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| REVIEW ARTICLE |
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| Year : 2014 | Volume
: 6
| Issue : 3 | Page : 139-150 |
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Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues
Kanika Madaan1, Sandeep Kumar1, Neelam Poonia1, Viney Lather2, Deepti Pandita1
1 Department of Pharmaceutics, J. C. D. M. College of Pharmacy, Sirsa, Haryana, India
2 Department of Pharmaceutical Chemistry, J. C. D. M. College of Pharmacy, Sirsa, Haryana, India
| Date of Submission | 05-Sep-2013 |
| Date of Decision | 29-Sep-2013 |
| Date of Acceptance | 14-Nov-2013 |
| Date of Web Publication | 24-Jun-2014 |
Correspondence Address:
Deepti Pandita
Department of Pharmaceutics, J. C. D. M. College of Pharmacy, Sirsa, Haryana
India
 Source of Support: The Science and Engineering
Research Board, Department of Science and Technology,
Government of India is acknowledged for funding through the project
SR/FT/LS.145/2011, Conflict of Interest: None  | Check |
DOI: 10.4103/0975-7406.130965
 Abstract | | |
Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. Keywords: Dendrimer, drug targeting, drug-dendrimer interactions, gene delivery, polyamidoamine
How to cite this article:
Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. J Pharm Bioall Sci 2014;6:139-50 |
How to cite this URL:
Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. J Pharm Bioall Sci [serial online] 2014 [cited 2021 Apr 15];6:139-50. Available from: https://www.jpbsonline.org/text.asp?2014/6/3/139/130965 |
Several therapeutic agents suffer from various limitations like low aqueous solubility and short half-life. Therefore it is necessary to design a delivery system, which can deliver a drug efficiently. Conventional drug delivery systems are useful to some extent in overcoming these issues, but they have failed to prove their effectiveness in delivering many drugs. Nanoparticle assisted drug delivery provides a platform to modify the basic properties of drug molecules viz. solubility, half-life, biocompatibility and its release characteristics. Several nanoparticle based therapeutic products have been launched in the market while some are under clinical and preclinical trials. [1] Liposomes and polymeric-drug conjugates hold the maximum share of it. For instance, Doxil® (doxorubicin HCl liposome injection) [2] and Abraxane® (paclitaxel protein-bound particles for injectable suspension) [3] are administered as first-line treatments in various cancer types. The stability and toxicity issues associated with these technologies has remained a matter of concern untilnow. [1] The traditional linear polymers viz. polyethylene glycol (PEG), polyglutamic acid, polysaccharide, poly (allylamine hydrochloride) and N-(2-hydroxypropyl) methylacrylamide have been reviewed as drug delivery vehicles and accepted for clinical use, [4] but these linear polymers have poorly defined chemical structures. In this scenario, many attempts have been made to alleviate the problems associated with them. Moreover, the considerable interest of scientists in delivering therapeutic, targeting and diagnostic agents together in a single system has led to the usage of the novel class of nanoparticles as multifunctional platforms. The introduction of highly branched, well-defined molecular architectural polymers, i.e. Dendrimers, firstly in 1978 by Vogtle has provided a novel and one of the efficient nanotechnology platforms for drug delivery. [5]
Dendrimers are three-dimensional, immensely branched, well-organized nanoscopic macromolecules (typically 5000-500,000 g/mol), possess low polydispersity index and have displayed an essential role in the emerging field of nanomedicine. The name has actually derived from the Greek word "dendron" meaning "tree," which indicates their unique tree-like branching architecture. They are characterized by layers between each cascade point popularly known as "Generations." The complete architecture can be distinguished into the inner core moiety followed by radially attached generations that possess chemical functional groups at the exterior terminal surface [Figure 1]. [6],[7] With the increase in generations, the molecular size and terminal surface groups amplifies that offer wide potential for multiple interactions and hence termed as highly functional [Figure 2]. This multivalency has subjected to the formation of various host-guest complexes that offer wide applications. [Table 1] highlights the different commercialized dendrimers and dendrimer-based products. The present review highlights the different strategies for their synthesis, recent updates in drug delivery applications, the specific interactions playing a significant role in entrapment/conjugation of drugs, the characterization techniques of dendrimers and their drug conjugates, several aspects of dendrimers like toxicity issues and other applications. | Table 1: List of commercially available dendrimers and dendrimer-based products
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 | Figure 1: Schematic representation of dendrimer components. Reproduced with permission from ref.,[7] Copyright 2005, Elsevier
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| Technology Platforms | |  |
The advances and innovations of polymer science and architectural chemistry have resulted in the development of dendrimers as multifunctional highly branched polymeric systems. Various dendritic platforms such as polyamidoamine (PAMAM), poly (propylene imine) (PPI), poly-L-lysine, melamine, poly (etherhydroxylamine) (PEHAM), poly (esteramine) (PEA) and polyglycerol have been synthesized and explored as drug delivery vehicles. [7],[18] The synthesis of dendrimers can be traced back to 1980's when D. Tomalia used "divergent methodology" to synthesize them. The strategy involves the coupling of monomeric molecules that possesses reactive and protective groups with the multifunctional core moiety which leads to stepwise addition of generations around the core followed by removal of protecting groups. PAMAM-NH 2 dendrimers were firstly synthesized by coupling N-(2-aminoethyl) acryl amide monomers to an ammonia core and today they are the most systematically synthesized and commercialized family of dendrimers using this methodology. This method offers an advantage of producing modified dendrimers by changing the end groups and in turn their physicochemical properties can be altered as per the required application. Although, this approach suffers from limitation of structural defects due to incomplete reaction of groups which can be trounced by the excessive addition of monomeric units. [6],[19]
Another approach "convergent methodology" of synthesizing dendrimers was pioneered by Hawker and Frechet in 1990's. This strategy refers to the inward growth by gradually assembling surface units with reactive monomers. This approach produces more homogenous and prιcised molecular weight products. The deactive side products produced during reactions gets easily separated by purification, but this becomes harder in higher generations due to similarity in products and reactants. The convergent methodology suffers from one major limitation that it gives low yield in the synthesis of large structures and hence is suitable for production of only lower generation dendrimers. [20] These synthesis methodologies are presented in [Figure 3]. | Figure 3: Schematic representation of dendrimer synthesis by (a) Divergent and (b) Convergent methodologies
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Other approaches that have been employed for dendrimer synthesis include "Hypercore and branched monomers"; "Double exponential"; "Lego chemistry" and "Click chemistry." The first approach involves the pre-assembly of oligomeric species to accelerate the production of dendrimers in few steps with high yield, [21] whereas the double exponential approach follows the production of monomer unit for both divergent and convergent growth from a single functionalized group. The produced monomer units are allowed to react, which produces an orthogonally protected trimer that is grown further. Advantages of this method include accelerated synthesis of dendrimers and this method can be applied to both convergent and divergent method. [21] Lego chemistry approach employed by Tomalia and Svenson involves the production of phosphorus dendrimers by utilizing highly functionalized core and branched monomers. Several changes have been made to the basic scheme of synthesis and more refined schemes are being developed, which involves the multiplication of terminal surface groups from 48 to 250 in one step. [22] The same authors used click chemistry method in successful production of triazole dendrimers using Cu (I)-catalyzed click chemistry reactions. Again, this methodology is involved in hasten synthesis of dendrimers by divergent approach with high purity and excellent yield. This technique involves the reaction of two different monomeric units of complimentary functionalities that render spontaneous synthesis by avoiding the use of activating agents/protecting groups and reducing the number of steps. [19] More future work is needed to find out the cost-effective synthesis strategies for successful commercialization of this technology.
| Dendrimers for Drug Delivery and Targeting | | |
The precise control over the distribution of drugs is highly valuable to abolish the typical drawbacks of traditional medicine. Thus, a drug delivery system should be designed to attain the site-specific delivery preferentially. In recent years, improved pharmacokinetics, biodistribution and controlled release of the drug to the specific targeted site has been achieved with polymer based drug delivery. [23] Unlike traditional polymers, dendrimers have received considerable attention in biological applications due to their high water solubility, [24] biocompatibility, [25] polyvalency [12] and precise molecular weight. [26] These features make them an ideal carrier for drug delivery and targeting applications. For investigating dendrimers as drug delivery vehicles, their biopermeability across the biological membranes should be considered. A study by Kitchens et al. reviewed the cationic PAMAM-NH 2 (G0-G4) dendrimers and evaluated its permeability across Caco-2 cell monolayers as a function of dendrimer generation, concentration and incubation time, for oral drug delivery. Various parameters viz. transepithelial electrical resistance, 14 C-mannitol permeability and leakage of lactate dehydrogenase enzyme were studied and it was suggested that these amine terminated PAMAM dendrimers could cross the biological membranes possibly by paracellular and endocytosis pathways. [27] Moreover, by optimizing the size and surface charge, these dendritic platforms can be developed into oral delivery systems.
Different categories of drugs that have been incorporated in these versatile nanoscopic carriers as summarized in [Table 2]. Recently, a dendrimer based prodrug has been developed for paclitaxel (P-gp efflux substrate) that has focused on enhancement of permeability and transportation of drug across cellular barriers. The highly functional lauryl-modified G3 PAMAM dendrimer-paclitaxel conjugates demonstrated good stability under physiological conditions and 12-fold greater permeability across Caco-2 cell and porcine brain endothelial cells monolayers than paclitaxel alone. Finally, the authors concluded that surface-modified G3 PAMAM dendrimers could be considered as potential nanocarriers for poorly water-soluble P-gp efflux transporter drugs. [32] Earlier Ooya et al. reported 400 times increase in the solubility of paclitaxel when incorporated in polyglycerol dendrimers. [30] | Table 2: Different therapeutic moieties studied using dendrimer platform
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The targeted delivery of chemotherapeutics is essential to reduce the side effects significantly associated with conventional therapy, where healthy tissues such as liver, spleen, kidneys and bone marrow can accumulate the toxic levels of drug. The site specific delivery of the drug could be achieved by surface modification of dendrimers employing various targeting moieties such as folic acid (FA), peptides, monoclonal antibodies and sugar groups. [56] Several successful active and passive targeting attempts were accomplished by engineering the branching units and surface groups of dendrimers. Patri et al. conjugated FA to G5 PAMAM dendrimer for the targeted delivery of methotrexate and observed receptor mediated drug delivery that demonstrated high specificity for KB cells overexpressing folate receptors and showed slower drug release. [35] The authors further conjugated the PhiPhiLux G1 D2, an apoptotic sensor to FA attached PAMAM dendrimers which showed 5 fold enhanced fluorescence, attributed to successful delivery of drug with cell-killing efficacy. [57] FA conjugated G5 PAMAM dendrimers for the targeted delivery of 2-methoxyestradiol to cancer cells, as confirmed by MTT assay, were recently reported. [58] Sideratou et al. prepared folate functionalized PEG coated nanocarrier based on fourth generation diaminobutane PPI dendrimers for targeted delivery of etoposide. [59] The encapsulation of the drug inside the dendrimeric scaffold resulted in enhanced solubility of etoposide, further the in vitro release of encapsulated drug from these functionalized dendrimers was found to be sustained and comparable to the non-functionalized dendrimers. These folate PEGylated dendrimers exhibited specificity for folate receptor with low toxicity. Furthermore, successful conjugation of FA to fifth generation PPI dendrimers was explored and its potential in targeted delivery of an anticancer drug doxorubicin was investigated. The results revealed that FA conjugated dendrimers displayed higher cell uptake in MCF-7 cancer cell lines and significantly reduced the toxicity. [60]
Further, Patri et al. group explored the usage of monoclonal antibodies for site-specific delivery by conjugating prostate specific membrane antigen (PSMA) J591, an anti-PSMA to G5 PAMAM dendrimers that showed targeted delivery in all prostate and non-prostate tumors. [61] Methotrexate bound to G5 PAMAM conjugate containing cetuximab [62] or anti- human epidermal growth factor receptor-2 [63] monoclonal antibodies have demonstrated their potential in tumor targeted drug delivery.
Using glycosylated dendrimers, terminally modified with sugar moieties is another strategy for targeting applications. In a study, colchicine was successfully conjugated with glycodendrimer that showed selective 20-100 times inhibition of HeLa cells than healthy cells. [64] A study done by Ciolkowski et al. examined the influence of dendrimers' surface modification on the strength of interaction with proteins. This study was carried out using PPI G4 and G3.5 PAMAM dendrimers as a drug carrier and hen egg white lysozyme as a model protein. As shown by differential scanning calorimetry (DSC) and circular dichroism studies the increasing maltose modification on the surface of PPI dendrimers resulted in diminishing ability of dendrimer to interact with lysozyme because the surface charge of complexes turned neutral from cationic. [65] In addition, a comparably strong influence exerted on lysozyme by positively charged PPI dendrimer and negatively charged PAMAM dendrimer.
| Dendrimers for Gene Delivery | | |
Gene transfer is an invaluable experimental tool that involves the introduction of new genetic material to host for treatment of diseases. Various vectors and physical methods are reported for in vivo delivery of therapeutic nucleic acids. Commonly two approaches viz. viral and non-viral based are being used to facilitate the transfer of genetic material successfully to target cells. Although viral carriers can achieve rapid transfection, but immunological and oncologic adverse effects associated with these vectors has remained a topic of concern. Non-viral gene delivery vectors offer the usage of natural/synthetic molecules or physical forces to transfer genetic material to targeted cells. Several advantages such as ease of fabrication, targeting ability, potential for repeat administration and low immune response have led to the usage of non-viral vectors preferably for gene therapy. Santos et al. extensively reviewed various physical and chemical methods for non-viral gene delivery, dendrimers based vectors and their applications in tissue engineering and regeneration. [66] Among various commercially available dendrimers, PAMAM dendrimers have received the most attention as potential non-viral gene delivery agents due to their cationic nature which enables deoxyribonucleic acid (DNA) binding at physiological pH. [67] Pandita et al. prepared dendrimer based gene delivery vectors taking advantage of the cationic nature and the "proton-sponge" effect of these dendrimers. Arginine-glycine-aspartic (RGD) nanoclusters were formed by conjugation of G5 and G6 PAMAM dendrimers with a varying number of peptides containing the RGD motif, in view of its targeting capabilities [Figure 4]a. Authors reported that the system wherein G6 PAMAM dendrimer was conjugated to eight peptide arms (RGD8-G6) enhanced the gene expression in mesenchymal stem cells and presented a 2-fold higher bone morphogenetic protein-2 expression in comparison to the G6 native dendrimer. [68] Various published literature suggests that functionalized dendrimers are much less toxic than the native dendrimers. Same group synthesized a new family of gene delivery vectors consisting of G5 PAMAM dendrimer core randomly linked to hydrophobic chains (with varying chain length and numbers) [Figure 4]b. In vitro studies revealed a remarkable capacity of these vectors for internalizing pDNA with very low levels of cytotoxicity, being this effect positively correlated with the CH 2 content present in the hydrophobic moiety. The results demonstrated that vectors containing the smallest hydrophobic chains (La1-G5 and La2-G5 functionalized dendrimers) showed the higher gene expression efficiency. [69] Further, functionalized PAMAM dendrimers exhibited low cytotoxicity and receptor-mediated gene delivery into mesenchymal stem cells and transfection efficiencies superior to those presented by native dendrimers and by partially degraded dendrimers. [70] A low affinity mesenchymal stem cells binding peptide and a high affinity mesenchymal stem cells binding peptide were conjugated with PAMAM dendrimers in the studies, providing for a mechanism of cell specific recognition [Figure 4]c. | Figure 4: Schematic representation of polyamidoamine dendrimer-based gene delivery vectors. (a) Schematic illustration of the synthesis of dendrimer/RGD conjugates (pathway A + B) and of the indirect estimation of the number of pyridyldithiol (PDP) units per dendrimer by spectrophotometry (pathway A + C). Reproduced with permission from ref.,[68] Copyright 2011, American Chemical Society. (b) Strategy of synthesis followed in dendrimer surface functionalization with alkyl chains (activation of the fatty acid + conjugation reaction). Reproduced with permission from ref.,[69] Copyright 2010, Elsevier. (c) The two-step reaction for the synthesis of peptide-functionalized G5 PAMAM dendrimers (pathway A + B), and for indirect estimation of the number of peptide units by spectrophotometry (pathway A + C). Reproduced with permission from ref.,[70] Copyright 2010, American Chemical Society
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The antigen-presenting cells specific delivery of DNA by peptide functionalized G5 PAMAM dendrimers is also described. In vivo study on mice suggested that functionalized PAMAM dendrimer complexes can be used for effective targeting to antigen-presenting cells so as to achieve high transfection efficiency. [71] More recently, Bai et al. investigated the efficacy of arginine-modified PAMAM dendrimers in delivering human interferon beta gene on a xenograft brain tumor mice model. The study revealed that functionalized dendrimers reduce the tumor size effectively, which confirms the tumor targeting potential of peptide functionalized dendrimers. [72]
Recently, Shan et al. reported a novel non-viral gene delivery vector based on dendrimers-entrapped gold nanoparticles synthesized using amine-terminated G5. NH 2 dendrimers as templates with different Au atom/dendrimer molar ratios, which showed higher transfection efficiency than that of dendrimers without Au nanoparticles entrapped. [73] Ferenc et al. investigated dendriplexes formed by short interfering RNA (siRNA) and cationic phosphorus dendrimers. The siRNA conjugated dendriplexes showed good stability as shown by laser doppler electrophoresis and circular dichroism spectra. [74] Previously, Drzewinska et al. functionalized PPI dendrimers by maltose or maltotriose conjugation and interacted it with anti-human immunodeficiency virus antisense oligonucleotides to form dendriplexes. These carbohydrate-modified PPI G4 dendrimers protected oligonucleotides from nucleolytic degradation at neutral pH but in an acidic environment, the protective effect of these dendrimers was weaker. [75] A high molecular weight bioreducable polymer was synthesized by Nam et al. for gene delivery by incorporating arginine-grafted poly (disulfide amine) into the PAMAM dendrimer. The resultant polyplexes significantly enhanced the cellular uptake and were less susceptible to reducing agents, ensuing superior transfection efficiency. [76]
| Drug-Dendrimer Interactions | | |
Dendrimers offer several mechanisms of interactions with different classes of drugs. The different types of drug-dendrimer interactions proposed for drug delivery are presented in [Figure 5]. [77] Broadly these interactions can be categorized under two categories viz. physical and chemical bonding. | Figure 5: Different types of drug-dendrimer interactions. The darkened oval represents an active substance. Reproduced with permission from ref.,[77] Copyright 2002, Elsevier
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Physical bonding
Incorporation of small organic molecules may be a result of non-bonding interactions with specific groups within dendrimer, i.e. just physical entrapment. Dendrimers can be used as dendritic boxes and unimolecular micelles (dendrimer-drug networks) for the incorporation of hydrophobic/hydrophilic molecules by host guest interactions inside their empty cavities (nanoscale containers) present around core. [78],[79] Jansen et al. were the first to entrap the rose bengal dye molecules in PPI dendrimers by using tert-butyloxycarbonyl (t-Boc) groups and led to the production of stable dendritic box that possess the bulky amino groups on the dendrimer surface. [80] The dendritic unimolecular micelles contain the hydrophobic cores surrounded by hydrophilic shells and they offer an advantage over conventional polymeric micelles such that the micellar structure is maintained at all the concentrations because the hydrophobic segments are covalently connected.
Chemical bonding
Alternatively, the exploitation of well-defined multivalent aspect of dendrimers allows the attachment of drug molecules to its periphery that result in complex formation. The resultant complexes are formed either due to the electrostatic interactions between the drug and dendrimer or conjugation of the drug to dendrimer molecule. Through electrostatic interactions, various ionizable drugs form complexes with the large number of ionizable terminal surface groups of dendrimers. In PAMAM dendrimers, both primary amine and tertiary amine groups present on the surface and within the core respectively are titrable and has pKa values of 10.7 and 6.5 respectively. [81] Hence, they possess the ionizable groups terminally as well as within their core and thus offer potential sites for drug interactions. Many of the drugs such as ibuprofen, [82] piroxicam, [83] indomethacin, [84] benzoic acid [85] have shown to form stable complexes through electrostatic interactions.
Moreover, the drugs can be covalently conjugated to dendrimers through some spacers that may include PEG, p-amino benzoic acid, p-amino hippuric acid and lauryl chains etc., or biodegradable linkages such as amide or ester bonds. This prodrug approach has been found to increase the stability of drugs and has affected their release kinetics significantly. Several researchers have successfully conjugated penicillin V, [86] venlafaxine, [87] 5-aminosalicylic acid, [88] naproxen, [50] propranolol [49] with PAMAM dendrimers. The results have shown the enhanced solubility and controlled release of drugs from these complexes in comparison to the pure drug. Apart from these, many anticancer drugs viz. cisplatin, [89] doxorubicin, [37] epirubicin, [90] methotrexate [24] and paclitaxel [33] have also been conjugated and used for drug targeting. For example, epirubicin prodrug was developed by conjugating it with PEG dendrimers containing aminoadipic acid as branching molecules. These conjugates exhibited increased blood residence time and showed improved therapeutic action. The study revealed that PEG dendrimers increased the stability of bound drug toward chemical degradation and hence can be used potentially in the development of prodrugs of large molecules. [90]
| Physicochemical Characterization of Dendrimers | | |
Various analytical techniques have been reported in literature to analyze the physicochemical parameters of dendrimers. It includes spectroscopic, dynamic light scattering (DLS), microscopic, chromatographic, rheological, calorimetric and electrophoretic characterization: Nuclear magnetic resonance (NMR), infrared, ultraviolet (UV)-Visible, fluorescence and mass spectroscopy; small angle X-ray scattering, small angle neutron scattering, laser light scattering; atomic force microscopy (AFM), transmission electron microscopy (TEM); size exclusion chromatography, high performance liquid chromatography (HPLC); DSC, temperature modulated calorimetry and dielectric spectroscopy; Polyacrylamide gel electrophoresis (PAGE) and capillary electrophoresis [Figure 6]. [91],[92] All these dendrimer characterization techniques can also be used to study the dendrimer-drug conjugates/complexes. Encapsulation of drug molecules or nanoparticles by dendrimers can be characterized by TEM, UV-Visible and Fourier transform infrared spectroscopy. Moreover, NMR and mass spectroscopic techniques are used to study the nature of complexes. Huang et al. characterized the silybin-PAMAM complexes by NMR and HPLC methods. Chemical shifts of methylene protons of the G2 dendrimers were determined by NMR spectroscopy which apparently was changed with the addition of silybin. [93] The downfield chemical shift in the outermost layer of the G2 dendrimer and the interior methylene protons confirmed the electrostatic interactions between the amine functional groups of the dendrimer and the phenolic hydroxyl groups of silybin; and the encapsulation of silybin molecules by hydrophobic interactions, respectively. HPLC method was used to determine the solubility of silybin and plasma drug concentration of silybin. | Figure 6: Various analytical techniques employed for the physicochemical characterization of dendrimers
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The shape and size of paclitaxel solubilized micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly (butylene oxide) (B)-poly (ethylene oxide) (E) block copolymer B16E42(BE) with a G2 PAMAM dendrimer were examined by DLS and cryo-TEM. The studies indicated that spherical micelles got transformed to worm-like micelles of the BE copolymer as a result of encapsulation of paclitaxel molecules. [33] Morilla et al. explored the potential of different generations of PAMAM dendrimers (G4, G5, G6 and G7) to deliver siRNA. [94] The formed complexes were investigated for three variables: The ionic strength of the medium (with or without 150 mM NaCl), G4, G5, G6 and G7 dendrimer generations and N/P ratio, i.e. nitrogen amines in PAMAM/phosphate in siRNA. Various analytical techniques viz. PAGE, DLS, TEM and AFM were used to characterize these variables. PAGE study revealed that in order to complexate the whole available siRNA molecules, a minimum N/P ratio of 5 (for G4, G5) and 10 (for G6, G7), was required. The sizes obtained using DLS, TEM and AFM provided the inverse relationship between size of the formed complex and its binding affinity; and also between the size of the complex and ionic strength of preparation media. Finally, the measured zeta potential of small siRNA PAMAM dendrimer complex was found to reduce from + 25 mV to 0, when drops of sodium chloride were added to the medium due to the formation of larger complexes or even aggregates. The results together indicated that ionic strength of the media was the main determinant of the size of siRNA-dendrimer complex and responsible for the inhibition of enhanced green fluorescent protein expression (silencing activity).
Recently, PAMAM and PPI dendrimers were synthesized by introducing 1,3 propane sultone in tertiary amine of these dendrimers and 1 H NMR studies were performed to calculate their degrees of acetylation and interior-functionalization. The spectrum obtained using correlation spectroscopy revealed J-coupled protons (geminal or vicinal protons) via cross-correlation peaks off the diagonal, which was further used to confirm the structure of the synthesized dendrimers. Further, 1 H- 1 H nuclear overhauser effect spectroscopy (NOESY) was used to characterize the inclusion structure of the synthesized dendrimer and methotrexate sodium complexes that mainly revealed the spatial conformation of dendrimer/drug complexes. The presence of nuclear overhauser effect signals between guest protons and dendrimer interior protons in a 1 H- 1 H NOESY spectrum suggested the encapsulation of the guest molecules within the pockets of dendrimers. [95]
| Toxicity Issues | | |
It is well-known that cationic macromolecules interact with negative biological membranes that result in their destabilization and cause cell lysis. [96],[97] The nanosized particles like dendrimers have the ability to interact with nanometric cellular components such as cell membrane, cell organelles and proteins. [98] Similar to macromolecules, dendrimers with cationic surface groups tend to interact with lipid bilayer, increases the permeability and decreases the integrity of biological membrane. The mechanism involved is the leakage of cyotosolic proteins such as luciferase and lactate dehydrogenase, on interaction of dendrimers with the cell membrane that finally causes its disruption and cell lysis. [99],[100] Typical representatives of this class of carriers are PAMAM-(Starburst™), PPI and polylysine-dendrimers. Among them, PAMAM dendrimers are shown to cause concentration and generation dependent cytotoxicity and hemolysis. [99],[101] In an article in 2003, Jevprasesphant et al., investigated the cytotoxicity of PAMAM dendrimers using Caco-2 cells and concluded that anionic or half generation dendrimers show significantly low toxicity in comparison to their respective cationic family. [102] Further, the in vitro cytotoxicity of cationic melamine dendrimers having surface groups such as amine, guanidine, carboxylate, sulfonate or phosphonate were reported and it was concluded that cationic dendrimers were much more cytotoxic than anionic or PEGylated dendrimers. [99] In a study, membrane disruption and loss of Caco-2 microvilli was reported when the cells were treated with 0.1 mM or higher concentration of G4-NH 2 , whereas the cells remained unaffected when treated with G3.5-COOH at the same concentration. [103] Extensive in vitro studies have been performed to assess the toxicity of various modified or native dendrimers on different cell lines. Few scientists also report the essential in vivo toxicity of dendrimers. According to the very first in vivo toxicological study, dose of 10 mg/kg appeared to be non-toxic up to fifth generation of PAMAM dendrimers, when G3, G5 and G7 generations were injected into mice and all the tested generations were found to be non-immunogenic. [104],[105] Recently, Jones et al. performed nano-toxicological studies on amine-terminated PAMAM dendrimers that revealed that intravenous administration was lethal to mice and caused disseminated intravascular coagulation-like condition. Using flow cytometry and microscopic analysis it was demonstrated that cationic fluorescein isothiocyanate labeled G7 PAMAM dendrimers caused platelet disruption, whereas neutral (hydroxyl terminated) and anionic (carboxyl terminated) PAMAM dendrimers did not alter platelet morphology or their function. [106] This recent study is in consistent with the previous studies and justifies that the anionic dendrimers are non-toxic in comparison to cationic ones. Tathagata and co-workers also investigated the toxicity profile of the fifth generation PPI dendrimers and some of its surface engineered derivatives. Functionalization with t-Boc, mannose and tuftsin led to the drastic reduction in the toxicity of PPI, this was attributed to the masking of primary amino groups responsible for the positive charge and thus the associated toxicity. Both PPI and surface engineered derivatives did not show any evidence of immunogenicity. Finally, it was concluded from these observations that functionalization of dendrimers leads to the drastic reduction of toxicity and increased biocompatibility. [107]
The oral acute toxicity study on PAMAM dendrimers in immune competent CD-1 mice was done taking size and charge of dendrimers in consideration. The results revealed that cationic dendrimers caused more toxicity than their anionic counterparts. Maximum tolerated doses of dendrimers was determined by a dose escalation study and it was concluded that the dendrimers were safe for oral administration except for G7-NH 2 and G7-OH, which exhibited signs of toxicity at relatively low dosage. [108] In general, two approaches are being reviewed to overcome the in vitro toxicity issues of dendrimer based nanosystems. Either biocompatible/biodegradable dendrimers viz. polyether, polyester or polyether-imine, polyether-copolyester, phosphate, citric acid, melamine, peptide or triazine dendrimers can be synthesized or the peripheral positively charged groups can be masked by acetylation and PEGylation. Moreover, the surface groups can be functionalized with carbohydrate, amino acid, antibody and FA that abates the overall positive charge and further the toxic effect of primary amines/imines. [109] Hence, it can be concluded that neutral and anionic dendrimers do not interact with biological membranes and are mostly compatible for implied clinical relevance.
| Other Applications | | |
The versatility of dendrimers also explains their importance in photodynamic therapy (PDT), boron neutron capture therapy and bioimaging applications.
Dendrimers in PDT
PDT refers to treatment of tumor cells by photosensitizers that on irradiation of light of appropriate wavelength pass their excess energy to nearby molecular oxygen to form reactive oxygen species such as singlet oxygen and free radicals which are toxic to cells and tissues. Dendrimers have been used as promising carriers for improved delivery of 5-aminolevulinic acid (a natural precursor of photosensitizer protoporphyrin 1X) that increases the accumulation of porphyrin in cells, which further results in toxicity. [110],[111],[112] Recently, polymeric micelles encapsulating dendrimer phthalocyanine have been developed as a photosensitizer formulation for enhanced photodynamic effect. [113]
More recently, G3 PAMAM grafted porous hollow silica nanoparticles (PHSNPs) were successfully fabricated as photosensitive drug carriers for PDT. The attachment of gluconic acid (GA) to this system was thereafter followed, for surface charge tuning. PAMAM-functionalized outer layer with a large number of amino groups provided high loading amount of aluminum phthalocyanine tetrasulfonate (AlPcS4), its retarded premature release and effective release to target tissue. The study demonstrated that irradiation of the AlPcS4 entrapped GA-G3-PHSNPs with light resulted in efficient generation of singlet oxygen that produced significant damage to tumor cells and suggested as effective photosensitizer formulation for PDT applications. [114]
Dendrimers in boron neutron capture therapy
Boron therapy is concerned with the treatment of cancers that is based on Boron capture reaction. [115] The applicability of PAMAM dendrimers in investigating intratumoral delivery of agents for neutron capture therapy is remarkable in biomedical science. In a study by Wu et al. functionalized G5 PAMAM dendrimers and conjugated cetuximab specific to EGF receptor to starburst dendrimers that carried around 1100 boron atoms. The in vivo results revealed that accumulation of conjugates were 10 times higher in brain tumor tissues in comparison to healthy brain tissues. This study was first to demonstrate the efficacy of a boronated monoclonal antibody for boron neutron capture therapy of an intracerebral glioma. [116] Dendrimer based boron neutron capture therapy in combination with EGF receptor targeting moieties can enhance the boron uptake in tumor tissues. [117]
Dendrimers as imaging agents
Gadolinium (III) (Gd) the paramagnetic contrast agent for magnetic resonance imaging has been successfully complexed with PAMAM dendrimers over the last decades for visualizing both tumor vasculature and lymphatic involvement. [118],[119] Recently, a tumor targeting biodegradable contrast agent has been developed from Gd chelates and PEG conjugated polyester dendrimer which contains FA at the distal end. This dendrimer conjugate contrasting agent has shown to produce enhanced contrast than commercially available product Magnevist® . Furthermore, it's retention in all the organs was low resulting in reduction of Gd induced toxicity. Thus, these positive outcomes, i.e. enhanced magnetic resonance imaging contrast and low Gd retention makes this dendrimer based biodegradable carrier a promising imaging agent. [120]
Outlook
Last decade has witnessed the amplified growth of usage of dendrimers in biological systems. The exclusive properties viz. well-defined structure, polyvalent character and monodispersity make them effective nanosystems for drug delivery applications. The current review has emphasized on the considerable opportunities that dendrimers offer in resolving fundamental issues of solubility, drug delivery and targeting of drug molecules. In spite of this, their use is constrained due to their high manufacturing cost and further they are not subjected to GRAS status due to the inherent toxicity issues associated with them. As highlighted in the present work, many attempts have been made to resolve the problems pertaining to safety, toxicity and efficacy of dendrimers and more research is going on to develop the functionalized moieties pertaining to its high potential as a nanocarrier. Besides drug delivery, dendrimers have been found to have a great emphasis in gene delivery, boron neutron capture therapy, PDT and as magnetic resonance imaging contrast agents. The use of dendrimers in the clinic has still not reached the success of linear polymers and several applications remain to be explored for its industrial as well as biomedical applications. With improved synthesis, further understandings of their unique characteristics and recognition of new applications, dendrimers will become promising candidates for further exploitation in drug discovery and clinical applications.
| Acknowledgement | | |
The authors would like to thank the Science and Engineering Research Board, Department of Science and Technology, Government of India for funding through the project SR/FT/LS-145/2011.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]
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Removal of heavy metals and organic pollutants from water using dendritic polymers based adsorbents: A critical review |
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| Muhammad Sajid,Mazen Khaled Nazal,Mazen Khaled Ihsanullah,Nadeem Baig,Abdalghaffar Mohammad Osman | | Separation and Purification Technology. 2018; 191: 400 | | [Pubmed] | [DOI] | | | 2 |
Carbosilane metallodendrimers based on copper (II) complexes: Synthesis, EPR characterization and anticancer activity |
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| Natalia Sanz del Olmo,Marta Maroto-Díaz,Rafael Gómez,Paula Ortega,Michela Cangiotti,M. Francesca Ottaviani,F. Javier de la Mata | | Journal of Inorganic Biochemistry. 2017; 177: 211 | | [Pubmed] | [DOI] | | | 3 |
Gd3+-Asparagine-Anionic Linear Globular Dendrimer Second-Generation G2 Complexes: Novel Nanobiohybrid Theranostics |
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| Nasim Hashempour Alamdari,Mahmood Alaei-Beirami,Seyed Ataollah Sadat Shandiz,Hadi Hejazinia,Rahimeh Rasouli,Mostafa Saffari,Seyed Esmaeil Sadat Ebrahimi,Artin Assadi,Mehdi Shafiee Ardestani | | Contrast Media & Molecular Imaging. 2017; 2017: 1 | | [Pubmed] | [DOI] | | | 4 |
Relation between biophysical properties of nanostructures and their toxicity on zebrafish |
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| C. S. Martinez,D. E. Igartúa,M. N. Calienni,D. A. Feas,M. Siri,J. Montanari,N. S. Chiaramoni,S. del V. Alonso,M. J. Prieto | | Biophysical Reviews. 2017; | | [Pubmed] | [DOI] | | | 5 |
Legionella Pneumophila and Dendrimers-Mediated Antisense Therapy |
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| Roghiyeh Pashaei-Asl,Khodadad Khodadadi,Fatima Pashaei-Asl,Gholamreza Haqshenas,Nasser Ahmadian,Maryam Pashaiasl,Reza Hajihosseini Baghdadabadi | | Advanced Pharmaceutical Bulletin. 2017; 7(2): 179 | | [Pubmed] | [DOI] | | | 6 |
Influence of the doxorubicin conjugated PAMAM dendrimer surface charge on cytotoxic effects and intracellular trafficking routes in tumor cells |
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| E. Nikolskaya,N. Yabbarov,O. Zhunina,O. Tereshenko,M. Mollaev,M. Faustova,I. Zamulaeva,E. Severin | | Materials Today: Proceedings. 2017; 4(7): 6849 | | [Pubmed] | [DOI] | | | 7 |
Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases |
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| Christos Tapeinos,Matteo Battaglini,Gianni Ciofani | | Journal of Controlled Release. 2017; 264: 306 | | [Pubmed] | [DOI] | | | 8 |
Perspectives on dendritic architectures and their biological applications: From core to cell |
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| Valikala Viswanath,Kannappan Santhakumar | | Journal of Photochemistry and Photobiology B: Biology. 2017; 173: 61 | | [Pubmed] | [DOI] | | | 9 |
Evaluation of G2 Citric Acid-Based Dendrimer as an Adjuvant in Veterinary Rabies Vaccine |
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| Vahid Asgary,Alireza Shoari,Majid Afshar Moayad,Mehdi Shafiee Ardestani,Razieh Bigdeli,Leila Ghazizadeh,Mohammad Sadeq Khosravy,Erfan Panahnejad,Alireza Janani,Rouzbeh Bashar,Maliheh Abedi,Reza Ahangari Cohan | | Viral Immunology. 2017; | | [Pubmed] | [DOI] | | | 10 |
Fast Dissolving Dendrimer Nanofiber Mats as Alternative to Eye Drops for More Efficient Antiglaucoma Drug Delivery |
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| Michael G. Lancina,Sudha Singh,Uday B. Kompella,Shahid Husain,Hu Yang | | ACS Biomaterials Science & Engineering. 2017; | | [Pubmed] | [DOI] | | | 11 |
Nanotechnology and nanocarrier-based approaches on treatment of degenerative diseases |
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| Anindita Chowdhury,Selvaraj Kunjiappan,Theivendren Panneerselvam,Balasubramanian Somasundaram,Chiranjib Bhattacharjee | | International Nano Letters. 2017; | | [Pubmed] | [DOI] | | | 12 |
Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers |
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| Kivilcim Öztürk,Günes Esendagli,Mustafa Ulvi Gürbüz,Metin Tülü,Sema Çalis | | International Journal of Pharmaceutics. 2017; 517(1-2): 157 | | [Pubmed] | [DOI] | | | 13 |
Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders |
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| Abhijeet Singh,Ankit Chokriwal,Madan Mohan Sharma,Devendra Jain,Juhi Saxena,Bjorn John Stephen | | ACS Chemical Neuroscience. 2017; 8(8): 1645 | | [Pubmed] | [DOI] | | | 14 |
Crossing the Blood–Brain Barrier: Recent Advances in Drug Delivery to the Brain |
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| Mayur M. Patel,Bhoomika M. Patel | | CNS Drugs. 2017; 31(2): 109 | | [Pubmed] | [DOI] | | | 15 |
Biocompatible nanomaterials based on dendrimers, hydrogels and hydrogel nanocomposites for use in biomedicine |
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| Cuu Khoa Nguyen,Ngoc Quyen Tran,Thi Phuong Nguyen,Dai Hai Nguyen | | Advances in Natural Sciences: Nanoscience and Nanotechnology. 2017; 8(1): 015001 | | [Pubmed] | [DOI] | | | 16 |
Positioning metal-organic framework nanoparticles within the context of drug delivery – A comparison with mesoporous silica nanoparticles and dendrimers |
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| Stefan Wuttke,Marjorie Lismont,Alberto Escudero,Bunyarat Rungtaweevoranit,Wolfgang J. Parak | | Biomaterials. 2017; | | [Pubmed] | [DOI] | | | 17 |
Dendritic polymers for dermal drug delivery |
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| Kaushalkumar Dave,Venkata Vamsi Krishna Venuganti | | Therapeutic Delivery. 2017; 8(12): 1077 | | [Pubmed] | [DOI] | | | 18 |
Carbon Nanotube as a Tool for Fighting Cancer |
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| Edson José Comparetti,Valber de Albuquerque Pedrosa,Ramon Kaneno | | Bioconjugate Chemistry. 2017; | | [Pubmed] | [DOI] | | | 19 |
Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung |
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| Eric Valeur,Stéphanie M. Guéret,Hélène Adihou,Ranganath Gopalakrishnan,Malin Lemurell,Herbert Waldmann,Tom N. Grossmann,Alleyn T. Plowright | | Angewandte Chemie. 2017; | | [Pubmed] | [DOI] | | | 20 |
New Modalities for Challenging Targets in Drug Discovery |
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| Eric Valeur,Stéphanie M. Guéret,Hélène Adihou,Ranganath Gopalakrishnan,Malin Lemurell,Herbert Waldmann,Tom N. Grossmann,Alleyn T. Plowright | | Angewandte Chemie International Edition. 2017; | | [Pubmed] | [DOI] | | | 21 |
Functionalized materials for multistage platforms in the oral delivery of biopharmaceuticals |
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| Francisca Araújo,José das Neves,João Pedro Martins,Pedro L. Granja,Hélder A. Santos,Bruno Sarmento | | Progress in Materials Science. 2017; 89: 306 | | [Pubmed] | [DOI] | | | 22 |
Dendrimers for ocular drug delivery |
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| Michael G. Lancina,Hu Yang | | Canadian Journal of Chemistry. 2017; : 1 | | [Pubmed] | [DOI] | | | 23 |
Stabilization of polypropylene-based materials via molecular retention with hyperbranched polymer |
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| Akanksha Matta,Ikki Katada,Junji Kawazoe,Patchanee Chammingkwan,Minoru Terano,Toshiaki Taniike | | Polymer Degradation and Stability. 2017; 142: 50 | | [Pubmed] | [DOI] | | | 24 |
Screening of the structural, topological, and electronic properties of the functionalized Graphene nanosheets as potential Tegafur anticancer drug carriers using DFT method |
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| Mahnaz Shahabi,Heidar Raissi | | Journal of Biomolecular Structure and Dynamics. 2017; : 1 | | [Pubmed] | [DOI] | | | 25 |
A Prominent Anchoring Effect on the Kinetic Control of Drug Release from Mesoporous Silica Nanoparticles (MSNs) |
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| Anh-Vy Tran,Sang-Wha Lee | | Journal of Colloid and Interface Science. 2017; | | [Pubmed] | [DOI] | | | 26 |
Dendrimers as Nanocarriers for Nucleic Acid and Drug Delivery in Cancer Therapy |
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| Livia Palmerston Mendes,Jiayi Pan,Vladimir Torchilin | | Molecules. 2017; 22(9): 1401 | | [Pubmed] | [DOI] | | | 27 |
Activated microglia targeting dendrimer-minocycline conjugate as therapeutics for neuroinflammation |
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| Rishi Sharma,Soo-Young Kim,Anjali Sharma,Zhi Zhang,Siva Pramodh Kambhampati,Sujatha Kannan,Rangaramanujam M Kannan | | Bioconjugate Chemistry. 2017; | | [Pubmed] | [DOI] | | | 28 |
Aptamer-targeted delivery of Bcl-xL shRNA using alkyl modified PAMAM dendrimers into lung cancer cells |
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| Sara Ayatollahi,Zahra Salmasi,Maryam Hashemi,Saeedeh Askarian,Reza Kazemi Oskuee,Khalil Abnous,Mohammad Ramezani | | The International Journal of Biochemistry & Cell Biology. 2017; | | [Pubmed] | [DOI] | | | 29 |
IL-6 Antibody and RGD Peptide Conjugated Poly(amidoamine) Dendrimer for Targeted Drug Delivery of HeLa Cells |
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| Shewaye Lakew Mekuria,Tilahun Ayane Debele,Hsiao-Ying Chou,Hsieh-Chih Tsai | | The Journal of Physical Chemistry B. 2016; 120(1): 123 | | [Pubmed] | [DOI] | | | 30 |
Polymers in Drug Delivery |
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| Apurva Srivastava,Tejaswita Yadav,Soumya Sharma,Anjali Nayak,Akanksha Akanksha Kumari,Nidhi Mishra | | Journal of Biosciences and Medicines. 2016; 04(01): 69 | | [Pubmed] | [DOI] | | | 31 |
Recent perspectives on the delivery of biologics to back of the eye |
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| Mary Joseph,Hoang M. Trinh,Kishore Cholkar,Dhananjay Pal,Ashim K. Mitra | | Expert Opinion on Drug Delivery. 2016; : 1 | | [Pubmed] | [DOI] | | | 32 |
From Diagnosis to Treatment |
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| Christopher S. Digesu,Sophie C. Hofferberth,Mark W. Grinstaff,Yolonda L. Colson | | Thoracic Surgery Clinics. 2016; 26(2): 215 | | [Pubmed] | [DOI] | | | 33 |
Effect of Several HIV Antigens Simultaneously Loaded with G2-NN16 Carbosilane Dendrimer in the Cell Uptake and Functionality of Human Dendritic Cells |
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| Daniel Sepúlveda-Crespo,Enrique Vacas-Córdoba,Valeria Márquez-Miranda,Ingrid Araya-Durán,Rafael Gómez,Francisco Javier de la Mata,Fernando Danilo González-Nilo,M Ángeles Muñoz-Fernández | | Bioconjugate Chemistry. 2016; 27(12): 2844 | | [Pubmed] | [DOI] | | | 34 |
Alternative approaches for the treatment of airway diseases: focus on nanoparticle medicine |
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| E. Ratemi,A. Sultana Shaik,A. Al Faraj,R. Halwani | | Clinical & Experimental Allergy. 2016; 46(8): 1033 | | [Pubmed] | [DOI] | | | 35 |
Dendrimers in anticancer drug delivery: mechanism of interaction of drug and dendrimers |
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| Jaspreet Singh,Keerti Jain,Neelesh Kumar Mehra,N. K. Jain | | Artificial Cells, Nanomedicine, and Biotechnology. 2016; : 1 | | [Pubmed] | [DOI] | | | 36 |
Nanocarriers based delivery of nutraceuticals for cancer prevention and treatment: A review of recent research developments |
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| Divya Arora,Sundeep Jaglan | | Trends in Food Science & Technology. 2016; 54: 114 | | [Pubmed] | [DOI] | | | 37 |
Peptide-Decorated Dendrimers and Their Bioapplications |
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| Jingjing Wan,Paul F. Alewood | | Angewandte Chemie International Edition. 2016; : n/a | | [Pubmed] | [DOI] | | | 38 |
Mit Peptiden dekorierte Dendrimere und ihre biotechnologische Nutzung |
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| Jingjing Wan,Paul F. Alewood | | Angewandte Chemie. 2016; : n/a | | [Pubmed] | [DOI] | | | 39 |
Dendrimer-based nanoparticles for potential personalized therapy in chronic lymphocytic leukemia: targeting the BCR-Signaling Pathway |
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| Ida Franiak-Pietryga,Henryk Maciejewski,Kinga Ostrowska,Dietmar Appelhans,Brigitte Voit,Malgorzata Misiewicz,Pawel Kowalczyk,Maria Bryszewska,Maciej Borowiec | | International Journal of Biological Macromolecules. 2016; | | [Pubmed] | [DOI] | | | 40 |
PAMAM dendrimer based targeted nano-carrier for bio-imaging and therapeutic agents |
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| Shewaye Lakew Mekuria,Tilahun Ayane Debele,Hsieh-Chih Tsai | | RSC Adv.. 2016; 6(68): 63761 | | [Pubmed] | [DOI] | | | 41 |
Peptide-Based Multicomponent Oligonucleotide Delivery Systems: Optimisation of Poly-l-lysine Dendrons for Plasmid DNA Delivery |
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| Khairul A. Kamaruzaman,Peter M. Moyle,Istvan Toth | | International Journal of Peptide Research and Therapeutics. 2016; | | [Pubmed] | [DOI] | | | 42 |
Therapeutic Potential of Foldamers: From Chemical Biology Tools to Drug Candidates? |
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| Ranganath Gopalakrishnan,Andrey I. Frolov,Laurent Knerr,William J. Drury,Eric Valeur | | Journal of Medicinal Chemistry. 2016; | | [Pubmed] | [DOI] | | | 43 |
Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis |
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| Ghasem Ghalamfarsa,Mohammad Hojjat-Farsangi,Mousa Mohammadnia-Afrouzi,Enayat Anvari,Shohreh Farhadi,Mehdi Yousefi,Farhad Jadidi-Niaragh | | Journal of Immunotoxicology. 2016; : 1 | | [Pubmed] | [DOI] | | | 44 |
Designing Dendrimer and Miktoarm Polymer Based Multi-Tasking Nanocarriers for Efficient Medical Therapy |
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| Anjali Sharma,Ashok Kakkar | | Molecules. 2015; 20(9): 16987 | | [Pubmed] | [DOI] | | | 45 |
Multifunctional nanoparticles: recent progress in cancer therapeutics |
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| G. Seeta Rama Raju,Leah Benton,E. Pavitra,Jae Su Yu | | Chem. Commun.. 2015; 51(68): 13248 | | [Pubmed] | [DOI] | | | 46 |
Supramolecular nanoscale assemblies for cancer diagnosis and therapy |
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| Sílvia Castro Coelho,Maria Carmo Pereira,Asta Juzeniene,Petras Juzenas,Manuel A.N. Coelho | | Journal of Controlled Release. 2015; 213: 152 | | [Pubmed] | [DOI] | | | 47 |
Drug Carrier for Photodynamic Cancer Therapy |
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| Tilahun Debele,Sydney Peng,Hsieh-Chih Tsai | | International Journal of Molecular Sciences. 2015; 16(9): 22094 | | [Pubmed] | [DOI] | | | 48 |
Nanotechnology Approaches for the Delivery of Exogenous siRNA for HIV Therapy |
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| Simeon K. Adesina,Emmanuel O. Akala | | Molecular Pharmaceutics. 2015; 12(12): 4175 | | [Pubmed] | [DOI] | | | 49 |
Oral Bioavailability: Issues and Solutions via Nanoformulations |
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| Kamla Pathak,Smita Raghuvanshi | | Clinical Pharmacokinetics. 2015; 54(4): 325 | | [Pubmed] | [DOI] | | | 50 |
Emerging therapeutic delivery capabilities and challenges utilizing enzyme/protein packaged bacterial vesicles |
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| Nathan J Alves,Kendrick B Turner,Igor L Medintz,Scott A Walper | | Therapeutic Delivery. 2015; 6(7): 873 | | [Pubmed] | [DOI] | | | 51 |
Polyanionic carbosilane dendrimer-conjugated antiviral drugs as efficient microbicides: Recent trends and developments in HIV treatment/therapy |
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| Daniel Sepúlveda-Crespo,Rafael Gómez,Francisco Javier De La Mata,José Luis Jiménez,Mª. Ángeles Muñoz-Fernández | | Nanomedicine: Nanotechnology, Biology and Medicine. 2015; 11(6): 1481 | | [Pubmed] | [DOI] | | | 52 |
Enhancing photodynamic therapy of refractory solid cancers: Combining second-generation photosensitizers with multi-targeted liposomal delivery |
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| Ruud Weijer,Mans Broekgaarden,Milan Kos,Remko van Vught,Erik A.J. Rauws,Eefjan Breukink,Thomas M. van Gulik,Gert Storm,Michal Heger | | Journal of Photochemistry and Photobiology C: Photochemistry Reviews. 2015; 23: 103 | | [Pubmed] | [DOI] | | | 53 |
Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: Current progress and advances |
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| Nishant S. Gandhi,Rakesh K. Tekade,Mahavir B. Chougule | | Journal of Controlled Release. 2014; | | [Pubmed] | [DOI] | |
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