Bioelectricity for Drug Delivery: The Promise of Cationic Therapeutics

Abstract

Biological systems overwhelmingly comprise charged entities generating electrical activity that can have significant impact on biological structure and function. This intrinsic bio-electrical activity can also be harnessed for overcoming the tissue matrix and cell membrane barriers, which have been outstanding challenges for targeted drug delivery, by using rationally designed cationic carriers. The weak and reversible long-range electrostatic interactions with fixed negatively charged groups facilitate electro-diffusive transport of cationic therapeutics through full-tissue thickness to effectively reach intra-tissue, cellular, and intracellular target sites. This article presents a perspective on the promise of using rationally designed cationic biomaterials in targeted drug delivery, the underlying charge-based mechanisms, and bio-transport phenomena while addressing outstanding concerns around toxicity and methods to mitigate them. We also discuss electrically charged drugs that are currently being evaluated in clinical trials and identify areas of further development that have the potential to usher in new treatments.

Milk exosomes with enhanced mucus penetrability for oral delivery of siRNA

“…8 Such viruses utilize weak, reversible charge-charge interactions to transiently bind to weakly negatively charged mucin constituents, 46 which enable rapid penetration through the full thickness of the mucin. 28,[52][53][54] A key design challenge in repurposing exosomes as an siRNA delivery vehicle is the efficient incorporation of high molecular weight RNA oligonucleotides into the exosome core without disrupting the lipid membrane. This is a limitation of exosomes compared to other vectors like liposomes and nanoparticles, since siRNA can be loaded into synthetic delivery vehicles during their preparation process.…”

Resveratrol and Curcumin AttenuateEx VivoSugar-Induced Cartilage Glycation, Stiffening, Senescence, and Degeneration

“…53 This can be overcome by delivering drugs using optimally charged cationic carriers that utilize electrostatic interactions to enhance their targeting, uptake and retention within the negatively charged cartilage. 53 -58 AGE accumulation within cartilage reduces GAG release levels ( Figs. 1f , 2f , and 6d ) and is associated with the loss of primary amines on collagen II, which can increase the tissue’s net negative fixed charge density (FCD).…”

“…1f , 2f , and 6d ) and is associated with the loss of primary amines on collagen II, which can increase the tissue’s net negative fixed charge density (FCD). This high negative FCD can be further utilized for enhancing intra-cartilage targeting 53,57 -59 and residence time of such drugs following their IA administration by making them positively charged. 54,56,60…”

Activatable Peptides for Rapid and Simple Visualization of Protease Activity Secreted in Living Cells

“…It is noteworthy that arginine-rich peptides, known as cell-penetrating peptides (CPPs), can translocate through living cell membranes because cancer cells are distinguished by their negatively charged surfaces due to their altered biosynthetic processes, which result in appended negative molecules such as phospholipids, glycolipids, and glycoproteins [18][19][20]. Within the mechanism that drives CPP translocation into cells, this study focused on proteaseactivated live-cell imaging through the intracellular uptake of cleavable peptides, where no bioactive cargo, such as proteins, polymers, or nanomaterials [21,22], is conjugated with peptides.…”