Number of end‐groups of dendrons for AB2, AB3 and PAMAM dendrimers and the size of PAMAM dendrimers.
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.
Dendrimers are spherical nanosized polymers that branch in a well‐defined manner. They were first synthesized and described by Franz Vögtle in 1978 . 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 .
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 . 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 . 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 ||Calculated ||Experimental hydrodynamic diameter |
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 . 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.  or Ref. . 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 . The antibacterial activity of dendrimers has been already reviewed by Tülü and Ertürk  and Mintzer and co‐workers . 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 . 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  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 . 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 . 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 . 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 . 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 . 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.
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.
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.