Biomedicine represents one of the main study areas for dendrimers, which have proven to be valuable both in diagnostics and therapy, due to their capacity for improving solubility, absorption, bioavailability and targeted distribution. Molecular cytotoxicity constitutes a limiting characteristic, especially for cationic and higher-generation dendrimers. Antineoplastic research of dendrimers has been widely developed, and several types of poly(amidoamine) and poly(propylene imine) dendrimer complexes with doxorubicin, paclitaxel, imatinib, sunitinib, cisplatin, melphalan and methotrexate have shown an improvement in comparison with the drug molecule alone. The anti-inflammatory therapy focused on dendrimer complexes of ibuprofen, indomethacin, piroxicam, ketoprofen and diflunisal. In the context of the development of antibiotic-resistant bacterial strains, dendrimer complexes of fluoroquinolones, macrolides, beta-lactamines and aminoglycosides have shown promising effects. Regarding antiviral therapy, studies have been performed to develop dendrimer conjugates with tenofovir, maraviroc, zidovudine, oseltamivir and acyclovir, among others. Furthermore, cardiovascular therapy has strongly addressed dendrimers. Employed in imaging diagnostics, dendrimers reduce the dosage required to obtain images, thus improving the efficiency of radioisotopes. Dendrimers are macromolecular structures with multiple advantages that can suffer modifications depending on the chemical nature of the drug that has to be transported. The results obtained so far encourage the pursuit of new studies.
The term “dendrimer” is a combination of two Greek words, “dendron” and “meros”, translated as tree and parts, thus explaining their branched structure. The first idea of branched molecules was stated by Flory in 1941, but the experimental support for it was not enough at that time. The first paper regarding dendritic structure was published by Vögtle and coworkers, in 1978. They created a dendritic structure by using divergent synthesis. Later on, this discovery was confirmed by Denkewalter et al. in 1981, Tomalia et al. in 1983 and Newkome et al. in 1985. The convergent approach was introduced by Hawker and Frechet in 1990.
Dendrimers are synthetic polymers characterized by branched repeating units that emerge from a focal point and possess a large number of exposed anionic, neutral or cationic terminal functionalities on the surface, which leads to hydrophilic or hydrophobic compounds. They are nanometric molecules that are radially symmetric, globular, mono-dispersed and homogenous.
The properties of dendrimers are different in comparison to conventional polymers. Due to their size, dendrimers are used in nanomedicine research. They are found to be useful as delivery or carrier systems for drugs and genes, but studies have shown that some dendrimers have medicinal uses of their own, mostly due to their antifungal, antibacterial and cytotoxic properties.
The benefits of many drugs cannot be exploited because of their poor solubility, toxicity or stability problems. The use of dendrimers as carriers of these compounds can solve these problems, thus improving their clinical applications.
The valorization of dendrimers represents an important progress in the current therapeutic field, and the biodegradable properties of these polymers can significantly increase their applicability. Dendrimers’ excretion (hepatic or renal) differs depending on the generation. Moreover, the structural versatility of dendrimers gives them special qualities in the context of using them as ideal carriers for many active drug molecules. In addition, the easy-to-control characteristics of dendrimers (namely: size, shape, liposome blockage in dendrimeric structures, branch length, surface functionality and synthesis of targeted dendritic scaffolds) makes these systems ideal carriers in many applications. The controllable and adjustable size, the interaction with cell membranes and various active drug molecules and the characteristics of their internal structures and cavities, makes dendrimers excellent candidates for drug delivery systems (DDS). Mainly, many recent studies involving DDS using dendrimers have been in the field of neoplastic diseases. Dendrimers are also studied as DDS in other therapeutic fields: anti-inflammatory, antiviral, antibiotic therapies, and in cardiovascular diseases, etc.
Compared to traditional surfactants, when they are used as carriers, dendrimers possess numerous advantages, like a high loading capacity of the drug through numerous functional surface groups and internal cavities, the high bioavailability of the attached drug through covalent or non-covalent bonds, and the high penetrability of biological barriers and cell membranes.
Due to their significance in the field of medicine, dendrimers have been studied intensively in the past few years, and because of the extensive number of studies performed regarding this subject, review articles that emphasize several aspects have been published. A great interest has been shown in the biomedical applications of dendrimers, especially for their capacity to be used as targeted drug and gene delivery systems. Advances in diagnostics that use imaging techniques were made, along with the improvement of treatments for diseases like cancer, cardio-vascular diseases, inflammatory diseases, and viral and bacterial infections. Even though dendrimers possess a wide range of applications in biomedicine, their toxicity was reported as well, for the assessment of limitations in their usage.
In order to obtain a better understanding of these compounds, the synthesis and physicochemical analysis of dendrimers were reviewed as well. Different types of dendrimers were compared from biological points of view, thus underlining their properties depending on their composition.
The aim of this review is to systematically present the extensive biomedical applications of dendrimers from a pharmaceutical point of view, focusing on the pharmacokinetic and pharmacodynamic advantages they provide. The objectives include: (a) the identification of dendrimer’s applications in therapy and diagnostics, (b) a display of dendrimer types and examples of complexes they form with active substances, grouped by the medical specialty they refer to, and (c) a presentation of dendrimer’s cytotoxicity, the main limiting characteristic of these substances from a medicinal and pharmaceutical perspective.
In order to introduce a new substance in therapeutics and the diagnostics of human illnesses, its properties have to be well documented. Beside the physicochemical characteristics and the pharmacological profile, the toxicological risk/benefit ratio must also be evaluated. Dendrimers, as biocompatible nanoparticle macromolecules, are used for their unique properties as carriers of other molecular structures, in order to improve the activity and efficiency of an active drug molecule and also to reduce its toxicity.
The special molecular structure of these entities determines the specificity of action. The macromolecules are defined by their molecular weight, highly branched spherical tridimensional structure, and the ability to create a monodisperse media.
The selection of the initial central atom, such as carbon, nitrogen and phosphorous, is important in determining the structure of the dendrimer, its branches and its cavities. There are over 100 families of dendrimers.
The essential characteristic of these nanomolecules is given by the generation they belong to. There are 13 generations, from G0 to G12, the number representing the branch layers. The schematic structure of these macromolecules is illustrated.
It has been shown that the cytotoxicity of the dendrimer depends on the generation to which it belongs and also on the nature of its surface, given by terminal functional groups. Cytotoxicity was highlighted in cationic, amine dendrimers. Studies also showed a correlation between cytotoxicity and dendrimer generation. For example, the cytotoxicity of poly(amidoamine) (PAMAM) and poly(propylene imine) (PPI) dendrimers is directly proportional to concentration and generation, due to the presence of primary amines terminal zones. Grafted polyethylene carbosilane dendrimers are less toxic and so are anionic terminal group dendrimers. Thus, the surface modification of cationic dendrimers in order to neutralize or completely modify them to anions is directly linked to reduced cytotoxicity.
Cationic dendrimers have the ability to interact with negatively charged cell membranes, disrupting their integrity. Punctual defects in the membrane lead to a cascade of events, ending with cell apoptosis.
Figure 2 shows the types of dendrimers and how surface charge affects their in vitro and in vivo cytotoxicity, biopermeability and immunogenicity.
The occurrence and modulation of dendrimers’ cytotoxicity was approached by studying various structural modulations, especially in the nanomolecules’ peripheral area, obtaining carbohydrates, acetyl and polyethylene glycol (PEG) derivatives that did not significantly affect cell viability, while maintaining other advantageous features.
Dendrimers are perfect partners for active pharmaceutical ingredients, due to their structural specificity, which allows the following: (a) inclusion inside the cavities (Figure 3a), (b) attachment of bioactive compounds/drug molecules to the functional groups at the periphery of the dendrimer (Figure 3b), and (c) both of the above—offering encapsulation (internal cavities) and a support for conjugates (on the surface) (Figure 3c). The interaction between drugs and dendrimers is beneficial since it improves solubility, thus improving the absorption and bioavailability of the drug molecule or its cytotoxicity.
Glycodendrimers are a newer type of dendrimers, these modulations leading to a significant decrease in cytotoxicity. The interaction of liposomes and human serum albumin (HSA) with glucose-modified carbosilane dendrimers, from first to third generation (dendrimer 1-3Glu), was evaluated. The interactions with both of the above-mentioned biological structures could not be related to the generation of the dendrimer, but because of the strong interactions with liposomes and the weak ones with HAS, theoretically, cancer cells can be targeted by the overexpression of glucose transporters, thus demonstrating that glucose-modified carbosilane dendrimers can be used as drug delivery carriers in the therapy of cancer.
Several dendrimers possess intrinsic pharmacodynamic properties. In order to be used for their biomedical activity, dendrimers must meet certain conditions, as follows: (a) they must show low toxicity, (b) low immunogenicity, and (c) high permeability, so that they can cross biological barriers, have a proper presence in the systemic circulation and be capable of specific targeting. The limiting characteristic in relation to the medical use of many dendrimers is their cytotoxicity.
Dendrimers have been investigated in relation to medical tasks, the targeted release of active molecules, or gene therapy, due to the malleability of their structure which permits the tailoring of their physicochemical properties. This possibility confers the uniqueness of dendrimers compared to other nanoparticles, their structure on generations (dendrons—branched concentric layers) (offering the possibility of synthesizing dendrimers as monodisperse systems), and the terminal groups offering possibilities for further interaction.
Cancer is an abnormal proliferation of cells caused by numerous changes under the action of physical, chemical, biological or genetic factors, leading to an imbalance between cell proliferation and apoptosis, and eventually evolving into distant-site invasive cells, causing significant morbidity and mortality. Despite sustained research efforts over recent decades to find effective therapies, cancer continues to be one of the leading causes of mortality.
Conventional antineoplastic therapy is associated with many important side effects. Commonly indicated radiotherapy can lead to the development of secondary gene mutations, which could cause complications and future new malignancies. Chemotherapy, immunotherapy and gene therapy are generally characterized by significant nonspecificity, which limits the bioavailability of the drug at the tumor site.
Chemotherapeutic drugs often have a nonspecific distribution, so that only a small part of the active substance reaches the site of action, and the pharmacokinetic characteristics are directly responsible for the in situ concentration o
