Nanoantibiotics containing membrane-active human cathelicidin LL-37 or synthetic ceragenins attached to the surface of magnetic nanoparticles as novel and innovative therapeutic tools: current status and potential future applications

Abstract

Nanotechnology-based therapeutic approaches have attracted attention of scientists, in particular due to the special features of nanomaterials, such as adequate biocompatibility, ability to improve therapeutic efficiency of incorporated drugs and to limit their adverse effects. Among a variety of reported nanomaterials for biomedical applications, metal and metal oxide-based nanoparticles offer unique physicochemical properties allowing their use in combination with conventional antimicrobials and as magnetic field-controlled drug delivery nanocarriers. An ever-growing number of studies demonstrate that by combining magnetic nanoparticles with membrane-active, natural human cathelicidin-derived LL-37 peptide, and its synthetic mimics such as ceragenins, innovative nanoagents might be developed. Between others, they demonstrate high clinical potential as antimicrobial, anti-cancer, immunomodulatory and regenerative agents. Due to continuous research, knowledge on pleiotropic character of natural antibacterial peptides and their mimics is growing, and it is justifying to stay that the therapeutic potential of nanosystems containing membrane active compounds has not been exhausted yet.

Keywords: Ceragenins; Human cathelicidin; LL-37 peptide; Membrane active compounds; Nanoantibiotics; Nanomedicine; Nanotechnology.

Fig. 1

Antimicrobial activitity of LL-37 peptide and ceragenins CSA-13 and CSA-131 both alone and in combinations against extracellular and intracellular pathogens. a Intracellular killing efficacies of LL-37 (black circles), CSA-13 (blue squares), CSA-131 (orange diamonds), and combination of LL-37 with CSA-13 (green triangles) and LL-37 with CSA-131 (yellow circles) against Candida albicans within bladder epithelial cells. The concentrations of used antibacterial agents were 5 and 10 μM; incubation time was 2 h. b, c Reduction of P. aeruginosa Xen 5 (grey column) chemiluminescence signal (~ 10⁸ CFU/ml) after LL-37 (10 µg/mL; white column); CSA-13 (10 µg/mL; blue column); CSA-131 (10 µg/mL; orange column) and combination of LL-37 with CSA-13 (1:1 10 µg/mL each; green column); LL-37 with CSA-131 (1:1 10 µg/mL each; yellow column); and LL-37 with CSA-13 with CSA-131 (1:1:1 10 µg/mL each; black column) after 30 min of incubation in LB broth (b) and urine (c)

Fig. 2

Broad spectrum of activities reported for cationic antimicrobial peptides and CAPs-containing nanosystems

Fig. 3

Improvement of anti-cancer activities of ceragenins CSA13, CSA-90 and CSA-192 after their immobilization on the surface of magnetic nanocarriers. a The level of lactate dehydrogenase release from lung carcinoma A549 and colon cancer DLD-1 cells after treatment with 10 µg/mL of ceragenin CSA-13 and its magnetic derivative. b IC50 values recorded for CSA-90, CSA-192 and their mixture with MNP against malignant melanoma A7, lung carcinoma A549, colon cancer DLD-1 and breast cancer MCF-7 cells. c Alterations in morphology and DNA fragmentation in colon cancer DLD-1 cells after their treatment with CSA-13 and MNP@CSA-13 at dose of 10 µg/mL for 24 h, investigated using phase contrast and fluorescence microscope, respectively