Bioactive Aliphatic Polycarbonates Carrying Guanidinium Functions: An Innovative Approach for Myotonic Dystrophy Type 1 Therapy

Abstract

Dystrophia myotonica type 1 (DM1) results from nuclear sequestration of splicing factors by a messenger RNA (mRNA) harboring a large (CUG)n repeat array transcribed from the causal (CTG)n DNA amplification. Several compounds were previously shown to bind the (CUG)n RNA and release the splicing factors. We now investigated for the first time the interaction of an aliphatic polycarbonate carrying guanidinium functions to DM1 DNA/RNA model probes by affinity capillary electrophoresis. The apparent association constants (Ka) were in the range described for reference compounds such as pentamidine. Further macromolecular engineering could improve association specificity. The polymer presented no toxicity in cell culture at concentrations of 1.6–100.0 μg/mL as evaluated both by MTT and real-time monitoring xCELLigence method. These promising results may lay the foundation for a new branch of potential therapeutic agents for DM1.

Aliphatic Polycarbonates from Cyclic Carbonate Monomers and Their Application as Biomaterials

“…These nanostructures have the ability to protect the gene cargo from enzymatic and hydrolytic degradation as well as effectively facilitate cellular uptake through endocytosis. In the case of polycarbonate-based polyplexes, cationic functionalities, such as polyethylenimine (PEI), guanidinium, and bis-tertiary amines, are commonly grafted onto the polycarbonate backbone, facilitating gene binding and endosomal escape of the formed nanocarriers. ,− For instance, Ong et al developed a polycarbonate gene vector through ROP of haloalkyl functionalized CCs, followed by functionalization with bis-tertiary amines and quaternization. The cationic polycarbonate effectively condensed DNA, generating nanoparticles (∼100 nm in diameter) with positive zeta potentials (27 mV).…”

Affinity Capillary Electrophoresis: A Critical Review of the Literature from 2018 to 2020

“…Fluorescence imaging was used to confirm that addition of EBAB inhibited cells that had been transfected with plasmid that transcribes into a CUG repeat RNA. In 2019, the same research group again used a similar msACE approach to explore bioactive polymers as candidates for DM1 treatment . They synthesized aliphatic polycarbonate with a cationic guanidinium functional group (P­(Guan)), which is biocompatible and biodegradable and can be broken down into nontoxic products.…”

“…In 2019, the same research group again used a similar msACE approach to explore bioactive polymers as candidates for DM1 treatment. 52 They synthesized aliphatic polycarbonate with a cationic guanidinium functional group (P(Guan)), which is biocompatible and biodegradable and can be broken down into nontoxic products. A longer RNA with 95 CUG repeats (CUG) 95 was applied as a target probe to compare the binding constants of P(Guan) with the same drugs, PTMD and EBAB.…”