The treatment of implant‐associated bacterial infections and biofilms is an urgent medical need and a grand challenge because biofilms protect bacteria from the immune system and harbor antibiotic‐tolerant persister cells. This need is addressed herein through an engineering of antibody‐drug conjugates (ADCs) that contain an anti‐neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. The ADCs designed herein release the conjugated drug without cell entry, via a novel mechanism of drug release which likely involves an interaction of ADC with the thiols on the bacterial cell surface. ADCs targeted toward bacteria are superior by the afforded antimicrobial effects compared to the non‐specific counterpart, in suspension and within biofilms, in vitro, and in an implant‐associated murine osteomyelitis model in vivo. The results are important in developing ADC for a new area of application with a significant translational potential, and in addressing an urgent medical need of designing a treatment of bacterial biofilms.
threads was generated by secreting liquid mussel foot proteins (Mfps) from mussel foot. These Mfps are assembled and manufactured by glands by injection molding reaction. [3] The foot of a mussel presses against the surface to create a vacuum chamber, which propels the delivery of fluidic Mfps. It is believed that Mfps confined to plaques, such as Mfp-2, Mfp-3, Mfp-4, and Mfp-5, create coacervates when exposed to saltwater. All mfps include the post-translational amino acid DOPA, and mfp-5 contains the largest concentration of DOPA residues (30 mol%) and leads to strong adhesion. [4] It was reported that the coacervation of mfps, which occurs in a variety of ways, such as complex coacervation driven by electrostatic interaction, as revealed in polyions of Mfp-131 and Mfp-151, [5] and self-coacervation driven by electrostatic and/or hydrophobic forces as revealed in Mfp-3S. [6] An essential component in mussel adhesion is the special amino acid L-DOPA with its catechol group. [7] The catechols act as chemical jack-of-all-trades or Janus-like chemicals and allow attachment to almost all types of material surfaces using either covalent or noncovalent bonds. [8] Several research groups have suggested mussel-inspired materials to be used as bio-inspired adhesives, [9] with efforts being made by including features of the mussel foot proteins in synthetic polymers. [8a,b,10] Hence, catechols and analogues thereof are highly relevant in materials design. [8e,g] Great strides have been made in harnessing mussel-inspired chemistry in materials, however, many of previous efforts lack a simple and efficient way to deliver the materials to a surface underwater for efficient adhesion. [11] The blue mussel is thought to deliver its adhesive in the form of complex fluids that spread spontaneously and exhibit strong reversible interfacial bonding and tunable cross-linking. [4] The complex fluids are coacervates [12] -mainly composing mixtures of polyelectrolytes that form a separate phase from the aqueous medium. Thus, the mussel maintains its complex fluid glue that upon meeting the surface, spreads and presents DOPA residues to the target surface for attachment and subsequent curing (Figure 1A,B). Indeed, coacervates are used widely in biology (Figure 1A), including in sandcastle worm adhesives [13] and to infiltrate squid beak scaffold materials with proteins. [14] In the blue mussel, the whole gluing process takes only a few minutes and occurs within the spatial confines of the byssus Adhesion underwater is a major challenge. Mussel-inspired complex coacervates functionalized with L-3,4-dihydroxyphenylalanine (L-DOPA) are proposed for underwater adhesives through versatile chemistry of DOPA, however, simple, efficient, controllable, and nontoxic procedures to harness them are still under investigation. In this study, inspired from the mussel byssus formation process, coacervate adhesives are formed underwater by simple injection of an acidic proto-coacervate of DOPA functionalized polyelectrolytes on underwater surface...
The newest generation of cell‐based technologies relies heavily on methods to communicate to the engineered cells using artificial receptors, specifically to deactivate the cells administered to a patient in the event of adverse effects. Herein, artificial synthetic internalizing receptors are engineered that function in mammalian cells in 2D and in 3D and afford targeted, specific intracellular drug delivery with nanomolar potency in the most challenging cell type, namely primary, donor‐derived T cells. Receptor design comprises a lipid bilayer anchor for receptor integration into cell membrane and a small xenobiotic molecule as a recognition ligand. Artificial receptors are successfully targeted by the corresponding antibody–drug conjugate (ADC) and exhibit efficient cargo cell entry with ensuing intracellular effects. Receptor integration into cells is fast and robust and affords targeted cell entry in under 2 h. Through a combination of the receptor design and the use of ADC, combined benefits previously made available by chimeric artificial receptors (performance in T cells) and the chemical counterpart (robustness and simplicity) in a single functional platform is achieved. Artificial synthetic receptors are poised to facilitate the maturation of engineered cells as tools of biotechnology and biomedicine.
Implant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms, in vitro and in vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms, in vitro and in vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatment in vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.