Pharmaceutical applications of dendrimers

Pharmaceutical research has grown considerably in the past decade. It led to the discovery of numerous compounds including small molecules, biologics (proteins, peptides and antibodies), and nucleic acids (DNA and RNA oligonucleotides, mRNA and various self-assembling complexes) which could benefit diagnosis and therapy of different disorders. It has also become apparent that many of these compounds are not immediately applicable for biomedical uses. Common challenges, which slow the translation of promising drugs to the clinic, include their inability to cross biological barriers and reach target sites, instability in biological matrices, transformation and loss of desirable properties under physiologically appropriate pH, off-target effects and toxicities to normal cells. Additional challenges, which are more typical for certain classes of pharmaceutical compounds also exist. For example, immunogenicity (i.e. the ability to elicit the immune response culminating with the production of anti-drug antibody) is a common concern for biologics, while poor water-solubility is typical for small molecules. To overcome these translational barriers nanotechnology carriers are increasingly considered. Global research efforts demonstrated that nanotechnology could help increasing the drug’s pharmacological properties such as better water solubility, availability at target levels, improved delivery, lower toxicity and better efficacy. Dendrimers are among such nanotechnology carriers which are researched worldwide to deliver better drugs to patients in need. Along with other classes of nanoparticles, dendrimers can protect drugs from the environment and help to cross biological membranes. For example, the presence of cationic moieties on PAMAM-NH₃ dendrimers or certain lipids in liposomes allow nanoparticle interaction with cellular membranes and improve drug delivery into the target cells. The unique opportunities offered by the dendrimer platforms include their well-defined synthesis and controllable physicochemical characteristics which play the key role in both the efficacy and toxicity of the final dendrimer-drug products. To improve the design of dendrimer carriers, several computational tools are available and include among others docking studies and molecular dynamics (MD) simulations. The docking studies, for example, can suggest how many molecules can be attached per dendrimer and estimate the size, chemical moieties, and hindrance effects of both the drug and the dendrimer-carrier. Like any other research tool, docking studies have some limitations. For example, they consider drugs as rigid systems. The molecular dynamics (MD) simulations are often recommended to address this limitation. MD simulations consider the small and macromolecular drugs as flexible systems. Moreover, they consider water and ions and allow making physiological approximations. In addition, MD simulations can show the internalisations of small molecules by the carrier and help to calculate the free energy values between dendrimers and drugs. This specialised issue is prepared to cover various topics pertinent to the dendrimer use in biology and medicine. The computational studies used to improve understanding of dendrimer-drug interactions and to design effective dendrimer-based drug delivery systems are reviewed by Bello M et al. [1] and Márquez-Miranda V et al. [2]. Translation of the dendrimer-drug products from design to biomedical applications requires accurate physicochemical characterization. Methods used to characterise dendrimer-based formulations are reviewed by Rodríguez-Fonseca R A et al. [3]. To show how the design and characterization efforts lead to the therapeutic utility of dendrimer-drug complexes, this theme issue includes several reviews focused on medical applications. Tekade RK et al. [4] and Kesavan A et al. [5] review dendrimer application in oncology. Utilisation of dendrimers and lipid carriers for drug delivery to the nervous system and therapy of neurological and neurodegenerative disorders are covered by Gagliardi M and Segura-Uribe JJ et al. [6, 7], respectively. Dobrovolskaia M.A. reviews beneficial and toxic effects of dendrimers on the immune system [8]. The theme is closed by Noé Rimondino G et al. [9] who consider challenges and opportunities for dendrimer-based hybrid nanocarriers.