New challenges in the development of nanotechnology-based drug delivery systems include: the possibility of scale-up processes that bring innovative therapeutic techniques to the market rapidly, and the possibility of obtaining multifunctional systems to carry out several biological and therapeutic requirements [68-70]. Thus, a drug delivery system should be multifunctional and possess the ability to switch on and switch off specified functions when urgent. Another important requirement is that different properties of the multifunctional drug delivery systems are harmonized in an optimal fashion [71-81].

Nanotechnology-based drug delivery systems

The purpose of drug delivery is to carry out sustained (or slow) and/or controlled drug release and therefore to improve efficacy, safety, and/or patient comfort [82-84]. Thus, the use of drug delivery systems has been suggested for passive targeting of infected cells of the mononuclear phagocytic system to enhance the therapeutic index of antimicrobials in the intracellular environment, while minimizing the side effects related with the systemic administration of the antibiotic [85-88]. These systems propose many advantages in drug delivery, mainly focusing on improved safety and efficacy of the drugs, e.g. providing targeted delivery of drugs, improving bioavailability, extending drug or gene effect in target tissue, and improving the stability of therapeutic agents against chemical/ enzymatic degradation [89].

Types of drug carriers in medicine

Polymeric nanoparticles

The advantage of using polymeric nanoparticles is to permit encapsulation of bioactive molecules and protect them against enzymatic and hydrolytic degradation [90]. Therapeutically used polymeric nanoparticles are composed of biodegradable or biocompatible materials, such as poly (ε-caprolactone) (PCL), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), alginic acid, gelatin and chitosan [91-93].Compared to free drugs, polymeric NCs have many other advantages including improved drug bioavailability, high carrier capacity, the ability to release the payload in a controlled behavior and to adapt to different routes of administration and to concentrate in inflammatory and infectious locations by virtue of their enhanced permeability and preservation.

Hydrogels

A hydrogel is a network of hydrophilic polymers that can swell in water and hold a large amount of water while maintaining the structure [94].Hydrogels are biocompatible hydrophilic networks that can be constructed from both synthetic and natural materials [95-96]. In an overall view, hydrogels can be classified based on a variety of characteristics, containing the nature of side groups (neutral or ionic), mechanical and structural features (affine or phantom), method of preparation (homo-or co-polymer), physical structure (amorphous, semicrystalline, hydrogen bonded, supermolecular, and hydrocollodial), and responsiveness to physiologic environment stimuli (pH, ionic strength, temperature, electromagnetic radiation, etc.

Metal nanoparticles

Most common metallic nanoparticles contain gold, nickel, silver, iron oxide, zinc oxide, gadolinium, and titanium dioxide particles Metal nanoparticles, which have a high specific surface area and a high fraction of surface atoms, have been studied extensively because of their unique physicochemical characteristics including catalytic activity, optical properties, electronic properties, antimicrobial activity, and magnetic properties [97-99].

Gold Nanoparticles

Gold nanoparticles (GNPs) have found many applications in many fields such as cancer diagnosis and therapy, drug and gene delivery, DNA and ptotein determination, etc. Due to their unique properties of small size, large surface area to volume ratio, high reactivity to the living cells, stability over high temperatures and translocation into the cells [100]. GNPs are suitable for the delivery of drugs to cellular destinations due to their ease of synthesis, functionalization and biocompatibility.

Silver Nanoparticles

Silver nanoparticles of size smaller than 100 nm contain about 10000–15000 silver atoms . They are prepared by engineering the metallic silver into ultrafine particles by numerous physical methods, which include spark discharging, electrochemical reduction, solution irradiation and cryochemical synthesis.

Magnetic Nanoparticles

Magnetic nanoparticles engineered as drug delivery devices retain the ability to track their movement through the body. This is significant because it allows clinicians to monitor the effectively of injected therapeutics to reach their target sites [101]. Iron oxide nanoparticles (IONPs) are magnetic Fe ₃O₄ or Fe₂O₃ nanocrystals which can interact with external magnetic fields, offering different opportunities in nanomedicine, e.g., as contrast agents in MRI, for magnetic hyperthermal therapies, or as magnetically trigger able drug delivery systems [102].

Silica nanoparticles

Silica materials are suitable for several important biological applications, such as drug delivery, imaging, oxygen carrier or controlled release. Silica materials have been proved to be efficient carriers for the local release of antibiotics, which could be of interest in the context of biofilm associated infections, which are a real challenge for the modern medicine. Moreover, mesoporous silica has been found to be relatively “non-toxic” and biocompatible, however of course depending on dose and administration route [103].

Micelles

Micelles are submicroscopic aggregates of surfactant molecules assembly of amphiphillic block copolymers or polymer-lipid conjugates or other surface-active molecules that self-assemble in aqueous media to form structures with a hydrophobic core [104-105].

Liposomes

Liposomes are small spherical vesicles in which one or more aqueous parts are completely surrounded by molecules that have hydrophilic and hydrophobic functionality. Liposomes change with composition, size, surface charge and method of preparation. They can be single or in multiple bilayers.

Solid lipid nanoparticles (SLN)

Solid lipid nanoparticles (SLN) were developed at the beginning of 1990s as an alterna‐tive carrier system to emulsions, liposomes and polymeric nanoparticles as a colloidal carrier system for controlled drug delivery. SLNs are sub-micron colloidal carriers, ranging from 50 nm to 1 μm, that are composed of physiological lipid dispersed in water or in aqueous surfactant solution.

Fullerenes

Fullerenes are a new form of carbon, other forms being diamond, graphite, and coal.The most abundant form of fullerenes is Buckminster fullerene (C60) with 60 carbon atoms arranged in a spherical structure .

Dendrimers

First discovered in the early 1980’s by Tomalia and co-workers, such hyper branched molecules were called dendrimers. Dendrimers are globular repeatedly branched macromolecules that exhibit controlled patterns of branching with multiple arms extending from a central core. The well defined structure, monodispersity of size, surface functionalization capability, and stability are properties of dendrimers that make them attractive drug carrier candidates. Asymmetric dendrimers are synthesized by coupling dendrons of different generations (G1-G4) to a linear core, which yields a branched dendrimers with a non-uniform orthogonal architecture. Dendrimers also possess many unique properties that make them a good nanoparticle platform for antimicrobial drug delivery. Dendrimer biocides may contain quaternary ammonium salts as functional end groups displaying greater antimicrobial activity against bacteria than small drug molecules, due to a high density of active antimicrobials on the dendrimer surfaces.

Figure 1. Different types of nano devices for delivery of antibacterial agents.

Discovery of dendrimers and dendritic polymers: a brief historical perspective

Dendritic architecture is perhaps one of the most pervasive topologies observed on our planet. Innumerable examples of these patterns may be found in both abiotic systems (e.g., lightning patterns, snow crystals, and tributary/erosion fractals) as well as in the biological world (e.g., tree branching/roots, plant/animal vasculatory systems, and neurons).In biological systems, these dendritic patterns may be found at dimensional length scales measured in meters (trees), millimeters/centimeters (fungi), or microns (neurons) as illustrated in Figure 1. The reasons for such extensive mimicry of these dendritic topologies at virtually all dimensional length scales are not entirely clear.The first inspiration for synthesizing such molecular level treelike structures evolved from a lifetime hobby enjoyed by one of the authors (D.A. Tomalia) as a horticulturist/tree grower. Although perhaps first conceptualized by Flory, the first successful laboratory synthesis of such dendritic complexity did not occur until the late 1970s. It required a significant digression from traditional polymerization strategies with realignment to new perspectives. This was the first time in the history of synthetic polymer science that precise abiotic macromolecules could be synthesized without the use of a biological system. The result was a unique core-shell macromolecular architecture, now recognized as dendrimers.

PAMAM dendrimers with molecular weights ranging from several hundred to over 1 million daltons were prepared in high yields. This original methodology was so successful that today it still constitutes the preferred commercial route to the trademarked Starburst dendrimer family. It is both remarkable and surprising to find that many of these Class IV dendritic structure controlled macro molecules possess topologies, function, and dimensions that scale very closely to a wide variety of important biological polymers and assemblies. Dendritic polymers, more specifically dendrimers, are expected to play a key role as an “Enabling Technology” in this challenge during the next century.

Dendrimers for antimicrobial drug delivery

Dendrimers are defined as highly ordered and regularly branched globular macromolecules produced by stepwise iterative approaches. The structure of dendrimers consists of three distinct architectural regions: a focal moiety or a core, layers of branched repeat units emerging from the core, and functional end groups on the outer layer of repeat units. Two synthetic approaches, divergent and convergent approaches, have been developed to synthesize dendritic systems for delivering various types of drugs. The divergent approach initiates the synthesis from a core and emanates outward through a repetition of coupling and activation steps. During the first coupling reaction, the peripheral functional groups of the core react with the complementary reactive groups to form new latent branch points at the coupling sites and increase the number of peripheral functional groups. These latent functional groups are then activated to couple with additional monomers.The activation of the latent functional groups can be achieved by removal of protecting groups, coupling with secondary molecules, or reactive functionalization. Large excess of reagents is required to drive the activation step to completion. The final resulted dendrimer products can be separated from the excess reagents by distillation, precipitation or ultrafiltration.Although the divergent approach is ideal for large-scale production, incomplete functionalization or side reactions can occur when the number of generation increases. These flawed dendrimers are usually difficult to be separated from the final products because of structural similarity.

In contrast, the convergent approach initiates the synthesis from the periphery and progresses inward. This approach starts with coupling end groups to each branch of the monomer, followed by the activation of a single functional group located at the focal point of the first wedge-shape dendritic fragment or dendron. Higher generation dendron is synthesized by the coupling of the activated dendron to an additional monomer. After repetition of coupling and activation step, a globular dendrimer is formed by attaching a number of dendrons to a poly functional core. Dendrimers thus synthesized can be effectively purified. However, synthesis of large dendrimers above the sixth generation is difficult [106].

Quaternary ammonium compounds (QACs) are antimicrobial agents that disrupt bacterial membranes. Dendrimer biocides have displayed greater antimicrobial activity against target bacteria than small drug molecules because of a high density of active antimicrobials present on the dendrimer surfaces. The polycationic structure of dendrimer biocides facilitates the initial electrostatic adsorption to negatively charged bacteria.

PAMAM is one of the most studied dendrimers for antimicrobial delivery because of its higher density of functional groups, which make the dendrimer more hydrophilic and more readily reactive to antimicrobial conjugation. Silver salts loaded PAMAM dendrimers have demonstrated significant antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Incorporation of antibacterial agents such as sulfamethoxazole (SMZ) into the ethylenediamine (EDA) core of PAMAM dendrimers has significantly improved the drug’s aqueous solubility and antibacterial activity against E. coli [107].

Physicochemical Properties of Dendrimers

The dendrimer structure may be divided into three parts:

· A multivalent surface, with a high number of functionalities. Dependent on the dendrimer generation, the surface may act as a borderline shielding off the dendrimer interior from the surroundings.

· The outer shell, which have a well-defined microenvironment, to some extent shielded from the surroundings by the dendrimer surface.

· The core, which as the dendrimer generation increases, gets increasingly shielded off from the surroundings by the dendritic wedges. The interior of the dendrimer creates a microenvironment which may have very different properties compared to the surroundings.

Dendrimers and the effect of molecular growth

The conformational behavior of a dendrimer upon growing to higher generations are determined by the molecular dimensions of the monomers short monomers induce rapid proliferation of chains within a small space, the flexibility of the dendrons and the ability of the end-groups to interact with each other, e.g. by hydrogen bonding creating a dense outer shell.

Dendrimers and the effect of solvent

The ability of the solvent to solvate the dendrimer structure is a very important parameter when investigating the conformational state of a dendrimer. Dendrimers of all generations generally all experience a larger extend of back-folding with decreasing solvent quality, i.e. decreasing solvation. However, being more flexible, the low generation dendrimers show the highest tendency towards back-folding as a result of poor solvation compared to the higher generation dendrimers.

Dendrimers and the effect of salt

Molecular simulations generally conclude that high ionic strength (high concentration of salts) has a strong effect on charged PPI dendrimers and favours a contracted conformation of dendrimers, with a high degree of back-folding somewhat similar to what is observed upon increasing pH or poor solvation. At low salt conditions, the repulsive forces between the charged dendrimer segments results in an extended conformation in order to minimize charge repulsion in the structure.

Dendrimers and the effect of concentration

In dendrimers with flexible structures the conformation is not only affected by small molecules like solvents, salts or protons, but may also be sensitive to larger objects, such as other dendrimers or surfaces which can have a great affect on the molecular density and conformation of the dendrimer. This molecular contraction may minimize the repulsive forces between the dendrimer molecules and increase the ability of the dendrimers to exhibit a more tight intermolecular packing.

TYPE OF DENDRIMERS

PAMAM Dendrimer

Poly (amidoamine) dendrimers (PAMAM) are synthesized by the divergent starting ammonia method from aethylene diamine initiator core. PAMAM dendrimers are commercially available, usually as methanol solutions. Starburst dendrimers is applied as a trademark name for a sub-class of PAMAM dendrimers based on a tris-amino ethylenamine core.

PAMAMOS Dendrimer

Radially layered poly (amidoamine-organosilicon) dendrimers (PAMAMOS) are inverted unimolecular micelles that consist of hydrophilic, nucleophilic polyamidoamine (PAMAM) interiors and hydrophobic organosilicon (OS) exteriors. These are silicone containing first commercial dendrimers.

PPI Dendrimer

PPI-dendrimers stand for “Poly (Propylene Imine)” describing the propylamine spacer moieties in the oldest known dendrimer type developed initially by Vogtle. These dendrimers are generally poly-alkyl amine, having primary amines as end groups; the dendrimer interior consists of numerous of tertiary tris-propylene amines.

Tecto- dendrimer

These are composed of a core dendrimer, surrounded by dendrimers of several steps to perform a function necessary for a smart therapeutic nanodevice.

Multilingual dendrimers

In these dendrimers, the surface contains multiple copies of a particular functional group.

Chiral dendrimers

The chirality in these dendrimers is based upon the construction of a constitutionally different but chemically similar branch to chiral core.

Hybrid dendrimers linear polymers

These are hybrids (block or graft polymers) of dendritic and linear polymers and having properties of both.

Amphiphilic dendrimers

They are built with two segregated chains of which one half is electron donating and other half is electron withdrawing.

Micellar dendrimers

These are unicellular micelles of water soluble and hyper branched polyphenylenes.

Multiple antigen peptide dendrimers

It is a Dendron like molecular construct upon a polylysine skeleton. Lysine with its alkyl amino side chain serves as a good for the introduction of monomer numerous of branching points. This dendrimer was type of introduce by J.P.Tam in 1988, predominately found its biological applications, e.g. and diagnostic vaccine research.

Frechet-type dendrimers

It is a more of dendrimer recent type developed by Hawker and Frechet based on poly benzyl ether hyper branched skeleton. These dendrimers usually have carboxylic acid groups as surface groups, serving as a good anchoring point for further surface functionlisation and as polar surface groups increase solubility of hydrophobic to this dendrimer type in polar solvents or aqueous media .

Solubility enhancement of poorly soluble drugs

PAMAM dendrimers enhanced the pharmacological activity of antifungal drugs by increasing their solubility. PAMAM dendrimers significantly increased the aqueous solubility of EM, despite the increase in the solubility, there was only slight influence on the antibacterial activity of EM and also found that there was no influence of PAMAM on the antibacterial activity of hydrophilic TOB.

Increases phagocytosis

Pneumococcal virulence factors common to all serotypes, such as choline-binding proteins (CBPs), are promising therapeutic targets in pneumococcal infections.. Inhibiting CBPs by micro molar concentrations of a choline dendrimer caused the formation of long pneumococcal chains that were readily phagocytosed by microglia. Long bacteria-dendrimer co-incubation resulted in a higher bacterial uptake than short co-incubation. Multivalent dendrimers containing choline end groups are promising antimicrobial agents for the management of pneumococcal diseases.

Permeability of bacterial cell membranes

PPI dendrimers penetrate through the cell wall more easily than glycodendrimers. Chen et al. showed that bacterial membranes have lower permeability of the larger dendrimer analogues .Destroying the cell membranes of microorganisms directly, or disrupting multivalent binding interactions between microorganisms and host cells, are the primary mechanisms of antimicrobial action by dendrimers .

Dendrimeric anti-microbial peptide

Antimicrobial drug resistance is a major human health threat. To tackle this problem, Peptide-based dendrimers can be designed to have higher potency than natural antimicrobial peptides with similar chemical structure but varying potency in terms of minimum inhibitory concentration were designed and at the same time they can evade the bacterial defense system.

Therapeutic macromolecules including dendrimers-based drug delivery systems exploit the pathophysiological patterns of solid tumour, particularly their leaky vasculature, to preferentially extravasate and accumulate in tumour tissue in a process known as the enhanced permeability and retention (EPR) effect.

Cationic antimicrobial peptides constitute an important component of the innate immunity against microbial infections [1±6]. Recently there is renewed interest in developing novel approaches for designing peptide-based antibiotics manifested by killing mechanisms that are less likely than conventional antibiotics to develop multidrug resistance [7±12]. Design elements desirable for therapeutics include activity under physiological conditions (100± 150 mM or high-salt conditions), low toxicity and proteolytic stability. They have designed antimicrobial peptides with unusual structural architectures using rigid scaffoldings such as cyclic peptides highly constrained with a cystineknot motif on two or three b strands [10±12] to cluster hydrophobic and charge regions that produce amphipathic structures important for antimicrobial activity.

Membrane disruption dendrimer peptide

The discovery of antimicrobial peptide dendrimers such as H1 and bH1 in which positive charges are provided by the multiple amino termini at the dendrimer periphery. The discovery of antimicrobial peptide dendrimers such as H1 and bH1 in which positive charges are provided by the multiple amino termini at the dendrimer periphery.

Nano conjugates for anti bacterial therapy

The bioactive agents may be condensed into the interior of the dendrimers or physically adsorbed/chemically attached onto the dendrimer surface. It has been shown that Modified dendrimers act as nano-drugs against bacteria, viruses and tumors.

Dual acting anti bacterial agents

Besides acting as antimicrobial compounds, dendrimers can be considered as agentsthat improve the therapeutic effectiveness of existing antibiotics.

Against resistant strain

PEGylated poly (propylene imine) dendritic architecture was loaded with Ciprofloxacin and targeted to the resistants produce strains of Staphylococcus aureus and Cryptococcus pneumonia.

Anti bacterial activity

Antimicrobial drugs either kill microbes (microbiocidal) or prevent the growth of microbes (microbiostatic). Disinfectants are antimicrobial substances used on non-living objects or outside the body. Antibacterial and antimicrobial are two similar concepts and sometimes they are used interchangeably.

Antibacterial agents work by

a. Interference with cell wall synthesis

Lactams: penicillins, cephalosporins, carbapenems, monobactams

Glycopeptides: vancomycin, teicoplanin

b. Protein synthesis inhibition

Bind to 50S ribosomal subunit: macrolides, chloramphenicol, clindamycin, quinupristin-dalfopristin, linezolid

Bind to 30S ribosomal subunit: aminoglycosides, tetracyclines

Bind to bacterial isoleucyl-tRNAsynthetase: mupirocin

c. Interference with nucleic acid synthesis

Inhibit DNA synthesis: fluoroquinolones

Inhibit RNA synthesis: rifampin

d. Inhibition of metabolic pathway: sulfonamides, folic acid analogues

e. Disruption of bacterial membrane structure: polymyxins, daptomycin

CONCLUSION:

Around the world in many healthcare facilities, bacterial pathogens that express multiple resistance mechanisms are becoming the norm, increasing both human morbidity and financial costs and complicating treatment. To eliminate most intracellular bacteria such us Brucella or Mycobaterium till now, no antibiotic therapy has been reported. To reduce the disease relapses down to 5-15% still more, a prolonged exposure to combined antibiotics is required. Keeping view in this, drug delivery scientists are searching for the ideal nano vehicle for the ideal nano drug delivery system; one that would dramatically improve in the drug absorption, reduce drug dosage so that the patient can take a smaller dose, and yet have the same benefit, deliver the drug to the right place in the living system, limit or eliminate side effects and increase the local concentration of the drug at the favorite site. Phagocytosis is enhanced powerfully by these polymeric particles and are suitable for antibacterial agents for intracellular delivery. There is no doubt that nano particle-based drug delivery systems will continue to improve treatment to bacterial infections due to the incessant attempts in this field.

REFERENCES:

1. Fréchet, J. M. J., Tomalia, D. A., 2001. Dendrimers and other dendritic polymers, John Wiley & Sons, Chichester.

2. Newkome, G. R., Moorefield, C. N., Vögtle, F., 2001.Dendrimers and Dendrons. Wiley-VCH, Weinheim.

3. Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev.1999, 99, 1665.

4. Bezouska, K. J, Biotechnol.2002, 90, 269

5. Stiriba, S. E., Frey, H.,Haag, R. Angew.,2002.Chem. Int. Ed.

6. Svenson, S., Tomalia, D. A.,2005. Adv. Drug Deliv. Rev.

7. Lee, C. C., MacKay, J. A., Fréchet, J. M., Szoka, F. C.,2005Nat. Bio-technol., 23, 1517.

8. Haag, R., Kratz, F., Angew. 2006. Chem. Int. Ed., 45, 1198.

9. Beutler, B., Jiang, Z., Georgel, P., Crozat, K., Croker, B., Rutsch-mann, S., Du, X., Hoebe, K.,2006.Annu. Rev. Immunol.24, 353.

10. Inohara; Chamaillard; McDonald, C.; Nunez, G. Annu. Rev. Bio-chem. 2005, 74, 355.

11. Figdor, C. G., van Kooyk, Y., Adema, G. J.,2002. Nat. Rev. Immunol, 77.

12. Robinson, M. J., Sancho, D., Slack, E. C., Leibunggut-Landmann, S., Sousa, C. R.,2006. Nat. Immunol,7, 1258.

13. Halary, F.,Amara, A., Lortat-Jacob, H., Messerle, M., Delaunay, T., Houles, C., Fieschi, F., Arenzana-Seisdedos, F., Moreau, J. F., chanet-Merville.2002. J. Immunity, 17, 653.

14. Geijtenbeek, T. B., van Vliet, S. J., Koppel, E. A., Sanchez-Hernandez, M., VandenbrouckeGrauls, C. M., Appelmelk, B., van Kooyk, Y.,2003. J. Exp.Med,197, 7.

15. Brown, G. D.; Taylor, P. R.; Reid, D. M.; Willment, J. A.; Wil-liams, D. L.; Martinez-Pomares, L.; Wong, S. Y.; Gordon, S. J.Exp. Med. 2002, 196, 407.

16. McGreal, E. P., Rosas, M., Brown, G. D., Zamze, S., Wong, S. Y., Gordon, S., Martinez-Pomares, L., Taylor, P. R.,2006. Glycobiology,16, 422.

17. Turville, S. G., Cameron, P. U., Handley, A., Lin, G., Pohlmann, S., Doms, R. W., Cunningham, A. L.,2002. Nat. Immunol, 3, 975.

18. Gramberg, T., Hofmann, H., Moller, P., Lalor, P. F., Marzi, A., Geier, M., Krumbiegel, M., Winkler, T., Kirchhoff, F., Adams, D. H., Becker, S., Munch, J., Pohlmann, S.,2005. Virology, 340, 224.

19. Liu, W. Tang, L., Zhang, G., Wei, H.; Cui, Y., Guo, L., Gou, Z., Chen, X., Jiang, D., Zhu, Y., Kang, G., He, F. 2004. J. Biol. Chem, 279, 18748.

20. Curtis, B. M., Scharnowske, S., Watson, A.,1992. J. Proc. Natl. Acad.Sci. U.S.A, 89, 8356.

21. Gramberg, T.; Zhu, T.; Chaipan, C.; Marzi, A.; Liu, H.; Wegele, A.; Andrus, T.; Hofmann, H.; Pohlmann, S. Virology2006, 347, 354.

22. Liu, H.; Hwangbo, Y., Holte, S.; Lee, J., Wang, C., Kaupp, N., Zhu, H., Celum, C., Corey, L.,McElrath, M. J., Zhu, T. J. 2004, Infect. Dis, 190, 1055.

23. Engering, A.; Geijtenbeek, T. B.; van Vliet, S. J.; Wijers, M.; van,

24. E.; Demaurex, N.; Lanzavecchia, A.; Fransen, J.; Figdor, C. G.; Piguet, V.; van Kooyk, Y. J. Immunol.2002, 168, 2118.

25. Kitov, P. I., Sadowska, J. M., Mulvey, G., Armstrong, G. D., Ling, H., Pannu, N. S., Read, R. J., Bundle, D. R.,2000. Nature, 403, 669.

26. Mulvey, G. L., Marcato, P., Kitov, P. I., Sadowska, J., Bundle, D. R., Armstrong, G. D.,2003. J. Infect. Dis,187, 640.

27. David, S. A., Silverstein, R., Amura, C. R., Kielian, T., Morrison,

28. C.,1999. Antimicrob. Agents Chemother, 43, 912.

29. Connell, H., Agace, W., Klemm, P., Schembri, M., Marild, S., Svanborg, C., 1996.Proc. Natl. Acad. Sci. U.S.A, 93, 9827.

30. Kotter, S., Krallmann-Wenzel, U., Ehlers, S., Lindhorst, T. K.,1998. J.Chem. Soc, Perkin Trans, 1, 2193.

31. Lindhorst, T. K., Dubber, M., Krallmann-Wenzel, U., Ehlers, S.,2000Eur. J. Org. Chem, 2027.

32. Lindhorst, T. K., Kotter, S., Krallmann-Wenzel, U., Ehlers, S.,2001. J.Chem. Soc. Perkin Trans, 1, 823.

33. Lindhorst, T. K., Kieburg, C., Krallmann-Wenzel, U.,1998. Glycoconjug, 15, 605

34. Bakker-Woudenberg, I. A. J. M., 1995. Delivery of antimicrobials to infected tissue macrophages. Adv. Drug Deliv. Rev,17, 5-20.

35. Coates, A., Hu, Y., Bax, R., Page, C., 2002. The future challenges facing the development of new antimicrobial drugs. Nat Rev Drug Discov,1, 895-910.

36. Walker, C. B., 1996. Selected antimicrobial agents: mechanisms of action, side effects and drug interactions. Periodontol 2000, 10, 12-28.

37. Zhang, L., Gu, F. X., Chan, J. M., Wang, A. Z., Langer, R. S., Farokhzad, O. C.,2008. Nanoparticles in medicine: therapeutic applications and developments. Clin. Pharmacol. Ther,83, 761-9.

38. Davis, M. E., Chen, Z. G., Shin, D. M.,2008. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov,7, 771-82.

39. Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R., Langer, R.,2007. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol, 2, 751-60.

40. Wagner, V., Dullaart, A., Bock, A.K., Zweck, A., 2006. The emerging nanomedicine landscape. Nat. Biotechnol, 24, 1211-7.

41. Zhang, L., Granick, S.,2006. How to stabilize phospholipid liposomes (using nanoparticles). Nano Lett, 6, 694-8.

42. Farokhzad, O. C., Langer, R.,2006. Developing Nanomedicine smarter therapeutic and diagnostic modalities. Adv Drug Deliv. Rev,58, 1456-9.

43. Lian, T., Ho, R. J.,2001.Trends and developments in liposome drug delivery systems. J. Pharm. Sci, 90, 667-80.

44. Hiemenz, J. W., Walsh, T. J.,1996. Lipid formulations of amphotericin B: recent progress and future directions. Clin. Infect. Dis., 22, 133-44.

45. Adler-Moore, J. P., Proffitt, R. T.,1993. Development, characterization, efficacy and mode of action of AmBisome, a unilamella liposomal formulation of amphotericin B. J. Liposome Res., 3, 429-50.

46. Adler-Moore, J. P., Proffitt, R. T.,1998. AmBisome: long circulating formulation of Amphotericin B. Long Circulating Liposome: OldDrugs, New Therapeutics, Springer-Verlag, Berlin,185-206.

47. Adler-Moore, J., Proffitt, R. T.,2002. AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J. An-timicrob. Chemother., 49, 21-30.

48. Alipour, M., Halwani, M., Omri, A., Suntres, Z. E.,2008. Antimicrobial effectiveness of liposomal polymyxin B against resistant Gram-negative bacterial strains. Int. J. Pharm, 355, 293-8.

49. Fischbach, M. A., Walsh, C. T.,2009. Antibiotics for emerging pathogens. Science, 325, 1089-93.

50. Schumacher, I., Margalit, R.,1997. Liposome-encapsulated ampicillin: physicochemical and antibacterial properties. J. Pharm. Sci, 86, 635-41.

51. Kim, H. J., Jones, M. N.,2004. The delivery of benzyl penicillin to Staphylococcus aureus biofilms by use of liposomes. J. LiposomeRes, 14, 123-39.

52. Magallanes, M., Dijkstra, J., Fierer, J., 1993. Liposome-incorporated ciprofloxacin in treatment of murine salmonellosis. Antimicrob.Agents Chemother, 37, 2293-7.

53. Venugopal, J., Prabhakaran, M. P., Low, S., Choon, A. T., Deepika, G., Dev, V. R., Ramakrishna, S.,2009. Continuous nanostructures for the controlled release of drugs. Curr. Pharm. Des, 15, 1799-808.

54. Langer, R., Folkman, J.,1976. Polymers for the sustained release of pro-teins and other macromolecules. Nature, 263, 797-800.

55. Gref, R., Minamitake, Y., Peracchia, M. T., Trubetskoy, V., Torchilin, V., Langer, R.,1994. Biodegradable long-circulating polymeric nanospheres. Science, 263, 1600-3.

56. Abeylath, S. C., Turos, E., Dickey, S., Lim, D. V., 2008. Glyconanobiotics: Novel carbohydrated nanoparticle antibiotics for MRSA and Bacillus anthracis. Bioorg. Med. Chem, 16, 2412-8.

57. Espuelas, M. S., Legrand, P.; Loiseau, P. M., Bories, C., Barratt, G., Irache, J. M., 2002. In vitro antileishmanial activity of amphotericin B loaded in poly(epsilon-caprolactone) nanospheres. J. Drug Target,10, 593-9.

58. Domb, A. J.,1993. Liposphere parenteral delivery system. Proc. Intern.Symp. Control. Rel. Bioact. Mater, 20, 346-7.

59. Muller, R. H., Radtke, M., Wissing, S. A.,2002. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev,54 131-55.

60. Wissing, S. A., Muller, R. H.,2003. Cosmetic applications for solid lipid nanoparticles (SLN). Int. J. Pharm, 254, 65-8.

61. Muller, R. H., Mader, K., Gohla, S.,2000. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur JPharm Biopharm, 50, 161-77.

62. Wissing, S., Lippacher, A., Muller, R., 2001. Investigations on the occlusive properties of solid lipid nanoparticles (SLN). J. Cosmet. Sci,52, 313-24.

63. Gupta, A. K., Cooper, E. A., 2008. Update in antifungal therapy of der-matophytosis. Mycopathologia,166, 353-67.

64. Bosman, A. W., Janssen, H. M., Meijer, E. W.,1999. About Dendrimers: Structure, Physical Properties, and Applications. Chem. Rev, 99, 1665-88.

65. Gillies, E. R., Frechet, J. M.,2005. Dendrimers and dendritic polymers in drug delivery. Drug Discov. Today, 10, 35-43.

66. Florence, A. T.,2005. Dendrimers: a versatile targeting platform. Adv.Drug Deliv. Rev, 57, 2104-5.

67. Chen, C. Z., Cooper, S. L.,2002. Interactions between dendrimer biocides and bacterial membranes. Biomaterials, 23, 3359-68.

68. Balogh, L., Swanson, D. R., Tomalia, D. A., Hagnauer, G. L., McManus, A. T., 2001. Dendrimer-Silver Complexes and Nanocompo-sites as Antimicrobial Agents. Nano Lett, 1, 18-21.

69. Ma, M., Cheng, Y., Xu, Z., Xu, P.,Qu, H., Fang, Y., Xu, T., Wen, 2007. Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug. Eur. J. Med. Chem, 42, 93-8.

70. Omri, A., Suntres, Z. E., Shek, P. N., 2002. Enhanced activity of liposo-mal polymyxin B against Pseudomonas aeruginosa in a rat model of lung infection. Biochem. Pharmacol, 64, 1407-13.

71. Mimoso, I. M., Francisco, A. P. G., Cruz, M. E. M.,1997. Liposomal formulation of netilmicin Int. J. Pharm, 147, 109-17.

72. Schiffelers, R., Storm, G., Bakker-Woudenberg, I.,2001. Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies. J.Antimicrob. Chemother, 48, 333-44.

73. Berton, M., Turelli, P., Trono, D., Stein, C. A., Allemann, E., Gurny, R.,2001. Inhibition of HIV-1 in cell culture by oligonucleotide-loaded nanoparticles. Pharm. Res, 18, 1096-101.

74. Shah, L. K., Amiji, M. M.,2006. Intracellular delivery of saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharm. Res,23, 2638-45.

75. Pandey, R., Khuller, G. K.,2006. Oral nanoparticle-based antituberculosis drug delivery to the brain in an experimental model. J. Antimicrob.Chemother, 57, 1146-52.

76. Souto, E. B., Muller, R. H.,2005. SLN and NLC for topical delivery of ketoconazole. J. Microencapsul, 22, 501-10.

77. Cheng, Y., Qu, H., Ma, M., Xu, Z., Xu, P., Fang, Y., Xu, T.,2007. Poly-amidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Eur. J. Med. Chem,42, 1032-8.

78. Bhadra, D., Bhadra, S., Jain, N. K.,2005. Pegylated lysine based co-polymeric dendritic micelles for solubilization and delivery of artemether. J. Pharm. Pharm. Sci, 8, 467-82.

79. Abeylath SC., Turos E., Dickey S., Lim DV.,2008.Glyconanobiotics: Novel carbohydrated nanoparticle antibiotics for MRSA and Bacillus anthracis. BioorgMed Chem, 16, 2412-2418.

80. Ahmad Z., Pandey R., Sharma S., Khuller GK.,2006. Alginate nanoparticles as antituberculosis drug carriers: formulation development, pharmacokinetics and therapeutic potential. Indian J Chest Dis Allied Sci. 48, 171-176.

81. Bala T., Armstrong G., Laffir F., Thornton R.,2011. Titania-silver and alumina-silver composite nanoparticles: Novel, versatile synthesis, reaction mechanism and potential antimicrobial application. Adv Colloid Interface Sci, 356, 395-403.

82. Balogh L., Swanson DR., Tomalia DA., Hagnauer GL., McManus AT.,2001. Dendrimer-Silver Complexes and Nanocomposites as Antimicrobial Agents. Nano Lett, 1, 18-21.

83. Beaulac C., Clement-Major S., Hawari J., Legace J.,1996. Eradication of mucoid Pseudomonas aeruginosa with fluid liposome-encapsulated tobramycin in an animal model of chronic pulmonary infection. Antimicrob Agents Chemother, 40, 665–669.

84. Berkowitz FE.,1995. Antibiotic resistance in bacteria. SouthMed J,88 ,797-804.

85. Bhadra D., Bhadra S., Jain NK.,2005. PEGylated peptide based dendritic nanoparticulate systems for delivery of artemether. J Drug Del Sci Tech, 15, 65-73.

86. Cavalli R., Gasco MR., Chetoni P., Burgalassi S., Saettone MF.,2002. Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin. Int J Pharm, 238, 241-245.

87. Chakraborty SP., Sahu SK., Mahapatra SK., Susmita S., Bal M., Roy S.,2010. Nanoconjugated vancomycin: new opportunities for the development of anti-VRSA agents. Nanotechnology, 21, 1-9.

88. Chan JM., Zhang L., Yuet KP., Liao G., Rhee JW., Langer R.,2009. PLGA–lecithin–PEG core–shell nanoparticles for controlled drug delivery. Biomaterials. 30, 1627-1634.

89. Cheng Y., Qu H., Ma M., Xu Z., Xu P., Fang Y.,2007. Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Eur J Med Chem, 42, 1032-1038.

90. Chopra I.,2007. The increasing use of silver-based products as antimicrobial agents: a useful development or a cause for concernJ Antimicro Chemother, 59, 587-590.

91. Chung YC., Wang HL., Chen YM., Li SL., 2003. Effect of abiotic factors on the antibacterial activity of chitosan against waterborne pathogens. Bioresour Technol, 82, 179-184.

92. Cohen ML., 2000. Changing patterns of infectious disease. Nature, 406, 762-767.

93. Espuelas MS., Legrand P., Campanero MA., Appel M., Cheron M., Gamazo C.,2003. Polymeric carriers for amphotericin B: in vitro activity, toxicity and therapeutic efficacy against systemic candidiasis in neutropenic mice. J Antimicrob Chemother, 52, 419-427.

94. Esteban TL., Malpartida F., Esteban CA., Pecharromán C., Moya JS., Antibacterial and antifungal activity of a soda-lime glass containing copper nanoparticles. Nanotechnology. 2009, 20, 505-701.

95. Ferrari M., 2005. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer, 5, 161-171.

96. Gillies ER., Frechet JM.,2005. Dendrimers and dendritic polymers in drug delivery. Drug Discov Today, 10, 35-43.

97. Gold HS., Moellering RC.,1996, Antimicrobial-drug resistance. N Engl J Med, 335, 1445-1453.

98. Hetrick EM., Shin JK., Paul HS., Schoenfisch MH.,2009. Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles. Biomaterials, 30, 2782-2789.

99. Jain KK.,2007. Applications of nanobiotechnology in clinical diagnostics. Clin Chem, 53, 2002–2009.

100. Kaur CD., Nahar M., Jain NK., 2008. Lymphatic targeting of zidovudine using surface-engineered liposomes. J Drug Target, 16, 798-805.Talyor PW., Stapleton PD., Luzio JP.,2002. New ways to treat bacterial infections. Drug Discov Today, 7, 1086-1091.

101. Taubes G.,2008. The bacteria fight back. Science, 321, 356-361.

102. Weinberg ED.,1999. Iron loading and disease surveillance. Emerg Infect Dis, 346-352.

103. Yang J.,2008. Hollow silica nanocontainers as drug delivery vehicles. Langmuir,24, 3417-3421.

104. Zhang L., Pornpattananangkul D., Hu CMJ., Huang CM., Development of nanoparticles for antimicrobial drug delivery. 2010. Curr Med Chem,17, 585-594.

105. Mizrahi, A., Ben-Ner, E., Katz, M. J., Kedem, K., Glus-man, J. G., Libersat, F. 2000 J .Comp Neurol, 422, 415.

106. Tomalia, D. A. Sci Am 1995, 272, 62– 66.

107. Flory, P. J. J Am Chem Soc 1941, 63, 3083.

Received on 15.02.2016 Modified on 25.02.2016

Research J. Pharm. and Tech. 9(3): Mar., 2016; Page 322-332

DOI: 10.5958/0974-360X.2016.00058.5