DENDRIMERS: NOVEL DRUG NANOCARRIERSHTML Full Text
DENDRIMERS: NOVEL DRUG NANOCARRIERS
Y. Kandekar*1, P. D. Chaudhari 2, V. S. Tambe 1, V. S.Vichare 1 and S. N.Dhole 1
PES’s Modern college of Pharmacy (For Ladies) 1, Borhadewadi, Dehu- Alandi Road, Moshi, Pune, Maharashtra, India
PES’s Modern college of pharmacy, Nigdi 2, Pune, Maharashtra, India
Dendrimers are unique class of the polymer which is characterized by its extensively branched 3D structure that provides a high degree of surface functionality and versatility. Many drugs used in various therapies are facing difficulties like toxicity or nonspecific targeting. New delivery technologies could help to overcome this challenge. Nanostructures with uniform and well-defined particle size and shape are of eminent interest in biomedical applications because of their ability to cross cell membranes and to reduce the risk of premature clearance from the body. Hydrophobic drugs can be complex within the hydrophobic dendrimers interior to make them water-soluble or drugs can be covalently coupled onto the surface of the dendrimers. Structural features of this nanomolecule can be effectively modified for drug delivery in the field of pharmaceutical sciences and biotechnology. Present review deals with various applications along with relevant examples of dendrimers in brief.
|Keywords:Branched 3D structure,
Surface functionality, Nanostructure,
INTRODUCTION: Development of completely bioavailable dosage form of a drug is always being challenge to the research scientist. Various approaches have been used to enhance the therapeutic effect of the drug with less toxicity these include improvement of solubility, microspheres, microemulsion, iontophoresis and sonophoresis, liposomes etc. In the last decade, the field of preparation of materials with low dimensionality and the investigation of their properties gained more and more importance. Nanotechnology has been applied on various platforms such as Targeted and controlled drug delivery, Medical devices, Cell/tissue engineering, Gene delivery, Molecular-tags, Biosensors, bioanalysis 1-6.
Nanoparticles have unusual properties that can be used to improve drug delivery. Where larger particles would have been cleared from the body, cells take up these nanoparticles because of their size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm Dendrimers is the class of synthetic polymeric macromolecule which play important role in emerging nanotechnology. It is described as highly branched macromolecule, which provides a high degree of surface functionality and versatility. It is derived from the Greek words Dendron (tree) and meros (part) 7.
It possess a 3-D features that resemble a tree. Their syntheses are attributed to Vogtle group 8 in the late 1970s, followed by the work of Tomalia et al., 9 in the early 1980s. Two major strategies have evolved for dendrimer synthesis: The first, divergent method in which growth of a dendron originates from a core site in which the dendrimer grows outwards from the core, diverging into space as shown in fig. 1. The second method is the convergent growth process which works inwards by gradually linking surface units together as given in fig. 2.
FIG. 1: DIVERGENT GROWTH METHOD
FIG. 2: CONVERGENT GROWTH METHOD
When the growing wedges are large enough, several are attached to a suitable core to give a complete dendrimer. 10-13 Dendrimers are built from a starting atom, such as nitrogen, to which carbon and other elements are added by a repeating series of chemical reactions that produce a spherical branching structure. As the process repeats, successive layers are added.
It possesses three distinguished architectural components as shown in fig. 3 14-16.
- An initiator core.
- Interior layers (generations) composed of repeating units, radically attached to the interior core.
- Exterior (terminal functionality) attached to the outermost interior generations.
FIG. 3: THE DENDRITIC STRUCTURE
Dendrimers are core-shell nanostructures with precise architecture and low polydispersity, which are synthesized in a layer-by-layer fashion (expressed in ‘generations’) around a core unit, resulting in high level of control over size, branching points and surface functionality. Dendritic macromolecules tend to linearly increase in diameter and adopt a more globular shape with increasing dendrimer generation. When dendrimers condense into globular structures, their many termini become fixed into an outwards orientation and also form a densely packed, membrane-like surface.
This structural arrangement provides numerous attachment points for covalent conjugation of bioactive molecules on the surface as well as enclosed cavities for occlusion of guest molecules within the dendrimers. Dendrimers are of great interest as carriers of functional groups because of their highly branched monodisperse structures in nanometer scale, the size of dendrimers can be carefully controlled during synthesis. Compared to polymers dendrimers reveal varied physical properties such as viscosity which tends to increase maximum at approximately the fourth generation and then declines, flexibility due to the extensive covalent bond networks, and density distribution, narrow molecular weight distribution, specific size and shape characteristics, and a highly- functionalized terminal surface.
The ability to tailor dendrimer properties to therapeutic needs makes them ideal carriers for small molecule drugs and biomolecules. The major properties of dendrimers are;
- Nanoscale container properties (i.e., encapsulation of a drug), Encapsulating in that void space reduces the drug toxicity and facilitates controlled release.
- Nano-scaffolding properties (i.e., surface adsorption or attachment of a drug), Surfaces that may be designed with functional groups to augment or resist trans-cellular, epithelial or vascular biopermeability.
- Biocompatibility, positive biocompatibility patterns that are associated with lower generation anionic or neutral polar terminal surface groups as compared to higher generation neutral nonpolar and cationic surface groups.
- None or low-immunogenicity associated with most dendrimer surfaces modified with small functional groups or polyethylene glycol (PEG).
- Surface groups that can be modified to optimize biodistribution; receptor mediated targeting, therapy dosage or controlled release of drug from the interior space.
- Ability to arrange excretion mode from body, as a function of nanoscale diameter 17-24.
The focus of this review is to discuss various drug delivery applications of dendrimers in detail.
Dendrimers for Cancer Treatment: Millions of humans from all age groups are affected by the cancer. Most of the current chemotherapeutic agents on the market are the low molecular weight which makes them easily excreted, hence a higher concentration is ultimately required, and additionally, these drugs when administrated alone, lack specificity and cause significant damage to noncancerous tissues. This results in serious, unwanted side effects 25.
Therapeutic agents can be internalized into the void space between the periphery and core, or covalently attached to functionalized surface groups .Dendrimers are small enough to slip through tiny openings in cell membranes and retention effect that improves the delivery of macromolecules to tumors, targeting moieties bound to the dendrimer surface can be used to preferentially treat cancer cells with certain over-expressed receptor targets 25. Dendrimer-drug conjugates generally consist of an antineoplastic agent covalently attached to the peripheral groups of the dendrimer. This method offers distinct advantages over drug-encapsulated systems. Multiple drug molecules can be attached to each dendrimer molecule and the release of these therapeutic molecules is partially controlled by the nature of the linkages. Mechanism of drug delivery includes Dendrimer lipid bilayer interaction. It was proposed that dendrimers shape and charge play a part in forming dendrimer-lipid vesicles by removing individual lipid molecules from the membrane. Dendrimers have charged group the interaction between these groups with the cell membrane disrupt the cell membrane. The ratio of lipid head groups (L) in contact with the dendrimer surface to the number of dendrimer peripheral end groups (P) seems to be a determining factor in hole formation 26.
The concept of dendrimer architecture and membrane bilayer hole creation was broadened to a range of linear and Dendritic polycationic polymers commonly investigated for drug delivery applications.27 Although membrane permeability may play a role in the cellular uptake of certain dendrimers conventional modes of endocytotic internalization are attributed to the uptake of many dendrimers 28. With the increase of molecular weight of the drug, dendrimer-drug interaction, the hydrodynamic volume increases causing longer circulation time and slower elimination of drug so cytotoxicity levels are lowered and dosage can be decreased 29.
There are numerous examples of dendrimer mediated targeted drug delivery: Poly(glycerol succinic acid) dendrimers, or PGLSA dendrimers, were investigated as delivery vehicles for camptothecins, In a preliminary study reported by the Grinstaff group, G4-PGLSA dendrimers with hydroxyl (G4-PGLSA-OH) or carboxylate (G4-PGLSA-COONa) peripheral groups were used to encapsulate 10-hydroxycamptothecin (10-HCPT) for delivery to cancer cells 30. The G4-PGLSA-OH -10-HCPT solution precipitated upon standing after mixing; the more water-soluble G4-PGLSA-COONa dendrimer was used to improve overall solubility and 10-HCPT was successfully encapsulated. Upon exposure to MCF-7 human breast cancer cells, unloaded dendrimer showed no cytotoxic effects, while 10-HCPT-encapsulated dendrimers led to significant cytotoxicity. An alternative triblock structure PEG 3400 core was introduced to the G4-PGLSA dendrimer to afford (G4-PGLSA-OH) 2-PEG3400. A 20-fold increase in 10-HCPT water solubility was observed following encapsulation. The conclusions drawn from these two studies led to the selection of G4-PGLSA-COONa dendrimer as a delivery vehicle for 10-HCPT and 7-butyl-10-aminocamptothecin (BACPT), a highly potent lipophilic camptothecin derivative. The release profile of 10-HCPTencapsulated G4-PGLSA-COONa showed full release of the drug within approximately 6 h, suggesting that the delivery system may be best utilized.
Uptake studies showed that dendrimer-encapsulated 10-HCPT was internalized much faster than free drug, with 16-fold intracellular concentrations at 2 h and 8-fold intracellular concentrations at 10 h. Drug delivered via the dendrimers also showed longer retention time in the cell, with 50% of delivered 10-HCPT present in the cell after 30 min, compared to 35% of free drug. Thus, delivered camptothecins was attributed to enhanced uptake and retention 26, 31-32.
Paclitaxel was conjugated to PEG or G4-PAMAM. Both PEG and PAMAM increased the aqueous solubility of paclitaxel (0.3 μg/mL) dramatically to 2.5 mg/mL and 3.2 mg/mL respectively. Upon exposure to human ovarian carcinoma A2780 cells, free paclitaxel accumulated in the cytoplasm near the plasma membrane. The polymer conjugates tended to distribute intracellularly in a more homogenous fashion compared to free drug. The availability of a drug is dramatically influenced by the architecture of its polymer conjugate 26, 33.
Tooru Ooya and et al., reported the solubility enhancement of Paclitaxel by using dendrimers of Oligo(ethylene glycol) methacrylate (OEGMA) and PEG 400. They have synthesized five different types of dendrimers as Poly(OEGMA), five- arm star poly (OEGMA) Polyglycerol dendrimers (dendri PGs) with generation 3, (G-3), 4 (G-4) and 5 (G-5) by two different methods of synthesis 34, 35. The ability to enhance the paclitaxel solubility at 10 wt % concentration was in the increasing order: G-5, G-4, G-3 dendrimers, star poly (OEGMA) and linear poly (OEGMA). Poly (OEGMA) increased the paclitaxel solubility, but a much more significant effect was observed with the five-arm star poly (OEGMA), even though the molecular weight of the arm segment in the star poly (OEGMA) was similar to that of poly (OEGMA).
Thus, the paclitaxel solubility in 10 wt % star poly (OEGMA), in G-3, G-4 and G-5 was 130, 270-, 370- and 430-fold higher respectively, than the paclitaxel solubility in water.
This result supports the hypothesis that increasing the density of PEG400 chains or ethylene glycol units is a key factor in enhancing the solubility of paclitaxel. From this point of view, the dendritic architecture of the polyglycerol dendrimers can be expected to further increase the density of the ethylene glycol units, the star and dendritic polymers consisting of ethylene glycol units are expected to be useful for both oral and parenteral delivery of paclitaxel and other poorly water-soluble drugs 36.
Etoposide can be encapsulated in a star polymer composed of amphiphilic block copolymer arms. The core of the star polymer is polyamidoamine (PAMAM) dendrimer, the inner block in the arm is lipophilic poly (epsilon-caprolactone) (PCL), and the outer block in the arm is hydrophilic poly(ethylene glycol) (PEG). The star-PCL polymer was synthesized first by ring-opening polymerization of epsilon-caprolactone with a PAMAM-OH dendrimer as initiator. The PEG polymer was then attached to the PCL terminus by an ester-forming reaction. A loading capacity of up to 22% (w/w) was achieved with a hydrophobic anticancer drug. A cytotoxicity assay demonstrated that the star-PCL-PEG copolymer is nontoxic in cell culture. This type of block copolymer can be used as a drug delivery carrier 37.
Dendrimers for Ocular Delivery: The anatomy, physiology, and biochemistry of the eye are one of the most complex.38 Many drug delivery systems are utilized for ophthalmic treatment such as eye drops, ointments, inserts, implants, colloids, and suspensions.39 However, all of these systems have their own advantages and disadvantages, intraocular bioavailability of topically applied drug is poor which ultimately responsible for ineffective treatment. Nanotechnology for ocular delivery drug delivery to eye is an emerging concept offers a more accurate targeted delivery and controlled drug release of drug. Size and versatile properties of the dendrimers can be effectively utilized as drug delivery system. Dendrimers are especially ideal for synthesizing hydrogels and are more similar to living tissue than any other synthetic compound. By adding polyethylene glycol or PEG groups to the dendrimers, these hydrogels have applications including cartilage tissue production and for sealing ophthalmic injuries 40. These compounds can be utilized to control the release of dendrimers.
Th. F. Vandamme and L. Brobeck prepared Poly (amidoamine) dendrimers for ocular delivery of pilocarpine nitrate and tropicamide. PAMAM dendrimers are liquid or semi-solid polymers and have a number of amine, carboxylic and hydroxyl surface groups which increases with the generation number (G0, G1, G2, etc.) The unique architecture of PAMAM dendrimers, polymers is able to solubilize strongly and poorly water soluble drugs 41, 42. This diversity of structure is mainly responsible for the types of interaction between dendrimers and various chemical or biological systems.
Functional groups as carboxyl, hydroxyl and amine establish electrostatic and hydrophobic interactions and hydrogen bonds with the underlying surface. Interaction between dendrimers and the surface of the cornea can lead to a structure with more rigid behavior and trapping some of the instilled solution. The release of this trapped solution will be slower because the solutes have to diffuse through this macromolecular structure. To make it easier to visualize the fluorescent solutions on the cornea, fluoresce in was added to the PAMAM dendrimer solutions. PAMAM dendrimers demonstrated physicochemical characteristics (pH, osmolality, viscosity) which are compatible with ocular dosage form formulations. In addition to size and molecular weight, charge and molecular geometry of bioadhesive dendrimers also influence ocular residence time and the increased bioavailability of drugs incorporated in eye drops 43.
The repair of wounds after traumatic or surgical injury is of significant of importance. Corneal wounds arise from surgical procedures (e.g., transplants, incisions for cataract removal and intraocular lens implantation, laser-assisted in situ keratomileusis), infections (ulcers), and traumatic injury (lacerations, perforations). Currently, these wounds are repaired using nylon sutures, but this technique is not ideal because the suture material does not actively participate in healing, and the procedure is inherently invasive. Therefore, alternative strategies using adhesive polymers have been used 44. Duan and Sheardown cross-linked collagen with multi-functional dendrimers. PPI octa amine dendrimers (G2) to generate highly cross-linked collagen hydrogels with mechanical properties that would make it appropriate for use as corneal tissue engineering scaffold 45. Grinstaff has developed a set of dendrimeric adhesives composed of dendrimers of different generations (G1, G2 and G3) combined with PEG, glycerol, and succinic acid for finding application in the repair of corneal wounds 46.
Dendrimers for Oral Delivery: Oral drug-delivery system has been the dominant route for many years because of its significant advantages. It is by far the most convenient administration route with good patient compliance, especially in the patient’s opinions. Along with these benefits, there are also some defects of oral delivery route like low solubility in aqueous solutions and low penetration across intestinal membranes 47, 48. Transport of dendrimers throughout epithelial part of gastrointestinal tract depends upon its characteristics 49. Packaging a drug in a dendrimer host not only makes it soluble but also allows it to bypass the transporter protein that would normally stop it from being absorbed in the intestines after it has been taken orally 50.
Mohammad Najlah and et al., have studied the use of G0 PAMAM dendrimers as drug carriers using naproxen as a prodrug in vitro. Direct amide linkage of naproxen to the G0 dendrimer produced prodrugs of high stability in plasma and liver homogenate. The use of the lactate ester linker gave prodrugs of high stability in plasma with slow hydrolysis in liver homogenate; such conjugates may have potential in controlled release systems or as prodrugs for drug targeting. In contrast, using diethylene glycol as a linker yielded an ester conjugate that showed high chemical stability, but readily released drug in plasma and liver homogenate. Cytotoxicity studies indicated non-toxic effects of G0 dendrimer and conjugates on Caco-2 monolayers. Conjugation of naproxen toG0PAMAMdendrimer appreciably increased its permeability in both directions. Amore pronounced increase of naproxen transport was observed when a lauroyl chain was attached to the surface of G0 PAMAM dendrimers. Results suggest that G0 PAMAM dendrimers demonstrate potential as nanocarriers for the enhancement of oral bioavailability 51.
Dendrimers for Transdermal Delivery: Transdermal delivery suffers poor rates of transcutaneous delivery due to barrier function of the skin. Stratum corneum acts as a major barrier for most of the drugs. PAMAM dendrimer complex with drugs could be improving the drug permeation through the skin as penetration enhancers. Chauhan AS and et al., investigated PAMAM dendrimers enhances the bioavailability of indomethacin in transdermal delivery applications. The effect of three different PAMAM dendrimers on the aqueous solubility of indomethacin and the bioavailability improvement was investigated. G4.0-NH2, G4.0-OH, and G4.5 PAMAM dendrimers were used and the order of solubility enhancement of indomethacin as G4.0-NH 2 > G4.0- OH > G4.5. It was noticed that with amine terminated dendrimers the solubility was enhanced on the basis of electrostatic interactions between the carboxyl group of indomethacin and the amino groups of the dendrimer. In case of G4.5 PAMAM and G4-OH PAMAM the proposed mechanism was molecular encapsulation and hydrogen bonding, respectively.
From this study with dendritic polymers, it could be concluded that the proposed system displayed better drug- targeting efficiency to the arthritic regions with sustained drug delivery 52. Cheng Y et al., studied the model drugs Ketoprofen and Diflunisal. These were conjugated with G5 PAMAM dendrimer and investigated for different studies. In vitro permeation studies on excised rat skin showed 3.4 times higher permeation of Ketoprofen from Ketoprofen–dendrimer complex than that from 2mg/mL Ketoprofen suspended in normal saline. Similarly, a 3.2 times higher permeated amount was observed with Diflunisal–dendrimer complex. Anti-nociception effect of drugs was studied on mice, results showed that Ketoprofen–dendrimer complex reducing writhing activity during the period of 1–8 h after Transdermal administration, while pure Ketoprofen suspension at the equivalent dose of Ketoprofen significantly decreased number of writhing between 4 and 6 h 53.
Wang et al., synthesized polyhydroxyalkanoate (PHA) matrix restraining PAMAM dendrimers penetrated quantity of tamsulosin through snake skin was 15.7 µg/cm2 /d and 24µg/cm2 /d from PHA and PAMAM dendrimers containing PHA matrices, correspondingly. It is found that PAMAM dendrimers enhances the diffusion of tamsulosin. They concluded that the PAMAM dendrimers itself does not voyage in the interior of the skin; however, it takes steps as polymeric skin permeation enhancer by altering the macroscopic constitution of water in the solution 48, 54.
Dendrimers for Pulmonary Delivery: Pegylated dendrimeric micelles prolong the half-life of low molecular weight heparin (LMWH), Enoxaparin and increase the drug’s pulmonary absorption, thereby efficacious in preventing deep vein thrombosis (DVT) in a rodent model. Shuhua Bai have prepared dendrimers of LMWH entrapped in PEG these produced a significant increase in pulmonary absorption and the relative bioavailability of the formulation was 60.6% compared to subcutaneous LMWH. The half-life of the PEG–dendrimer-based formulation was 11.9 h, which is 2.4-fold greater than the half-life of LMWH in a saline control formulation. When the formulation was administered at 48-h intervals, the efficacy of LMWH encapsulated in pegylated dendrimers in reducing thrombus weight in a rodent model was very similar to that of subcutaneous LMWH administered at 24-h intervals 55.
Dendrimers for Targeted Delivery: Dendrimers have ideal properties which are useful in targeted drug-delivery system. The targeted delivery of chemotherapeutics to tumor cells reduced side effects compared to systemic delivery. Macromolecular delivery of anti-cancer drugs using multifunctional dendritic architectures allows for the conjugation of both drugs and targeting moieties such as folic acid, monoclonal antibodies, and peptides to the dendrimer periphery for increasingly specific delivery. The two general strategies of targeting include the passive targeting of bulk cancerous tissue and the active targeting of unique tumor cells.
Non-specific or passive targeting of tumors is achieved by increasing the hydrodynamic radius of the dendrimer though Pegylation, leading to the accumulation of dendrimer in tumor tissue via the enhanced permeability retention (EPR) effect. The EPR effect is a result of tumor induced angiogenesis leading to neovasculature that is irregular, leaky or defective with disorganized endothelial cells; tumor tissues also suffer from poor lymphatic drainage, all leading to the accumulation and retention of macromolecules in the tumor mass Specific or active targeting relies on the conjugation of one or more targeting moieties to the dendrimer to facilitate cell-receptor-mediated interactions 56.
Hong et al., explicitly quantified the binding avidity of multi-valent targeted G5-PAMAM containing different numbers of folic acid molecules Binding avidity to folic acid receptor-over expressing cells increased with each additionally bound FA molecule conjugated to the dendrimer, saturating at 5-6 moieties per dendrimer, though the rate of intracellular internalization was not significantly affected with increased binding. The dendrimers demonstrated a dramatic enhancement of binding avidity of almost 5 orders of magnitude. It was suggested that aggregates of 5-6 FA receptors are pre organized on the membrane and that the key factor in reported tumor reduction is enhanced residence time on the cell and not the rate of endocytosis 57.
Methotrexate can be successfully targeted by using folic acid. The Baker group has investigated several variations of folic acid-conjugated dendrimers for targeted drug delivery. Surface conjugated folic acid G5-PAMAM dendrimers were prepared where the remaining free amine groups were capped with glycidol to neutralize the positive charges, and then further reacted with methotrexate (MTX) to form ester linkages A comparison between encapsulated MTX vs. covalently bound drug release showed a rapid release for the free drug over 2.5 h (~75%), compared to a much slower release for the bound drug over the same period of time (~5%).
Furthermore, encapsulated drug displayed diffusion characteristics similar to free drug. Folic acid-targeted MTX conjugates demonstrated high specificity for KB cells over expressing folic acid receptors 58. In a separate study, folic acid, fluorescein, and methotrexate were conjugated to PAMAM and examined in vitro against KB cells. Anti-proliferative activity was slightly lower for the dendrimer-drug conjugates compared to free methotrexate. Dose-dependent binding to KB cells was demonstrated and compared to fluorescein-modified PAMAM not containing folic acid. Targeting was diminished yet still significant against KB cells under expressing FA receptors. The drug-dendrimer conjugates became ineffective when the cells were pretreated with free folic acid. A comparable study was performed with folic acid, fluorescein, and paclitaxel conjugated to partially acetylated PAMAM dendrimers. Again, folic acid-targeting occurred, preferentially delivering paclitaxel-conjugated dendrimers to KB cells. Internalization was not detected when dendrimers were exposed to down-regulated KB cells 26, 59, 60.
Dendrimers for Bacterial and Viral Infection: Sialylated dendrimers, called sialo dendrimers, have been used to treat influenza infection. The first step in the infection of a cell by influenza virus is the attachment of the virion to the cell membrane. The attachment occurs through the interaction of a virus receptor haemagglutinin with sialic acid groups presented on the surface of the cell 61. Sialodendrimers bind to haemagglutinin and thus prevent the attachment of the virus to cells. Attaching sialinic acid moieties to the dendrimer surface enhances the therapeutic effect and allows the dendrimer to attain a higher activity in inhibiting influenza infection. A larger effect occurs with an increase in the number of sialinic acid groups 62, 63.
Poly (lysine) dendrimers modified with sulfonated naphthyl groups have been found to be useful as antiviral drugs against the herpes simplex virus can potentially prevent/reduce transmission of HIV and other sexually transmitted diseases (STDs). This dendrimer-based nano-drug inhibited early stage virus/cell adsorption and later stage viral replication by interfering with reverse transcriptase and/or integrase enzyme activities 64, 65. The general mode of action of antibacterial dendrimers is to adhere to and damage the anionic bacterial membrane, causing bacterial lysis.66 PPI dendrimers with tertiary alkyl ammonium groups attached to the surface have been shown to be potent antibacterial biocides against Gram positive and Gram negative bacteria. The nature of the counter ion is important, as tetra-alkyl ammonium bromides were found to be more potent antibacterials over the corresponding chlorides 67. Poly (lysine) dendrimers with mannosyl surface groups are effective inhibitors of the adhesion of E. coli to horse blood cells in a haemagglutination assay, making these structures promising antibacterial agents 68. Triazine-based antibiotics were loaded into dendrimers beads at high yields. The release of the antibiotic compounds from a single bead was sufficient to give a clear inhibition effect 69.
Michelle K. Calabretta et al., investigated amino-terminated G5 PAMAM dendrimers are effective antimicrobial agents against common Gram-negative and Gram-positive pathogens P. aeruginosa and Staphylococcus aureus. Although unmodified, amino-terminated PAMAM is toxic to Human Corneal Epithelial Cells, partial coating of the dendrimers with PEG reduces cytotoxicity. The partial PEG coating maintains a high toxicity to the Gram-negative pseudomonal species, although it results in a large decrease in toxicity to Gram-positive staphylococcal species. These findings show that PAMAM derivatives could be an excellent candidate for a new class of antimicrobial compounds that could be incorporated to contact lenses to combat pseudomonal keratitis 70.
Dendrimers in Gene Transfection: Dendrimers can act as vectors, in gene therapy. Amino-terminated PAMAM or PPI dendrimers as non-viral gene transfer agents, enhancing the transfection of DNA by endocytosis and, ultimately, into the cell nucleus 71, 72. Dendrimers of high structural flexibility and partially degraded high- generation dendrimers (i.e., hyper branched architectures) appear to be better suited for certain gene delivery operations due to their enhanced flexibility, which allows the formation of more compact complexes with DNA. It has been found that maximum transfection efficiency is obtained with a net positive charge on the complexes (i.e., an excess of primary amines over DNA phosphates) 73, 74, 75. Kukowska-Latallo et al. reported that intravenous administration of G9 PAMAM dendrimer-complexed pCF1CAT plasmid could result in high level of gene expression in the lung tissues of rats. It enhances the transfection efficiency and expression pattern of dendrimers 76.
Dendrimers as Imaging Agent: Paramagnetic metal chelates such as Gd(III)-N, NV, NW, Nj-tetracarboxymethyl-1, 4, 7, 10-tetraazacyclododecane (Gd (III)-DOTA), Gd(III)-diethylenetriamine pentaacetic acid (Gd(III)-DTPA), and their derivatives increase the relaxation rate of surrounding water protons and are used as contrast agents for magnetic resonance imaging (MRI) However, shortcomings of these low molecular weight contrast agents are short circulation times within the body and inefficient discrimination between diseased and normal tissues.
Lauterbur, Wiener and Tomalia pioneered the use of dendrimer-based MRI contrast agents by reporting some of the highest known relaxivities for these agents 77, 78. These extraordinary properties have been studied extensively in vivo during the last decade by Kobayashi and Brechbiel. These properties appear to result from a combination of the geometrical amplification of chelated gadolinium that is possible on a dendrimers surface and higher rotational correlation times with minimal segmental motion that are intrinsic to these dendrimer conjugates. Consequently, dendrimer-based Gd(III) chelates consisting of generations 2 and 6 PAMAM dendrimers with 12 and 192 terminal surface amines conjugated to the chelating ligand 2-(4-isothiocyanatobenzyl)-6-methyl diethylene triamine pentaacetic acid through a thiourea linkage were synthesized and used in vivo with rabbits. These contrast agents exhibited excellent MRI images of blood vessels upon intravenous injection. The blood circulation times were sufficiently long, with more than 100 min for large dendrimer conjugates such as the G = 6 PAMAM-TU-Gd(III) - DTPA 79, 80.
Boron Neutron Capture Therapy: Boron neutron capture therapy is a cancer treatment based on a nuclear capture reaction. When 10B is irradiated with low energy or thermal neutrons, highly energetic a-particles and 7Li ions are produced that are toxic to tumor cells. To achieve the desired effects, it is necessary to deliver 10B to tumor cells at a concentration of at least 109 atoms per cell. One study, involving intratumoral injection of a conjugate between PAMAM dendrimer G5 carrying 1100 boron atoms at its surface and cetuximab, the monoclonal antibody specific for the EGF receptor, showed that the conjugate was present at an almost 10-fold higher concentration in brain tumors than in normal brain tissue 81.
Tissue Engineering (Te) Applications of Dendrimers: The use of dendrimers’ architectures in cells and TE applications is still in its infancy. Ligand-modified dendrimers have been proposed for use as substratum for cell culture and high performance bioartificial organs 82. Dendrimers are used in bone, cartilage tissue engineering.
CONCLUSION: The main purpose of this review is to focus various valuable applications of dendrimers which can be platform for the development of optimized novel drug delivery systems. Dendrimers drug delivery is in its infancy, it offers several attractive features. This novel class of polymers and their derivatives exhibit unique physicochemical and biological properties, which have great potential for use in a variety of applications. It has greater flexibility in design.
High control over the branching length, shape and size allows modification according to delivery system, so these can serve as ideal carrier for drug and various other applications. We still do not know whether these synthetic polymers, once they entered the body can cause damage to other tissues. Even though toxicity problems if arise, they will be minimized by modifying dendrimer architecture. As the synthesis involves multistep process future work is necessary to find out cost effective synthesis strategies with minimum efforts and the relationship between dendrimer-drug molecules for effective commercial utilization of this technology.
ACKNOWLEDGEMENTS: The authors are grateful to Mr. Sourabh S. Shahane and Mr. Praveen B. Ghadge for their valuable help, kind support and guidance.
- Bikram M, Gobin AM,Whitmire RE, West JL. Temperature-sensitive hydrogels with SiO2–Au nanoshells for controlled drug delivery. Journal of Control Release 2007; 123:219–27.
- Pinna M, Guo X, Zvelindovsky AV. Block copolymer nanoshells. Polymer 2008; 49:2797–800.
- Spuch-Calvar M, Pérez-Juste J, Liz-Marzán LM. Hematite spindles with optical functionalities: growth of gold nanoshells and assembly of gold nanorods. Journal of Colloid Interface Science 2007; 310:297–301.
- Huang X, El-Sayed IH, Qian W, El-Sayed MA. Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. Journal American Chemical Society 2006; 128:2115–20.
- Fahmy TM, Schneck JP, Saltzman WM. A nanoscopic multivalent antigen-presenting carrier for sensitive detection and drug delivery to T Cells. Nanomedicine 2007; 3:75–85.
- Wu C, Brechbiel MW, Kozak RW, Gansow OA. Metal-chelatedendrimer-antibody constructs for use in radioimmunotherapy and imaging. Bioorganic and Medicinal Chemistry Letters 1994; 4:449–54.
- Breitenbach J. Spektrum der Wissenschaft/Digest: Moderne Chemie 1998:96–7.
- Buhleier E, Wehner W, Vögtle F. Cascade- and nonskid-chain-like syntheses of molecular cavity topologies. Synthesis 1978:155–8.
- Tomalia DA, Baker H, Dewald JR, Hall M, Kallos G, Martin S. A new class of polymers: starburst-dendritic macromolecules. Polymer Journal 1985; 17:117–32.
- Sonke S and Tomalia DA. Dendrimers in biomedical applications reflections on the Field. Advanced Drug Delivery Reviews 2005; 57:2106 – 2129.
- Christine D, Ijeoma FU and Andreas GS. Dendrimers in gene delivery. Advanced Drug Delivery Reviews 2005; 57: 2177– 2202.
- Freeman AW and Frechet JMJ. Developments in the Accelerated Convergent Synthesis of Dendrimers. Dendrimers and other Dendritic Polymers Edited by Jean M. J. Fre´chet and Donald A. Tomalia, 91-101.
- Barbara K. and Maria B. Dendrimers: properties and applications. Acta Biochimica Polonica 2005; 48 (1): 199–208.
- Pushkar S, Philip A, Pathak K and Pathak D. Dendrimers: Nanotechnology Derived Novel Polymers in Drug Delivery. Indian Journal of Pharmaceutical Education and Research 2006; 40 (3): 153-158.
- Sakthivel T and Florence AT. Adsorption of Amphipathic Dendrons on Polystyrene Nanoparticles. International Journal of Pharmaceutics 2003; 254(1): 23-26.
- Tomalia DA. Birth of a new macromolecular architecture – dendrimers as quantized building blocks for nanoscale synthetic polymer chemistry. Progress in Polymer Science 2005; 30:294–324.
- Svenson S. Dendrimers Kirk-Othmer Encyclopedia of Chemical Technology 2007; fifth ed.: 26:. 786–812.
- Jain NK and Gupta U. Application of dendrimer-drug complexation in the enhancement of drug solubility and bioavailability. Expert opinion on drug metabolism and toxicology 2008; 4(8):1035-52.
- Gillies ER and Fréchet JMJ. Dendrimers and dendritic polymers in drug delivery. Drug Discovery. Today 2005;10: 35–42.
- Gupta U, Agashe HB, Asthana A and Jain NK. Dendrimers: novel polymeric nanoarchitectures for solubility enhancement. Biomacromolecule 2006; 7: 649– 658.
- Cheng Y, Wang J, Rao T, He X and Xu T. Pharmaceutical applications of dendrimers: promising nanocarriers for drug delivery. Frontiers in Biosciences 2008; 13: 1447–1471.
- Klajnert B and Bryszewska M. Dendrimers: Properties and applications. Acta Biochimica Polonica 2001; 48:199–208.
- Fre´chet J M J. Functional polymers and dendrimers: Reactivity, molecular architecture, and interfacial energy. Science 1994; 263: 1710–1715.
- Tomalia DA, Reyna LA and Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging .Biochemical Society Transaction 2007; 35: 161–67.
- Luo Y and Prestwich GD. Cancer-targeted polymeric drugs. Current Cancer Drug Targets 2002; 2:209–226.
- Wolinsky JB and Grinstaff MW. Therapeutic and diagnostic applications of dendrimers for cancer treatment. Advance Drug Delivery Review 2008; l60:1037–1055.
- Mecke A, Majoros IJ, Patri AK, Baker JR Jr., Holl MM and Orr BG. Lipid bilayer disruption by polycationic polymers: the roles of size and chemical functional group. Langmuir 2005; 21: 10348–10354.
- Hong S, Leroueil PR, Janus EK, Peters JL, Kober MM, Islam MT, Orr BG, Baker JR Jr. and Holl MM. Interaction of polycationic polymers with supported lipid bilayers and cells: nanoscale hole formation and enhanced membrane permeability. Bioconjugate Chemistry 2006; 17: 728–734.
- Seib FP, Jones AT and Duncan R. Comparison of the endocytic properties of linear and branched PEIs, and cationic PAMAM dendrimers in B16f10 melanoma cells. Journal of Control Release 2007; 117 : 291–300.
- Morgan MT, Carnahan MA, Immoos CE, Ribeiro AA, Finkelstein S, Lee SJ and Grinstaff MW. Dendritic molecular capsules for hydrophobic compounds. Journal of American Chemical Society 2003; 125: 15485–15489.
- Morgan MT, Carnahan MA, Finkelstein S, Prata CA, Degoricija L, Lee SJ and Grinstaff MW, Dendritic supramolecular assemblies for drug delivery, Chemical Communications (Camb) 2005; 4309–4311.
- Morgan MT, Nakanishi Y, Kroll DJ, Griset AP, Carnahan MA, Wathier M, Oberlies NH, Manikumar G, Wani MC and Grinstaff MW. Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention afford enhanced anticancer activity in vitro. Cancer Research 2006; 66: 11913–11921.
- Khandare JJ, Jayant S, Singh A, Chandna P, Wang Y, Vorsa N and Minko T. Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of paclitaxel. Bioconjugate Chemistry 2006; 17 :1464–1472
- Ooya T, Lee J and Park K. Star-shaped poly (ethylene glycol monomethacrylate) and polyglycerol dendrimers as new drug delivery systems. Polymer Preprints, Division of Polymer Chemistry ACS 43 2002; 2: 717– 718.
- Haag R, Sunder A, Stumbe F. An approach to glycerol dendrimers and pseudo-dendritic polyglycerols. Journal of American Chemical Society 2000; 122: 2954–2955.
- Tooru Ooyaa, Jaehwi Leeb, Kinam Park, Effects of ethylene glycol-based graft, star-shaped, and Dendritic polymers on solubilization and controlled release of paclitaxel, Journal of Controlled Release 2003;93: 121– 127.
- Wang F, Bronich TK, Kabanov AV, Rauh RD and Roovers J. Synthesis and evaluation of a star amphiphilic block copolymer from poly (epsilon-caprolactone) and poly(ethylene glycol) as a potential drug delivery carrier. Bioconjugate Chemistry 2005;16(2):397-405
- Sahoo S, Sanjeeb K., Fahima D, and Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discovery Today 2008; 13(3/4): 144-151.
- Saettone and Marco Fabrizio. Progress and Problems in Ophthalmic Drug Delivery. Business Briefing: Pharmatech. 2002:167-171.
- 40 Desai PN and Yang Hu. Synthesis and Characterization of Photocurable Polyionic Hydrogels. Personal Communication.
- Milhem OM, Myles C, Mc Keown NB, Attwood D and D’Emanuelle A. Polyamidoamine StarburstR dendrimers as solubility enhancers. International Journal of Pharmaceutics 2000; 197: 239–241.
- Bhadra D, Bhadra S, Jain S and Jain NK. A pegylated dendritic nanaparticulate carrier of fluorouracil. International Journal of Pharmaceutics 2003; 257:111 –124.
- Vandamme ThF and Brobeck L. Poly(amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide. Journal of Controlled Release 2005;102 :23–38
- Joaquim Miguel Oliveiraa,b, António José Salgadoc, Nuno Sousac, João Filipe Manoa,b,
- Rui Luís Reisa. Dendrimers and derivatives as a potential therapeutic tool in regenerative medicine strategies. Progress in Polymer Science 2010.
- Duan X and Sheardown H. Dendrimer crosslinked collagen as a corneal tissue engineering scaffold: mechanical properties and corneal epithelial cell interactions. Biomaterials 2006; 27:4608–17.
- Grinstaff MW. Designing hydrogel adhesives for corneal wound repair. Biomaterials 2007; 28:5205–14.
- Csaba N, Garcia-Fuentes M and Alonso MJ. Expert Opinion on Drug Delivery 2006; 3: 463–478.
- 48Gajbhiye V, Vijayaraj Kumar P, Sharma A, Agarwal A, Asthana A andJain NK. Dendrimeric nanoarchitectures mediated transdermal and oral delivery of bioactives. Indian Journal of Pharmaceutical Science. 2008; 70(4): 431-439.
Demanuele A, Jevprasesphant R, Penny J and Attwood D. The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability. Journal of Control Release 2004; 95:447-453.
- Purohit G, Sakthivel T and Florence AT. The interaction of cationic dendrons with albumin and their diffusion through cellulose membranes. International Journal of Pharmaceutics 2003; 254: 37-41.
- Najlah M, Freeman S, Attwood D and D’Emanuele A. In vitro evaluation of dendrimer prodrugs for oral drug delivery. International Journal of Pharmaceutics 2007; 336: 183–190.
- Chauhan AS, Sridevi S, Chalasani KB, Jain AK, Jain SK and Jain NK. Dendrimer mediated transdermal delivery: Enhanced bioavailability of indomethacin. Journal of Control Release 2003; 90:335-43.
- Cheng Y, Man N, Xu T, Fu R, Wang X and Wen L. Journal of Pharmaceutical Sciences 2007;96: 595–602.
- Wang Z, Itoh Y, Hosaka Y, Kobayashi I, Nokano Y and Maeda I, Novel transdermal drug delivery system with Polyhydroxyalkanoate and starburst polyamidoamine dendrimer. Journal of Biosciences and Bioengineering 2003; 95:541-3.
- Shuhua B and Fakhrul A. Synthesis and Evaluation of Pegylated Dendrimeric Nanocarrier for Pulmonary Delivery of Low Molecular Weight Heparin. Pharmaceutical Research 2004; 26(3): 539-548.
- Iyer AK, Khaled G, Fang J and Maeda H, Exploiting the enhanced permeability and retention effect for tumor targeting, Drug Discovery Today 2006;11: 812–818.
- Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR Jr., Banaszak Holl MM. The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chemistry and Biology 2007; 14: 107–115.
- Patri AK, Kukowska-Latallo JF, Baker JR Jr. Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. Advance Drug Delivery Review 2005; 57: 2203–2214.
- Thomas TP, Majoros IJ, Kotlyar A, Kukowska-Latallo JF, Bielinska A, Myc A, Baker JR Targeting and inhibition of cell growth by an engineered dendritic nanodevice, Journal of Medicinal Chemistry 2005; 48: 3729–3735.
- Majoros IJ, Myc A, Thomas T, Mehta CB, Baker JR Jr . PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules 2006; 7: 572–579.
- Sigal, GB, Mammen M, Dahmann G and Whitesides GM. Polyacrylamides bearing pendant _-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus: The strong inhibition reflects enhanced binding through cooperative polyvalent interactions. Journal of American Chemical Society 1996; 118: 3789–3800.
- Roy R, Zanini D, Meunier SJ and Romanowska A. Solid-phase synthesis of Dendritic sialoside inhibitors of influenza A virus haemagglutinin. Journal of Chemical Society and Chemical Communication 1993; 1869–1872.
- Zanini D and Roy R. Practical synthesis of Starburst PAMAM _-thiosialodendrimers for probing multivalent carbohydrate-lectin binding properties. Journal of Organic. Chemistry 1998; 63: 3486–3491.
- Gong Y, Matthews B, Cheung, Tam T, Gadawski I, Leung D, Holan G, Raff J and Sacks S. Evidence of dual sites of action of dendrimers: SPL-2999 inhibits both virus entry and late stages of herpes simplex virus replication. Antiviral Research 2002; 55: 319– 329.
- Witvrouw M, Fikkert V, Pluymers W, Matthews B, Mardel K, Schols D, Raff J, Debyser Z, DeClercq E, Holan G and Pannecouque C. Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (Reverse transcriptase/integrase) in the virus replicative cycle. Molecular Pharmacology 2000; 58: 1100– 1108.
- Chen CZ and Cooper SL. Interactions between dendrimers biocides and bacterial membranes, Biomaterials 2002; 23: 3359– 3368.
- Chen CZ, Beck-Tan NC, Dhurjati P, Van Dyk TK, LaRossa RA and Cooper SL. Quaternary ammonium functionalized poly (propylene imine) dendrimers as effective antimicrobials:structure–activity studies. Biomacromolecules 2000; 1: 473– 480.
- Nagahori N, Lee RT, Nishimura S, Page D, Roy R and Lee YC. Inhibition of adhesion of type 1 fimbriated Escherichia coli to highly mannosylated ligands. Chem Bio Chem 2002; 3:836– 844.
- Lebreton S, Newcombe N and Bradley M. Antibacterial single bead screening. Tetrahedron 2003; 59: 10213– 10222.
- Calabretta M K, Amit Kumar, McDermott A M, and Chengzhi Cai. Antibacterial Activities of Poly (amidoamine) Dendrimers Terminated with Amino and Poly (ethylene glycol) Groups. Biomacromolecules 2007; 8(6): 1807–1811.
- Bielinska AU, Chen C, Johnson J, Baker JR DNA complexing with polyamidoamine dendrimers: implications for transfection. Bioconjugate Chemistry 1999; 10: 843–850.
- Shah DS, Sakthivel T, Toth I, Florence AT, Wilderspin AF. DNA transfection and transfected cell viability using amphipathic asymmetric dendrimers. International Journal of Pharmaceutics 2000; 208: 41–48
- Tang MX and Szoka FC. The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes. Gene Therapy 1997; 4: 823–832.
- Zinselmeyer BH, Mackay SP, Schatzlein AG and Uchegbu IF. The lower-generation polypropylenimine dendrimers are effective gene-transfer agents. Pharmaceutical Research 2002; 19: 960– 967.
- Gebhart CL and Kabanov AV. Evaluation of polyplexes as gene transfer agents. Journal of Control Release 2001; 73:401– 416.
- Kukowska-Latallo JF, Chen C, Raczka E, Qunintana A, Rymaszewski M and Baker JR. Human Gene Therapy 2000; 11:1385–1395.
- Wiener EC, Tomalia DA and Lauterbur PC. Relaxivity and stabilities of metal complexes of starburst dendrimers: a new class of MRI contrast agents, inWorks in Progress, Society of Magnetic Resonance in Medicine, 9th Annual Meeting and Exhibition, New York, New York, p. 1106.
- Wiener EC, Brechbiel MW, Brothers H, Magin RL, Gansow OA, Tomalia DA, Lauterbur PC, Dendrimer-based metal chelates: a new class of magnetic resonance imaging contrast agents, Magnetic Resonance in Medicine 1994; 31: 1 – 8.
- Kobayashi H and Brechbiel MW. Dendrimer-based macromolecular MRI contrast agents: characteristics and application, Molecular Imaging 2003; 2:1– 10.
- Wiener EC, Auteri FP, Chen JW, Brechbiel MW, Gansov OA, Schneider DS, Belford RL, Clarkson RB and Lauterbur PC. Molecular dynamics of ion–chelate complexes attached to dendrimers. Journal of American Chemical Society 1996; 118: 7774– 7782.
- Wu G, Barth RF, Yang WL, Chatterjee M, Tjarks W, Ciesielski MJ and Fenstermaker RA. Site-specific conjugation of boron-containing dendrimers to anti-EGF receptor monoclonal antibody cetuximab (IMC-C225) and its evaluation as a potential delivery agent for neutron capture therapy. Bioconjugate Chemistry 2004; 15: 185–194.
Kawase M, Kurikawa N, Higashiyama S, Miura N, Shiomi T and Ozawa C. Effectiveness of polyamidoamine dendrimers modified with tripeptide growth factor, glycyl-l-histidyl-l-lysine, for enhancement of function of hepatoma cells. Journal of Biosciences and Bioengineering 1999; 88:433–7
U. Y. Kandekar*, P. D. Chaudhari , V. S. Tambe , V. S.Vichare and S. N.Dhole
PES’s Modern college of Pharmacy (For Ladies), Borhadewadi, Dehu- Alandi Road, Moshi, Pune, Maharashtra, India
21 January, 2011
26 February, 2011
12 April, 2011
01 May, 2011