L‐Arg‐Rich Amphiphilic Dendritic Peptide as a Versatile NO Donor for NO/Photodynamic Synergistic Treatment of Bacterial Infections and Promoting Wound Healing

Abstract

The development of alternative strategies for the efficient treatment of subcutaneous abscesses that do not require the massive use of antibiotics and surgical intervention is urgently needed. Herein, a novel synergistic antibacterial strategy based on photodynamic (PDT) and NO gas therapy is reported, in which, a PDT‐driven NO controllable generation system (Ce6@Arg‐ADP) is developed with l‐Arg‐rich amphiphilic dendritic peptide (Arg‐ADP) as a carrier. This carrier not only displays superior bacterial association and biofilm penetration performance, but also acts as a versatile NO donor. Following efficient penetration into the interior of the biofilms, Ce6@Arg‐ADP can rapidly produce massive NO via utilizing the H2O2 generated during PDT to oxidize Arg‐ADP to NO and l‐citrulline, without affecting singlet oxygen (1O2) production. The combination of 1O2 and the reactive by‐products of NO offers notable synergistic antibacterial and biofilm eradication effects. Importantly, following efficient elimination of all bacteria from the abscess site, Arg‐ADP can further generate trace quantities of NO to facilitate the angiogenesis and epithelialization of the wound tissues, thereby notably promotes wound healing. Together, this study clearly suggests that Arg‐ADP is a versatile NO donor, and the combination of PDT and NO represents a promising strategy for the efficient treatment of subcutaneous abscesses.

Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications

“…The same trend was observed for alkyl chain and exterior functionality modified PAMAM dendrimers, which have very different MBCs despite similar structures and NO release kinetics [101,138]. In the case of the L-Arg-rich amphiphilic dendritic peptides, described above, compared to the Ce6@Lys-ADP control, which is adsorbed onto MRSA cell surface, Ce6@Arg-ADP is internalized or tightly bound to MRSA, a factor that contributes to its high bactericidal activity upon irradiation and release of ROS and NO [137]. For h-polyaminoglycosides/NO, the high density of aminoglycosides, an antibiotic, can contribute to its antimicrobial activity [166].…”

“…Hu et al made use of chlorin e6 (Ce6) as a high ROS-generating photosensitizer in α-CD-Ce6-NO-DA, for which the mechanism of biofilm eradication has been previously described [134]. Likewise, Zhu et al designed a PDT-driven NO controllable generation system (Ce6@Arg-ADP, Figure 3) with L-Arg-rich amphiphilic dendritic peptide (Arg-ADP) as a carrier [137]. Enhanced antibacterial activity and biofilm penetration is achieved to a lesser extent via amino groups and to a larger extent through the presence of abundant surface guanidine groups of the Arg-ADP peptide that can associate with and promote bacterial cell rupture.…”

“…In a similar manner, Near Infrared (NIR) irradiation of AI-MDPA at 808 nm generates heat, inducing ICG release and ROS production, which in turn catalyzes NO release from L-Arg. NO production of NIR-triggered AI-MPDA is power-density and concentration dependent, and a higher laser power was used here compared to other studies [134,137]. A total of 4 µM NO was produced when 0.2 mg AI-MPDA was irradiated with NIR at 1 W/cm 2 .…”

“…N-diazeniumdiolate-functionalized hyperbranched polyaminoglycosides can have a NO payload of 0.4-1.28 µmol/mg, depending on the amine content of the aminoglycoside monomer [41,166]. NO donors such as L-arg may also be incorporated into dendrimers [137].…”

Role of Amino Acid Arginine and Nitric Oxide in Mechanisms of Cytoprotective Effect of Non-Opiate Leu-Enkephalin Analogue In Vitro

“…The mechanisms of the cytoprotective effect of NALE remain unclear. Probably, its effect is determined by the C-terminal Arg and stimulation of NO synthesis by NO synthase [21].…”