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.

Keywords: cationic drug carriers; cell-penetrating peptides; cytotoxicity; drug delivery; electrostatic interactions; multilevel targeting.

FIG. 1.

Cationic carrier or carrier-drug conjugates can interact with negatively charged fixed intra-tissue and cellular moieties, enabling multilevel drug targeting at tissue, cellular, and intracellular levels. (A) Cationic carriers can rapidly penetrate the tissue in high concentrations owing to electrostatic interactions with the high density of negatively charged matrix GAGs, after which they can successively penetrate (B) the cell and (C) the nucleus to reach their target sites via charge-mediated pathways. GAGs, glycosaminoglycans.

FIG. 2.

(A) Transport mechanism of cationic carriers in negatively charged tissues. Concentration of the cationic carrier is enhanced from C at the administration site to KC at the interface of negatively charged tissue due to Donnan partitioning effect, which increases the intra-tissue concentration gradients, resulting in enhanced electro-diffusive transport and high uptakes. Weak-reversible binding interactions enable carriers to penetrate through the full-tissue thickness to effectively reach their cell targets in sufficient doses. Dashed line represents early initial concentration profile of the cationic carrier across the tissue, whereas solid line across the tissue refers to intra-tissue concentration of cationic carriers after equilibrium has been reached. (B) Targeted drug delivery to cartilage by using optimally charged cationic carriers. (i) Confocal images showing depth of penetration of CPCs in cartilage within 24 h. (ii) Charge-dependent equilibrium uptake of CPCs of various charge (between +8 and +20) in cartilage. Figure adapted with permission from Vedadghavami et al. (iii) Immunohistochemical analysis showing presence of Avidin through the full thickness of rabbit articular cartilage even at 3 weeks post-ACLT, which correlates with the spatial GAG density stained by Safranin-O (red). Figure adapted with permission from Bajpayee et al. (C) Targeted drug delivery to ocular tissues by using an electrostatically formed complex of pRFP, PAMAM, and penetratin peptide. Fluorescent images of rat retina 4 h after topical administration of the complexes (blue, green, and red represent cell nuclei, penetratin, and pRFP, respectively). Figure adapted with permission from Liu et al. (D) Drug delivery across mucosal barrier. Insulin-encapsulated PLGA nanoparticles coupled with cationic R8 and negatively charged Pho, capable of dissociation through digestion with IAP and resulting in a net positive charge. R8 and Pho were coupled to PLGA by using a DSPE-PEG bridge. Fluorescent images of rat intestinal villi post-oral administration (white arrows show absorption of particles in the interior of intestinal villi). Figure adapted with permission from Wu et al. ACLT, anterior cruciate ligament transected; CPCs, cationic peptide carriers; DAPI, 4,6-diamidino-2-phenylindole; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino-(poly{ethylene glycol})]; FAM, 5-carboxyfluorescein; IAP, intestinal alkaline phosphatase; NPs, nanoparticles; PAMAM, poly(amidoamine); Pho, phosphoserine; PLGA, poly(lactic-co-glycolic-acid); pRFP, red fluorescent protein plasmid.

FIG. 3.

Mechanisms facilitating cell membrane translocation of cell-penetrating peptides: (A) direct penetration, (B) receptor-mediated or nonspecific endocytosis, and (C) formation of transitory structures such as inverted micelles.

FIG. 4.

Undesired bioactivity of cationic carriers. (A) High concentrations of cationic carriers can shield the intra-tissue electrostatic repulsion between fixed negatively charged groups. Highly positively charged carriers can displace the sodium ions (Na⁺) to create a higher density of positive charges near the fixed negative groups, thereby resulting in a steeper exponential drop of electric potential, ɸ (x) and reducing the spacing between the negatively charged groups (x′ < x) causing osmotic deswelling of tissues. (B) Undesired nonspecific binding of cationic drug carriers with serum proteins and blood cells, resulting in formation of aggregates and hindering their delivery to desired target sites. These aggregates can also disrupt the phospholipid cell membrane and facilitate poration. (C) Excessive pumping of protons to help ionization of amines after intracellular uptake of highly charged cationic carriers results in an excessive inward flow of chloride ions (Cl⁻) and water molecules to maintain charge electroneutrality in the endosome (proton-sponge theory), resulting in osmotic swelling and rupture of the endosome.