Number of end‐groups of dendrons for AB2, AB3 and PAMAM dendrimers and the size of PAMAM dendrimers.
Abstract
Dendrimers represent a distinct class of polymers—highly branched and uniform, with a relatively small size when compared to their mass. They are composed of the core, from which branched polymeric dendrons diverge and they are end‐capped with selected terminal groups. Recently, dendrimers have attracted considerable attention from medicinal chemists, mostly due to their well‐defined and easy‐to‐modify structure. This chapter aims to compile dendrimer applications and activities especially for prevention and fighting off infections caused by bacteria and fungi, viruses, and parasites/protozoa. Our goal in this review is to discuss selected modifications of dendrimers of potential value for pharmaceutical chemistry.
Keywords
- antibacterial
- antimycotic
- dendrimer
- nanomaterials
- polymers
1. Introduction
Dendrimers are spherical nanosized polymers that branch in a well‐defined manner. They were first synthesized and described by Franz Vögtle in 1978 [1]. For the last 30 years, they have gained a lot of attention, mainly due to the discovery of their stunning complexation abilities. In medicinal chemistry, they reveal interesting pharmacological properties of potential value for various medical fields. In pharmaceutical sciences, these nanostructures are particularly interesting as they can be potentially useful in pharmaceutical technology for preparation of water‐soluble complexes with poorly soluble active pharmaceutical ingredients (API). It is worth noting that at the same time a decrease in API's overall toxicity is observed.
In this chapter, the aim is to describe the potential use of dendrimers in fighting off infectious diseases. Infectious diseases continue to constitute a problem around the globe, and a proper surveillance is required, as the amount of reports regarding occurrence of bacteria and fungi resistant to all clinically used antibiotics and antimycotics is growing. From one year to the next, the number of potentially useful antimicrobials is slowly decreasing, while only a few APIs have been introduced to clinical practice in recent years. Therefore, even treatment of common diseases has the potential to become a serious problem in the near future. The link between pollution and health although complex is obvious. An increasing pollution of the environment with pharmaceuticals intended to fight infectious diseases as well as their enhanced consumption over the last 70 years has led to the development of resistance mechanisms. Additionally, the treatment of infectious diseases in developing countries is quite problematic due to the lack of regulations in drug marketing. Another factor is the price of what is often referred to as last resort medicines; the contribution of public funding is often essential for the implementation of therapy with such medicinal products. Moreover, decreased hygiene level and underdeveloped sanitation favour the occurrence of bacterial, fungal and parasitic infections [2, 3].
Currently, the amount of novel antibiotic classes seems to be constant. In parallel, the propagation of multidrug resistant microbes indicates the necessity of searching for novel agents and methods, which can be used as a revolutionary approach. Therefore, present research wrestles with the problem of whether novel dendrimer nanoparticles alone or in complexes with APIs can be of potential usage in medicinal and pharmaceutical chemistry. The goal is to develop novel antibiotics, antimicrobial and antiparasitic/protozoa therapies. Currently, there are many ongoing attempts that aim at increasing the efficiency of strategies against bacteria and fungi in planktonic and biofilm modes of growth. There are researched methods that lead to biofilm growth inhibition, disruption or eradication. These approaches include APIs with new mechanisms of action, like enzymes, salts, metal nanoparticles, antibiotics, acids, plant extracts or antimicrobial photodynamic therapy. Regarding all this, dendrimers could be a material that might help to reach this goal [4].
2. Dendrimer structural versatility
Dendrimers do not form a uniform group based on their chemical structure. They are different from other dendritic structures such as dendronic and dendritic surfaces, dendronized polymers, dendriplexes and dendrigrafts. Schematic representation of dendrimeric nanoparticle, which constitutes the main subject of this short review, is presented in Figure 1 [5]. Generally, dendrimers are composed of three elements: (
A system was proposed describing the specific branching architecture of dendrimers, with general abbreviation ABn—where n stands for new branches that arise from a node. For example, AB2 and AB3 states for two and three branches outgoing from each node, respectively. For graphical description, see Figure 3 [6]. The most common dendrimers that can be found in the literature are built of AB2 building blocks. Among those to the most popular belong
The core part of dendrimers may be a variety of molecules—starting with single atoms (like nitrogen in some PAMAMs), aliphatic chains, alicyclic or aromatic rings through polyaromatic moieties, inorganic frameworks, and ending with other polymers and peptides. The core of a dendrimer can be simply a scaffold to which dendrons are attached. However, in some cases, the core is a molecule that expresses its own activity and added dendrons modify the periphery of the central molecule, thus affecting its physico‐chemical properties (solubility, photochemical and electrochemical properties, protection from enzymes, etc.) [8–12]. Dendrons serve mainly as carriers for other compounds. The controlled release of drugs from dendron‐drug complexes can be modulated at certain pH values present in the environment of living organisms. An acidic environment is often associated with cancerous tissues, which was the subject of research by Wang
Dendron generation | Number of end‐groups | PAMAM dendrimer size [nm] | |||
---|---|---|---|---|---|
AB2 dendron | AB3 dendron | PAMAM dendrimer [7] | Calculated [14] | Experimental hydrodynamic diameter [7] | |
0 | 1 | 1 | 4 | N/A | 1.5 |
1 | 2 | 3 | 8 | 1.0 | 2.2 |
2 | 4 | 9 | 16 | 1.4 | 2.9 |
3 | 8 | 27 | 32 | 1.6 | 3.6 |
4 | 16 | 81 | 64 | 2.1 | 4.5 |
5 | 32 | 243 | 128 | 2.8 | 5.4 |
6 | 64 | 729 | 256 | 3.6 | 6.7 |
7 | 128 | 2187 | 512 | 4.5 | 8.1 |
8 | 256 | 6561 | 1024 | 5.7 | 9.7 |
9 | 512 | 19683 | 2048 | 6.8 | 11.4 |
10 | 1024 | 59049 | 4096 | 8.6 | 13.5 |
Dendrimer end‐groups can be easily modified. Modification changes their polarity and solubility in different solvents. In this way, high toxicity associated with many free amino groups in PAMAM and PPI dendrimers may be overcome by substituting them partially with non‐toxic moieties [15, 16]. Alternatively, appending the end‐groups with hydrophobic substituents may be considered, when they are intended to be utilized as carriers in hydrophobic formulations. In this way, the toxicity of prepared dendrimer is kept at bay and its complexation capabilities in hydrophobic mediums are increased. Utilizing this method, Hamilton
Alternatively, the end‐groups may be substituted with active substances, targeting molecules and others, that are relevant and needed for modern applications. Najlah and D'Emanuele reviewed the literature on the subject of dendrimer‐drug conjugates [18]. The main benefit from combining APIs with dendrimers in such manner is that dendrimer‐API conjugates are more stable in various conditions as compared to their complexes based on non‐covalent bonds. A good example for covalent bonding of APIs to dendrimer surface groups is the use of dendrimers as carriers for immunoactive peptides in the formation of vaccines. Such approach has been successfully tested by Skwarczynski
The plethora of different modifications that can be proposed makes dendrimers perfect molecules for any chosen application with endless possibilities. For more insight into the potential applications of dendrimers and a broad spectrum of different properties of these nanosized polymers, the reader can refer to the comprehensive reviews such as Ref. [5] or Ref. [22]. Astruc
For pharmaceutical technology, dendrimers are mostly known for their carrier abilities. They exhibit great complexation potential for biologically active compounds, drugs, dyes and metal ions. Dendrimer carrier abilities for various chemical molecules (drugs, pigments, salts) comprise both drug encapsulation and chemical bonding to the periphery (Figure 4). Dendrimers have already found some commercial applications, for example, as a component of sexually transferred diseases preventing gel (
3. Use of dendrimers against infectious diseases
3.1. Dendrimers as antibacterials and antifungals
Therapeutic efficiency of dendrimers as nanocarriers has been proved so far for, for example, potent anticancer, nonsteroidal and anti‐inflammatory, antimicrobial and antiviral drugs. In this respect, two strategies have been applied for the application of dendrimers as drug carriers. The first one was encapsulation of drugs inside dendrimers or their binding to peripheral groups of dendrimers by electrostatic or ionic interactions. The second one concerned covalent bonding of drugs to the periphery of dendrimers [5]. The antibacterial activity of dendrimers has been already reviewed by Tülü and Ertürk [23] and Mintzer and co‐workers [24]. The aim was to highlight the diversity of dendrimer structural modifications that led to an increased
Commercially available PAMAM dendrimers are effective antibacterial compounds (Figure 5). Amino‐terminated G2 PAMAM dendrimer revealed differentiated minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) activities against various strains of
A highly active but also toxic dendrimer is G4 PPI. Felczak
Another type of dendrimers, poly(phosphorhydrazone) dendrimers appended with PEG chains were synthesized on a solid support provided by silica nanoparticles [33]. These composites were used for hosting silver‐based nanoparticles and assessed on the basis of their antibacterial activity, which was found to reach Gram‐negative (
An amino acid‐based dendrimer [36] was found to exhibit low toxicity and high antibacterial activity against usually resistant bacterial strains of
Quite a lot of attention has also been given to so‐called antimicrobial peptides. These are short, naturally occurring peptides that exhibit high antimicrobial activity. Problems associated with the use of these compounds are related to their susceptibility to bacterial enzymes and a not fully recognized mechanism of action. Reports published on this subject regarding antibacterial activity of synthetic short dendrimeric peptides suggest the high potential of such an approach. Lind
Another approach of utilizing dendrimers in the fight against bacteria is to combine them with other structures or compounds. In this way, PAMAMs were combined with multiwalled carbon nanotubes and CdS or Ag2S quantum dots to form novel hybrid materials [43]. Nano‐hybrids were found to be highly active against bacteria and the activity was found to be just as high or higher than for each component alone. As a continuation of this study, authors functionalized the surface of multiwalled carbon nanotubes with polyamide dendrons [44]. This composite material was used for synthesis of silver nanoparticles and then applied as a carrier for these. Organic–inorganic hybrid was assessed and proven effective as antimicrobial against
Almost all dendrimers described in this chapter derive their high antibacterial and antifungal activity from the so‐called starburst effect. Dendrimers mentioned earlier are characterized by the exponential growth of the number of terminal groups. Such a rapid increase in the number of active sites of small molecules (by means of their volume) is the result of this phenomenon. In case of dendrimers as antimicrobial drug carriers, dendrimeric formulations are often just as effective or even more so on pathogens as a drug used alone. Use of dendrimers usually results in prolonged release of the drug with simultaneously decreased toxicity comparing to the parent compound. This can be clearly seen for a plethora of drug molecules. For example, such a study was performed for sulfamethoxazole, which is a poorly soluble sulfonamide. Its solubility increased in the formulations prepared with PAMAM dendrimers [51]. This increase was generation‐dependent. As the result of this change, an increase of sulfamethoxazole antibacterial activity and sustained release of the drug were observed. Navath
3.2. Dendrimers for treatment and prevention of virus‐related infection
Dendrimers have been applied for treatment and prevention of virus‐related infections (Figure 6). The best‐known dendrimer acting in an antiviral manner is probably SPL7013, discovered by Starpharma, which is the active ingredient of VivaGel [58]. It is a G4 PLL dendrimer with functionalized end‐groups used in the form of a gel and marketed as condom lubrication. SPL7013 successfully underwent second‐stage clinical trials and was found to prevent sexually transmitted diseases, most notably
Carbosilane dendrimers were also investigated in terms of other potential antiviral applications [62, 63]. Knowing that dendrimers are excellent non‐viral transfection agents, two polycationic G1 carbosilane dendrimers with different cores were assessed for gene therapy in order to inhibit the development of ongoing HIV infection. Both dendrimers were found to exhibit properties making them suitable for their planned use. Their non‐toxicity was confirmed (MTT assay). They were able to form complexes with nucleic acids and—as siRNA complexes—inhibit replication of HIV‐1 and affect macrophage response, thus encouraging further study on this subject.
Antiviral PPI dendrimers were also assessed for potential anti‐HIV treatment [64]. In this case, dendrimers up to their third generation were modified on the periphery with anionic groups such as carboxylate or sulfonate functional groups. Modified dendrimers were used to complex bivalent metal ions: Cu2+, Ni2+, Co2+ or Zn2+. Metal complexes were assessed for their HIV infection potential applying
Dendrimers have been also assessed as potential vaccine carriers. For an excellent review on this subject, the paper by Heegaard
A quite different approach was undertaken by Yandrapu
3.3. Dendrimers in fighting off the parasitic/protozoa infection
The action of dendrimers on protozoa and parasitic infections is mostly unexplored areas in comparison with their antiviral and antibacterial activity (Figure 7). There is also only limited data on the drug delivery of compounds for treating such infections using dendrimer carriers. Below is a summary and discussion of some reports on this subject.
Heredero‐Bermejo
Sulfadiazine is one of the drugs used for treatment of
It is worth noting that Wang
3.4. Dendrimers for sensing of infective microbes
Dendrimers were also considered as components of microbial sensing devices (Figure 8). Use thereof as bacterial and viral presence has been reviewed by Satija
Use of dendrimers for sensing parasitic presence was assessed by Perinoto
4. Conclusions and perspectives
In recent years, dendrimers, which represent a distinct class of polymers, have gained considerable attention from medicinal chemists and pharmaceutical technologists, mostly due to their known and potential applications for medicine. Although there are still many unresolved issues on the topic of dendrimers, our goal in this review was to discuss selected modifications of dendrimers dedicated to the prevention and fighting of infections caused by bacteria, fungi, viruses and parasites.
A great increase of dendrimer‐related research is to some extent bound to their commercial availability (mostly PAMAMs) as well as novel and efficient methods of their synthesis. In this regard, the development and commercial availability of various innovative building blocks for the synthesis of full‐grown dendrimers is especially important. Dendrimer chemistry continues to develop year by year and many research groups and companies are interested in studying their properties and potential uses. In this chapter, many potential and practical applications of dendrimers in prevention of diseases, diagnostics of microbes have been discussed.
Based on the reviewed literature, dendrimers have proven to be useful in many ways. The starburst effect of nanopolymers obtained is magnified exponentially, resulting in unprecedented outcomes. A plethora of various studies on PAMAMs revealed how the dendrimers activity and toxicity changes upon a slight modification in their structure. Formation of dendriplexes quite often increases the biological activity of both dendrimer and encapsulated drug molecules. Furthermore, discoveries in the field of dendrimers encourage various studies in pharmaceutical technology on poor water‐soluble APIs, which otherwise would not be considered useful for clinical practice. Moreover, there is still much to be done in regard to Gram‐negative bacteria. Because of differences in cell wall structure, they are not as susceptible to anti‐bacterials and disinfectants as their Gram‐positive counterparts. In addition, studies published on dendrimers do not point out their mechanism of action. Based on the non‐specific action of dendrimers on bacteria and fungi, one cannot assume that dendrimers always exhibit an identical mechanism of action on these organisms.
Only a few reports deal with the subject of infective fungi and there is almost none regarding the parasitic and protozoan infections. Systemic fungal infections are on the rise in developed countries because of the increasing use of immunosuppressive drugs after transplantations and due to opportunistic infections associated with HIV infected people suffering from AIDS. In terms of viruses, the research on the application of dendrimers for the improvement of vaccines is very important. As for parasites, encouraging are studies aimed at developing diagnostic methods for the detection of these organisms. Generally, high possibilities of modifying dendrimer core, branches and terminal groups, as well as development of methods on combining them with other active moieties make them unique and highly promising molecules for future use.
Acknowledgments
Authors thank the National Science Centre, Poland for funding (grant no. 2012/05/E/NZ7/01204). Authors would like to thank Mrs Agata Kaluzna‐Mlynarczyk for her help with the graphics.
References
- 1.
Buhleier E, Wehner W, Vögtle F. “Cascade”‐ and “nonskid‐chain‐like” syntheses of molecular cavity topologies. Synthesis 1978; 1978:155-8. doi:10.1055/s‐1978‐24702 - 2.
Braine T. Race against time to develop new antibiotics. Bull World Health Organ 2011; 89: 88-9. doi:10.2471/BLT.11.030211 - 3.
Hof H. Will resistance in fungi emerge on a scale similar to that seen in bacteria? Eur J Clin Microbiol Infect Dis 2008; 27: 327-34. doi:10.1007/s10096‐007‐0451‐9 - 4.
Collins TL, Markus EA, Hassett DJ, Robinson JB. The effect of a cationic porphyrin on Pseudomonas aeruginosa biofilms. Curr Microbiol 2010; 61: 411-6. doi:10.1007/s00284‐010‐9629‐y - 5.
Astruc D, Boisselier E, Ornelas C. Dendrimers designed for functions: from physical, photophysical, and supramolecular properties to applications in sensing, catalysis, molecular electronics, photonics, and nanomedicine. Chem Rev 2010; 110: 1857-959. doi:10.1021/cr900327d - 6.
Campagna S, editor. Designing dendrimers. Hoboken, NJ: Wiley; 2012. - 7.
Fréchet JMJ, Tomalia DA, editors. Dendrimers and other dendritic polymers. John Wiley & Sons, Ltd; Baffins Lane, Chichester, West Sussex, 2001. - 8.
Setaro F, Ruiz‐González R, Nonell S, Hahn U, Torres T. Synthesis, photophysical studies and 1O2 generation of carboxylate‐terminated zinc phthalocyanine dendrimers. J Inorg Biochem 2014; 136: 170-6. doi:10.1016/j.jinorgbio.2014.02.007 - 9.
Wieczorek E, Piskorz J, Popenda L, Jurga S, Mielcarek J, Goslinski T. First example of a diazepinoporphyrazine with dendrimeric substituents. Tetrahedron Lett 2017; 58: 758-761. doi:10.1016/j.tetlet.2017.01.027 - 10.
Mlynarczyk DT, Lijewski S, Falkowski M, Piskorz J, Szczolko W, Sobotta L, et al. Dendrimeric sulfanyl porphyrazines: synthesis, physico‐chemical characterization, and biological activity for potential applications in photodynamic therapy. ChemPlusChem 2016; 81: 460-70. doi:10.1002/cplu.201600051 - 11.
Falkowski M, Rebis T, Piskorz J, Popenda L, Jurga S, Mielcarek J, et al. Improved electrocatalytic response toward hydrogen peroxide reduction of sulfanyl porphyrazine/multiwalled carbon nanotube hybrids deposited on glassy carbon electrodes. Dyes Pigm 2016; 134: 569-79. doi:10.1016/j.dyepig.2016.08.014 - 12.
Tillo A, Stolarska M, Kryjewski M, Popenda L, Sobotta L, Jurga S, et al. Phthalocyanines with bulky substituents at non‐peripheral positions: synthesis and physico‐chemical properties. Dyes Pigm 2016; 127: 110-5. doi:10.1016/j.dyepig.2015.12.017 - 13.
Wang M, Wang Y, Hu K, Shao N, Cheng Y. Tumor extracellular acidity activated “off–on” release of bortezomib from a biocompatible dendrimer. Biomater Sci 2015; 3: 480-9. doi:10.1039/C4BM00365A - 14.
Maiti PK, Çagın T, Wang G, Goddard WA. Structure of PAMAM dendrimers: generations 1 through 11. Macromolecules 2004; 37: 6236-54. doi:10.1021/ma035629b - 15.
Calabretta MK, Kumar A, McDermott AM, Cai C. Antibacterial activities of poly(amidoamine) dendrimers terminated with amino and poly(ethylene glycol) groups. Biomacromolecules 2007; 8: 1807-11. doi:10.1021/bm0701088 - 16.
Felczak A, Wrońska N, Janaszewska A, Klajnert B, Bryszewska M, Appelhans D, et al. Antimicrobial activity of poly(propylene imine) dendrimers. New J Chem 2012; 36: 2215. doi:10.1039/c2nj40421d - 17.
Hamilton PD, Jacobs DZ, Rapp B, Ravi N. Surface hydrophobic modification of fifth‐generation hydroxyl‐terminated poly(amidoamine) dendrimers and its effect on biocompatibility and rheology. Materials 2009; 2: 883-902. doi:10.3390/ma2030883 - 18.
Najlah M, D'Emanuele A. Synthesis of dendrimers and drug‐dendrimer conjugates for drug delivery. Curr Opin Drug Discov Devel 2007; 10: 756-67. - 19.
Skwarczynski M, Zaman M, Urbani CN, Lin I‐C, Jia Z, Batzloff MR, et al. Polyacrylate dendrimer nanoparticles: a self‐adjuvanting vaccine delivery system. Angew Chem Int Ed 2010; 49: 5742-5. doi:10.1002/anie.201002221 - 20.
Majoros IJ, Myc A, Thomas T, Mehta CB, Baker JR. PAMAM dendrimer‐based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules 2006; 7: 572-9. doi:10.1021/bm0506142 - 21.
Albertazzi L, Mickler FM, Pavan GM, Salomone F, Bardi G, Panniello M, et al. Enhanced bioactivity of internally functionalized cationic dendrimers with PEG cores. Biomacromolecules 2012; 13: 4089-97. doi:10.1021/bm301384y - 22.
Klajnert B, Peng L, Cena V, editors. Dendrimers in biomedical applications; RSC Publishing, Cambridge, 2013. - 23.
Tülü M, Ertürk AS. Dendrimers as antibacterial agents 2012. In: Bobbarala V, editor. A search for antibacterial agents. 1st ed. Rijeka: Intech. p. 89-106. doi:10.5772/46051 - 24.
Mintzer MA, Dane EL, O'Toole GA, Grinstaff MW. Exploiting dendrimer multivalency to combat emerging and re‐emerging infectious diseases. Mol Pharm 2012; 9: 342-54. doi:10.1021/mp2005033 - 25.
Xue X, Chen X, Mao X, Hou Z, Zhou Y, Bai H, et al. Amino‐terminated generation 2 poly(amidoamine) dendrimer as a potential broad‐spectrum, nonresistance‐inducing antibacterial agent. AAPS J 2013; 15: 132-42. doi:10.1208/s12248‐012‐9416‐8 - 26.
Pryor JB, Harper BJ, Harper SL. Comparative toxicological assessment of PAMAM and thiophosphoryl dendrimers using embryonic zebrafish. Int J Nanomed 2014; 9: 1947-56. doi:10.2147/IJN.S60220 - 27.
Lopez AI, Reins RY, McDermott AM, Trautner BW, Cai C. Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers. Mol Biosyst 2009; 5: 1148. doi:10.1039/b904746h - 28.
Worley BV, Schilly KM, Schoenfisch MH. Anti‐biofilm efficacy of dual‐action nitric oxide‐releasing alkyl chain modified poly(amidoamine) dendrimers. Mol Pharm 2015; 12: 1573-83. doi:10.1021/acs.molpharmaceut.5b00006 - 29.
Lu Y, Slomberg DL, Shah A, Schoenfisch MH. Nitric oxide‐releasing amphiphilic poly(amidoamine) (PAMAM) dendrimers as antibacterial agents. Biomacromolecules 2013; 14: 3589-98. doi:10.1021/bm400961r - 30.
Felczak A, Zawadzka K, Wrońska N, Janaszewska A, Klajnert B, Bryszewska M, et al. Enhancement of antimicrobial activity by co‐administration of poly(propylene imine) dendrimers and nadifloxacin. New J Chem 2013; 37: 4156. doi:10.1039/c3nj00760j - 31.
Wrońska N, Felczak A, Zawadzka K, Janaszewska A, Klajnert B, Bryszewska M, et al. The antibacterial effect of the co‐administration of poly(propylene imine) dendrimers and ciprofloxacin. New J Chem 2014; 38: 2987. doi:10.1039/c3nj01338c - 32.
Cheng Y, Qu H, Ma M, Xu Z, Xu P, Fang Y, et al. Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Eur J Med Chem 2007; 42: 1032-8. doi:10.1016/j.ejmech.2006.12.035 - 33.
Hameau A, Collière V, Grimoud J, Fau P, Roques C, Caminade A‐M, et al. PPH dendrimers grafted on silica nanoparticles: surface chemistry, characterization, silver colloids hosting and antibacterial activity. RSC Adv 2013; 3: 19015. doi:10.1039/c3ra43348j - 34.
Wang L, Erasquin UJ, Zhao M, Ren L, Zhang MY, Cheng GJ, et al. Stability, antimicrobial activity, and cytotoxicity of poly(amidoamine) dendrimers on titanium substrates. ACS Appl Mater Interfaces 2011; 3: 2885-94. doi:10.1021/am2004398 - 35.
Ciepluch K, Katir N, Kadib A El, Felczak A, Zawadzka K, Weber M, et al. Biological properties of new viologen‐phosphorus dendrimers. Mol Pharm 2012; 9: 448-57. doi:10.1021/mp200549c - 36.
Pires J, Siriwardena TN, Stach M, Tinguely R, Kasraian S, Luzzaro F, et al. In vitro activity of the novel antimicrobial peptide dendrimer G3KL against multidrug‐resistantAcinetobacter baumannii andPseudomonas aeruginosa . Antimicrob Agents Chemother 2015; 59: 7915-8. doi:10.1128/AAC.01853‐15 - 37.
Abd‐El‐Aziz AS, Abdelghani AA, El‐Sadany SK, Overy DP, Kerr RG. Antimicrobial and anticancer activities of organoiron melamine dendrimers capped with piperazine moieties. Eur Polym J 2016; 82: 307-23. doi:10.1016/j.eurpolymj.2016.04.002 - 38.
Meyers SR, Juhn FS, Griset AP, Luman NR, Grinstaff MW. Anionic amphiphilic dendrimers as antibacterial agents. J Am Chem Soc 2008; 130: 14444-5. doi:10.1021/ja806912a - 39.
Fuentes‐Paniagua E, Hernández‐Ros JM, Sánchez‐Milla M, Camero MA, Maly M, Pérez‐Serrano J, et al. Carbosilane cationic dendrimers synthesized by thiol‐ene click chemistry and their use as antibacterial agents. RSC Adv 2014; 4: 1256-65. doi:10.1039/C3RA45408H - 40.
Lind T, Polcyn P, Zielinska P, Cárdenas M, Urbanczyk‐Lipkowska Z. On the antimicrobial activity of various peptide‐based dendrimers of similar architecture. Molecules 2015; 20: 738-53. doi:10.3390/molecules20010738 - 41.
Bruschi M, Pirri G, Giuliani A, Nicoletto SF, Baster I, Scorciapino MA, et al. Synthesis, characterization, antimicrobial activity and LPS‐interaction properties of SB041, a novel dendrimeric peptide with antimicrobial properties. Peptides 2010; 31: 1459-67. doi:10.1016/j.peptides.2010.04.022 - 42.
Staniszewska M, Bondaryk M, Zielińska P, Urbańczyk‐Lipkowska Z. The in vitro effects of new D186 dendrimer on virulence factors of Candida albicans . J Antibiot (Tokyo) 2014; 67: 425-32. - 43.
Neelgund GM, Oki A, Luo Z. Antimicrobial activity of CdS and Ag2S quantum dots immobilized on poly(amidoamine) grafted carbon nanotubes. Colloids Surf B Biointerfaces 2012; 100: 215-21. doi:10.1016/j.colsurfb.2012.05.012 - 44.
Neelgund GM, Oki A. Deposition of silver nanoparticles on dendrimer functionalized multiwalled carbon nanotubes: synthesis, characterization and antimicrobial activity. J Nanosci Nanotechnol 2011; 11: 3621-9. doi:10.1166/jnn.2011.3756 - 45.
Tang J, Chen W, Su W, Li W, Deng J. Dendrimer‐encapsulated silver nanoparticles and antibacterial activity on cotton fabric. J Nanosci Nanotechnol 2013; 13: 2128-35. doi:10.1166/jnn.2013.6883 - 46.
Mahltig B, Cheval N, Astachov V, Malkoch M, Montanez MI, Haase H, et al. Hydroxyl functional polyester dendrimers as stabilizing agent for preparation of colloidal silver particles—a study in respect to antimicrobial properties and toxicity against human cells. Colloid Polym Sci 2012; 290: 1413-21. doi:10.1007/s00396‐012‐2650‐x - 47.
Strydom SJ, Rose WE, Otto DP, Liebenberg W, de Villiers MM. Poly(amidoamine) dendrimer‐mediated synthesis and stabilization of silver sulfonamide nanoparticles with increased antibacterial activity. Nanomed Nanotechnol Biol Med 2013; 9: 85-93. doi:10.1016/j.nano.2012.03.006 - 48.
Staneva D, Vasileva‐Tonkova E, Makki MSI, Sobahi TR, Abdеl‐Rahman RM, Boyaci IH, et al. Synthesis and spectral characterization of a new PPA dendrimer modified with 4‐bromo‐1,8‐naphthalimide and in vitro antimicrobial activity of its Cu(II) and Zn(II) metal complexes. Tetrahedron 2015; 71: 1080-7. doi:10.1016/j.tet.2014.12.083 - 49.
Zainul Abid CKV, Jackeray R, Jain S, Chattopadhyay S, Asif S, Singh H. Antimicrobial efficacy of synthesized quaternary ammonium polyamidoamine dendrimers and dendritic polymer network. J Nanosci Nanotechnol 2016; 16: 998-1007. doi:10.1166/jnn.2016.10656 - 50.
Gangadharan D, Dhandhala N, Dixit D, Thakur RS, Popat KM, Anand PS. Investigation of solid supported dendrimers for water disinfection. J Appl Polym Sci 2012; 124: 1384-91. doi:10.1002/app.34967 - 51.
Ma M, Cheng Y, Xu Z, Xu P, Qu H, Fang Y, et al. Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti‐bacterial drugs using sulfamethoxazole (SMZ) as a model drug. Eur J Med Chem 2007; 42: 93-8. doi:10.1016/j.ejmech.2006.07.015 - 52.
Navath RS, Menjoge AR, Dai H, Romero R, Kannan S, Kannan RM. Injectable PAMAM dendrimer–PEG hydrogels for the treatment of genital infections: formulation and in vitro andin vivo evaluation. Mol Pharm 2011; 8: 1209-23. doi:10.1021/mp200027z - 53.
Wrońska N, Felczak A, Zawadzka K, Poszepczyńska M, Różalska S, Bryszewska M, et al. Poly(propylene imine) dendrimers and amoxicillin as dual‐action antibacterial agents. Molecules 2015; 20: 19330-42. doi:10.3390/molecules201019330 - 54.
Gardiner J, Freeman S, Leach M, Green A, Alcock J, D'Emanuele A. PAMAM dendrimers for the delivery of the antibacterial triclosan. J Enzyme Inhib Med Chem 2008; 23: 623-8. doi:10.1080/14756360802205257 - 55.
Wróblewska M, Winnicka K. The effect of cationic polyamidoamine dendrimers on physicochemical characteristics of hydrogels with erythromycin. Int J Mol Sci 2015; 16: 20277-89. doi:10.3390/ijms160920277 - 56.
Winnicka K, Wroblewska M, Wieczorek P, Sacha P, Tryniszewska E. The effect of PAMAM dendrimers on the antibacterial activity of antibiotics with different water solubility. Molecules 2013; 18: 8607-17. doi:10.3390/molecules18078607 - 57.
Sonawane SJ, Kalhapure RS, Rambharose S, Mocktar C, Vepuri SB, Soliman M, et al. Ultra‐small lipid‐dendrimer hybrid nanoparticles as a promising strategy for antibiotic delivery: in vitro and in silico studies. Int J Pharm 2016; 504: 1-10. doi:10.1016/j.ijpharm.2016.03.021 - 58.
©Starpharma Holdings Limited. Accessed January 8, 2017 from http://www.starpharma.com/vivagel - 59.
Sánchez‐Rodríguez J, Díaz L, Galán M, Maly M, Gómez R, la Mata FJ de, et al. Anti‐human immunodeficiency virus activity of thiol‐ene carbosilane dendrimers and their potential development as a topical microbicide. J Biomed Nanotechnol 2015; 11: 1783-98. doi:10.1166/jbn.2015.2109 - 60.
Vacas‐Córdoba E, Maly M, la Mata FJ de, Gómez R, Pion M, Munoz‐Fernandez MA. Antiviral mechanism of polyanionic carbosilane dendrimers against HIV‐1. Int J Nanomed 2016;11: 1281-1294. doi:10.2147/IJN.S96352 - 61.
Ceña Diez R, García Broncano P, la Mata FJ de, Gómez R, Munoz‐Fernandez MA. Efficacy of HIV antiviral polyanionic carbosilane dendrimer G2‐S16 in the presence of semen. Int J Nanomed 2016;11: 2443-2450. doi:10.2147/IJN.S104292 - 62.
Weber N, Ortega P, Clemente MI, Shcharbin D, Bryszewska M, la Mata FJ de, et al. Characterization of carbosilane dendrimers as effective carriers of siRNA to HIV‐infected lymphocytes. J Control Release 2008; 132: 55-64. doi:10.1016/j.jconrel.2008.07.035 - 63.
Perisé‐Barrios AJ, Jiménez JL, Domínguez‐Soto A, la Mata FJ de, Corbí AL, Gomez R, et al. Carbosilane dendrimers as gene delivery agents for the treatment of HIV infection. J Control Release 2014; 184: 51-7. doi:10.1016/j.jconrel.2014.03.048 - 64.
García‐Gallego S, Díaz L, Jiménez JL, Gómez R, la Mata FJ de, Muñoz‐Fernández MÁ. HIV‐1 antiviral behavior of anionic PPI metallo‐dendrimers with EDA core. Eur J Med Chem 2015; 98: 139-48. doi:10.1016/j.ejmech.2015.05.026 - 65.
Han S, Yoshida D, Kanamoto T, Nakashima H, Uryu T, Yoshida T. Sulfated oligosaccharide cluster with polylysine core scaffold as a new anti‐HIV dendrimer. Carbohydr Polym 2010; 80: 1111-5. doi:10.1016/j.carbpol.2010.01.031 - 66.
Han S, Kanamoto T, Nakashima H, Yoshida T. Synthesis of a new amphiphilic glycodendrimer with antiviral functionality. Carbohydr Polym 2012; 90: 1061-8. doi:10.1016/j.carbpol.2012.06.044 - 67.
Ceña‐Díez R, Sepúlveda‐Crespo D, Maly M, Muñoz‐Fernández MA. Dendrimeric based microbicides against sexual transmitted infections associated to heparan sulfate. RSC Adv 2016; 6: 46755-64. doi:10.1039/C6RA06969J - 68.
Heegaard PMH, Boas U, Sorensen NS. Dendrimers for vaccine and immunostimulatory uses. A review. Bioconjug Chem 2010; 21: 405-18. doi:10.1021/bc900290d - 69.
Chahal JS, Khan OF, Cooper CL, McPartlan JS, Tsosie JK, Tilley LD, et al. Dendrimer‐RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc Natl Acad Sci 2016; 113: E4133-42. - 70.
Ullas PT, Madhusudana SN, Desai A, Sagar BKC, Jayamurugan G, Rajesh YRD, et al. Enhancement of immunogenicity and efficacy of a plasmid DNA rabies vaccine by nanoformulation with a fourth‐generation amine‐terminated poly(ether imine) dendrimer. Int J Nanomed 2014; 9: 627. doi:10.2147/IJN.S53415 - 71.
Blanco E, Guerra B, la Torre BG de, Defaus S, Dekker A, Andreu D, et al. Full protection of swine against foot‐and‐mouth disease by a bivalent B‐cell epitope dendrimer peptide. Antiviral Res 2016; 129: 74-80. doi:10.1016/j.antiviral.2016.03.005 - 72.
Yandrapu SK, Kanujia P, Chalasani KB, Mangamoori L, Kolapalli RV, Chauhan A. Development and optimization of thiolated dendrimer as a viable mucoadhesive excipient for the controlled drug delivery: an acyclovir model formulation. Nanomed Nanotechnol Biol Med 2013; 9: 514-22. doi:10.1016/j.nano.2012.10.005 - 73.
Gajbhiye V, Ganesh N, Barve J, Jain NK. Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated‐mannosylated poly(propyleneimine) dendrimers. Eur J Pharm Sci 2013; 48: 668-79. doi:10.1016/j.ejps.2012.12.027 - 74.
Heegaard PM, Boas U. Dendrimer based anti‐infective and anti‐inflammatory drugs. Recent Patents Anti‐Infect Drug Disc 2006; 1: 333-51. - 75.
Heredero‐Bermejo I, Copa‐Patiño JL, Soliveri J, García‐Gallego S, Rasines B, Gómez R, et al. In vitro evaluation of the effectiveness of new water‐stable cationic carbosilane dendrimers against Acanthamoeba castellanii UAH‐T17c3 trophozoites. Parasitol Res 2013; 112: 961-9. doi:10.1007/s00436‐012‐3216‐z - 76.
Prieto MJ, Bacigalupe D, Pardini O, Amalvy JI, Venturini C, Morilla MJ, et al. Nanomolar cationic dendrimeric sulfadiazine as potential antitoxoplasmic agent. Int J Pharm 2006; 326: 160-8. doi:10.1016/j.ijpharm.2006.05.068 - 77.
Jain K, Verma AK, Mishra PR, Jain NK. Characterization and evaluation of amphotericin B loaded MDP conjugated poly(propylene imine) dendrimers. Nanomed Nanotechnol Biol Med 2015; 11: 705-13. doi:10.1016/j.nano.2014.11.008 - 78.
Jain K, Verma AK, Mishra PR, Jain NK. Surface‐engineered dendrimeric nanoconjugates for macrophage‐targeted delivery of amphotericin B: formulation development and in vitro andin vivo evaluation. Antimicrob Agents Chemother 2015; 59: 2479-87. doi:10.1128/AAC.04213‐14 - 79.
Daftarian PM, Stone GW, Kovalski L, Kumar M, Vosoughi A, Urbieta M, et al. A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis. J Infect Dis 2013; 208: 1914-22. doi:10.1093/infdis/jit378 - 80.
Wang X, Dai Y, Zhao S, Tang J, Li H, Xing Y, et al. PAMAM‐Lys, a novel vaccine delivery vector, enhances the protective effects of the SjC23 DNA vaccine against Schistosoma japonicum infection. PLoS One 2014; 9: e86578. doi:10.1371/journal.pone.0086578 - 81.
Satija J, Sai VVR, Mukherji S. Dendrimers in biosensors: concept and applications. J Mater Chem 2011; 21: 14367. doi:10.1039/c1jm10527b - 82.
Castillo G, Spinella K, Poturnayová A, Šnejdárková M, Mosiello L, Hianik T. Detection of aflatoxin B1 by aptamer‐based biosensor using PAMAM dendrimers as immobilization platform. Food Control 2015; 52: 9-18. doi:10.1016/j.foodcont.2014.12.008 - 83.
Mejri‐Omrani N, Miodek A, Zribi B, Marrakchi M, Hamdi M, Marty J‐L, et al. Direct detection of OTA by impedimetric aptasensor based on modified polypyrrole‐dendrimers. Anal Chim Acta 2016; 920: 37-46. doi:10.1016/j.aca.2016.03.038 - 84.
Perinoto ÂC, Maki RM, Colhone MC, Santos FR, Migliaccio V, Daghastanli KR, et al. Biosensors for efficient diagnosis of leishmaniasis: innovations in bioanalytics for a neglected disease. Anal Chem 2010; 82: 9763-8. doi:10.1021/ac101920t