PAMAM dendrimers as a carbamazepine delivery system for neurodegenerative diseases: A biophysical and nanotoxicological characterization

Abstract

Carbamazepine (CBZ) is an antiepileptic drug, which also could be used in the treatment of neurodegenerative diseases, such as the Alzheimer's disease. However, its use has been limited due to its low solubility, inefficient pharmacokinetic profiles, and multiple side effects. PAMAM dendrimers, ethylenediamine core, generation 4.0 (amine terminal groups) and 4.5 (carboxylate terminal groups) (DG4.0 and DG4.5 respectively) are polymers that can increase drug solubility through complexation. Thus, the aim of this work was to obtain and characterize complexes between CBZ and dendrimers. Both DG4.0 and DG4.5 allowed the incorporation of ∼20 molecules of CBZ per dendrimer, into their hydrophobic pockets. DG4.0-CBZ and DG4.5-CBZ complexes were found to be stable for 90 days at 37 °C and resistant to a lyophilization process, presenting controlled drug release. Also, the complexes nanotoxicity was tested ex vivo (human red blood cells), in vitro (N2a cell line), and in vivo (zebrafish). No hemolytic effect was observed in the ex vivo model. As regards in vitro toxicity, the DG4.5-CBZ complexes significantly reduced the toxicity caused by the free drug. Moreover, the DG4.5-CBZ did not cause neurotoxicity or cardiotoxicity in zebrafish larvae. In conclusion, a stable and biocompatible drug delivery system based on the DG4.5 capable of complex the CBZ has been developed. This achievement highlights the advantages of using negatively charged dendrimers for nanomedicine.

Advancements in nanotherapeutics for Alzheimer’s disease: current perspectives

“…Drug release from the carbamazepine‐dendrimer conjugates was found to be controlled, and the developed formulations were less toxic than free carbamazepine in vitro and in vivo. Recently, a new type of dendrimer consisting of a core composed of poly(propylene imine) and a maltose–histidine shell (G4HisMal) was developed by Azo et al . to protect transgenic mice against AD‐induced memory loss, to enhance BBB penetration and to improve biocompatibility.…”

Use of Polyamidoamine Dendrimers in Brain Diseases

“…Since the PAMAM dendrimer itself is extremely water-soluble, encapsulation within the cavities is an ideal way to solubilize poorly water-soluble drugs in aqueous solutions. For example, Igartúa and colleagues found that a G4 PAMAM dendrimer with an amine surface (or a G4.5 PAMAM dendrimer with a carboxyl surface) could encapsulate about 20 molecules of the anti-epileptic drug, carbamazepine, which has potential for treating neurodegenerative diseases [ 30 ]. Recent reviews on the use of PAMAM dendrimers for encapsulating drugs are available [ 5 , 31 ].…”

“…However, it is poorly soluble in water and shows unpredictable pharmacokinetic profiles. Generation 4.5 carboxyl-terminated dendrimers were loaded with CBZ to yield stable, soluble and safe (as tested on RBCs and zebrafish) formulations for potential applications in the treatment of neurodegenerative diseases associated with toxicity of aggregated proteins such as Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease [ 30 ]. No further studies were performed to see if the CBZ-dendrimer formulations were effective for the treatment of these diseases.…”

Folic acid magnetic nanotheranostics for delivering doxorubicin: Toxicological and biocompatibility studies on Zebrafish embryo and larvae

“…The spontaneous movement was studied in a multichannel analog to digital converter system (WMicrotracker, Designplus SRL, Argentina) as we previously described (Igartúa et al, 2015;Igartúa et al, 2018). Activity events were recorded for 15 min at 1, 4, 24, and 48 hpi, at room temperature.…”