Diabetic foot ulcers infected with antibiotic‐resistant bacteria form a severe complication of diabetes. Antimicrobial‐loaded hydrogels are used as a dressing for infected wounds, but the ongoing ...rise in the number of antimicrobial‐resistant infections necessitates new, nonantibiotic based designs. Here, a guanosine‐quadruplex (G4)‐hydrogel composed of guanosine, 2‐formylphenylboronic acid, and putrescine is designed and used as a cascade‐reaction container. The G4‐hydrogel is loaded with glucose‐oxidase and hemin. The first cascade‐reaction, initiated by glucose‐oxidase, transforms glucose and O2 into gluconic acid and H2O2. In vitro, this reaction is most influential on killing Staphylococcus aureus or Pseudomonas aeruginosa in suspension, but showed limited killing of bacteria in biofilm‐modes of growth. The second cascade‐reaction, however, transforming H2O2 into reactive‐oxygen‐species (ROS), also enhances killing of biofilm bacteria due to hemin penetration into biofilms and interaction with eDNA G‐quadruplexes in the biofilm matrix. Therewith, the second cascade‐reaction generates ROS close to the target bacteria, facilitating killing despite the short life‐time of ROS. Healing of infected wounds in diabetic mice proceeds faster upon coverage by these G4‐hydrogels than by clinically common ciprofloxacin irrigation. Moreover, local glucose concentrations around infected wounds decrease. Concluding, a G4‐hydrogel loaded with glucose‐oxidase and hemin is a good candidate for infected wound dressings, particularly in diabetic patients.
A supramolecular guanosine‐quadruplex (G4)‐hydrogel containing glucose oxidase and hemin provides a cascade‐reaction container suitable as an antibacterial dressing for infected wounds. The cascade‐reaction in the G4‐hydrogel generates reactive‐oxygen‐species inside an infectious biofilm from endogenous glucose, killing multidrug resistant bacteria on a nonantibiotic basis, yielding faster healing of infected wounds, and reducing local glucose levels in diabetic mice.
Extracellular polymeric substances (EPS) hold infectious biofilms together and limit antimicrobial penetration and clinical infection control. Here, we present zwitterionic micelles as a previously ...unexplored, synthetic self-targeting dispersant. First, a pH-responsive poly(ε-caprolactone)-
-poly(quaternary-amino-ester) was synthesized and self-assembled with poly(ethylene glycol)-
-poly(ε-caprolactone) to form zwitterionic, mixed-shell polymeric micelles (ZW-MSPMs). In the acidic environment of staphylococcal biofilms, ZW-MSPMs became positively charged because of conversion of the zwitterionic poly(quaternary-amino-ester) to a cationic lactone ring. This allowed ZW-MSPMs to self-target, penetrate, and accumulate in staphylococcal biofilms in vitro. In vivo biofilm targeting by ZW-MSPMs was confirmed for staphylococcal biofilms grown underneath an implanted abdominal imaging window through direct imaging in living mice. ZW-MSPMs interacted strongly with important EPS components such as eDNA and protein to disperse biofilm and enhance ciprofloxacin efficacy toward remaining biofilm, both in vitro and in vivo. Zwitterionic micellar dispersants may aid infection control and enhance efficacy of existing antibiotics against remaining biofilm.
Inadvertent photosensitizer-activation and singlet-oxygen generation hampers clinical application of photodynamic therapies of superficial tumors or subcutaneous infections. Therefore, a reversible ...photoswitchable system was designed in micellar nanocarriers using ZnTPP as a photosensitizer and BDTE as a photoswitch. Singlet-oxygen generation upon irradiation didnot occur in closed-switch micelles with ZnTPP/BDTE feeding ratios >1:10. Deliberate switch closure/opening within 65–80 min was possible through thin layers of porcine tissue in vitro, increasing for thicker layers. Inadvertent opening of the switch by simulated daylight, took several tens of hours. Creating deliberate cell damage and prevention of inadvertent damage in vitro and in mice could be done at lower ZnTPP/BDTE feeding ratios (1:5) in open-switch micelles and at higher irradiation intensities than inferred from chemical clues to generate singlet-oxygen. The reduction of inadvertent photosensitizer activation in micellar nanocarriers, while maintaining the ability to kill tumor cells and infectious bacteria established here, brings photodynamic therapies closer to clinical application.
Photothermal nanoparticles can be used for non-antibiotic-based eradication of infectious biofilms, but this may cause collateral damage to tissue surrounding an infection site. In order to prevent ...collateral tissue damage, we encapsulated photothermal polydopamine-nanoparticles (PDA-NPs) in mixed shell polymeric micelles, composed of stealth polyethylene glycol (PEG) and pH-sensitive poly(β-amino ester) (PAE). To achieve encapsulation, PDA-NPs were made hydrophobic by electrostatic binding of indocyanine green (ICG). Coupling of ICG enhanced the photothermal conversion efficacy of PDA-NPs from 33% to 47%. Photothermal conversion was not affected by micellar encapsulation. No cytotoxicity or hemolytic effects of PEG-PAE encapsulated PDA-ICG-NPs were observed. PEG-PAE encapsulated PDA-ICG-NPs showed good penetration and accumulation in a
biofilm. Penetration and accumulation were absent when nanoparticles were encapsulated in PEG-micelles without a pH-responsive moiety. PDA-ICG-NPs encapsulated in PEG-PAE-micelles found their way through the blood circulation to a sub-cutaneous infection site after tail-vein injection in mice, yielding faster eradication of infections upon near-infrared (NIR) irradiation than could be achieved after encapsulation in PEG-micelles. Moreover, staphylococcal counts in surrounding tissue were reduced facilitating faster wound healing. Thus, the combined effect of targeting and localized NIR irradiation prevented collateral tissue damage while eradicating an infectious biofilm.
Bacterial-infections are mostly due to bacteria in an adhering, biofilm-mode of growth and not due to planktonically growing, suspended-bacteria. Biofilm-bacteria are much more recalcitrant to ...conventional antimicrobials than planktonic-bacteria due to (1) emergence of new properties of biofilm-bacteria that cannot be predicted on the basis of planktonic properties, (2) low penetration and accumulation of antimicrobials in a biofilm, (3) disabling of antimicrobials due to acidic and anaerobic conditions prevailing in a biofilm, and (4) enzymatic modification or inactivation of antimicrobials by biofilm inhabitants. In recent years, new nanotechnology-based antimicrobials have been designed to kill planktonic, antibiotic-resistant bacteria, but additional requirements rather than the mere killing of suspended bacteria must be met to combat biofilm-infections. The requirements and merits of nanotechnology-based antimicrobials for the control of biofilm-infection form the focus of this Tutorial Review.
Bacterial infection is becoming the biggest threat to human health. The scenario is partly due to the ineffectiveness of the conventional antibiotic treatments against the emergence of ...multidrug‐resistant bacteria and partly due to the bacteria living in biofilms or cells. Adaptive biomaterials can change their physicochemical properties in the microenvironment of bacterial infection, thereby facilitating either their interactions with bacteria or drug release. The trends in treating bacterial infections using adaptive biomaterials‐based systems are flourishing and generate innumerous possibility to design novel antimicrobial therapeutics. This feature article aims to summarize the recent developments in the formulations, mechanisms, and advances of adaptive materials in bacterial infection diagnosis, contact killing of bacteria, and antimicrobial drug delivery. Also, the challenges and limitations of current antimicrobial treatments based on adaptive materials and their clinical and industrial future prospects are discussed.
Adaptive biomaterials can adapt their physicochemical properties under the trigger of infection environmental factors, thereby facilitating either their interaction with bacteria or payload release. This feature article summarizes the recent developments of adaptive materials in bacterial infection diagnosis, contact killing of bacteria, and antimicrobial drug delivery. Also, the challenges and limitations of current adaptive materials and future prospects are discussed.
Autophagy is an important biological mechanism for eukaryotic cells to regulate growth, death, and energy metabolism, and plays an important role in removing damaged organelles, misfolded or ...aggregated proteins, and clearing pathogens. It has been found that autophagy is closely related to cell survival and death, and is of great significance in cancerigenesis and development, playing a bidirectional role in cancer inhibition and cancer promotion. Therefore, treating cancers by regulating autophagy has attracted much attention. A large amount of research evidence indicates that polymeric nanomaterials are able to regulate cellular autophagy, and their good biocompatibility, degradability, and functionalizable modification open up a broad application prospect for improving the therapeutic effect of cancers. This review provides an overview of the research progress of polymeric nanomaterials for modulating autophagy in the treatment of cancers.
•DNase was be conjugated to PAE to form pH-responsive, self-targeting micelles.•PAE-conjugated DNase in micellar shells is not inactivated by blood enzymes.•PEG/PAE-DNase micelles disperse biofilms ...by degrading matrix eDNA.•Biofilm bacteria are more effectively killed by antibiotics after matrix degradation.•Murine pneumonia can be treated effectively with ciprofloxacin loaded PEG/PAE-DNase micelles.
DNase can break down the extracellular matrix that keeps infectious bacterial biofilm together through cleavage of eDNA. Herewith, biofilm bacteria can become dispersed to assist antibiotic eradication but this has hitherto remained an in vitro possibility. In vivo DNase is rapidly broken down in blood, impeding blood-injection of DNase combined with antibiotics to cure bacterial infections. Herein, we report the synthesis of pH-responsive, self-targeting micelles self-assembled from a solution of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and poly(ε-caprolactone)-block-poly(amino ester) (PCL-b-PAE) with DNase conjugated to PAE-blocks. At physiological pH, this conjugation protected DNase inside the micellar shell, while PEG prevented adsorption of blood-borne proteins to the micelles. PAE became positively-charged below pH 6.4 facilitating self-targeting to an infectious biofilm. Simultaneously, PAE became hydrophilic and stretched to expose DNase upon accumulation in an infectious S. aureus biofilm where it degraded the biofilm matrix. PEG/PAE-DNase micelles internally core-loaded with ciprofloxacin significantly better eradicated murine pneumonia after blood-injection than ciprofloxacin-loaded PEG/PAE micelles without conjugated DNase or ciprofloxacin free in solution. Considering that DNase is clinically approved for use in cystic fibrosis patients, this paves the way for clinical translation of ciprofloxacin-loaded, PEG/PAE-DNase micelles for the treatment of pneumonia and other infections that can be reached through self-targeting after blood-injection.
Radiosensitizers hold great promise for enhanced cancer radiotherapeutics. However, apoptosis evasion of cancerous cells usually limits the efficiency of radiosensitive strategies. Herein, an in situ ...self‐assembled supramolecular antagonist is developed to reinforce the treatment outcome of radiotherapy by inhibiting tumor apoptosis evasion. The supramolecular antagonist is composed of self‐assembled peptide functionalized with apoptosis‐inducing peptide SmacN7 and alkaline phosphatase (ALP)‐responsive group. Upon reaching the tumor site, the supramolecular antagonist can in situ form membrane‐localized nanofibers triggered by ALP overexpressing in tumor cells, leading to enhanced cellular internalization. As a result, the cell‐permeable supramolecular antagonist effectively binds to the inhibitor of apoptosis proteins (IAPs) and eliminates their inhibitory effect on caspase activity, thereby remarkably blocking the apoptosis evasion of tumor cells and boosting the therapeutic efficacy of radiotherapy. Furthermore, in vivo studies confirm that treatment with in situ self‐assembled supramolecular antagonists can enhance radiation‐induced tumor destruction without perceptible systemic toxicity. This study offers a novel strategy of tumor apoptosis evasion inhibition to potentiate radiotherapy, which may be instructive to the development of advanced cancer therapies.
An in situ self‐assembled supramolecular antagonist is proposed to enhance the radiation‐mediated antitumor activity by deactivating the tumor apoptosis evasion. Through self‐assembled into nanofibers under the activation by ALP overexpressed in tumor cells, supramolecular antagonists can effectively bind to inhibitor of apoptosis proteins and active caspase cascading response, thus inhibiting the tumor apoptosis evasion and amplifying tumor destruction of radiotherapy.
Internalization of Staphylococcus aureus by macrophages can inactivate bacterial killing mechanisms, allowing intracellular residence and dissemination of infection. Concurrently, these staphylococci ...can evade antibiotics that are frequently unable to pass mammalian cell membranes. A binary, amphiphilic conjugate composed of triclosan and ciprofloxacin is synthesized that self‐assemble through micelle formation into antimicrobial nanoparticles (ANPs). These novel ANPs are stabilized through encapsulation in macrophage membranes, providing membrane‐encapsulated, antimicrobial‐conjugated NPs (Me‐ANPs) with similar protein activity, Toll‐like receptor expression and negative surface charge as their precursor murine macrophage/human monocyte cell lines. The combination of Toll‐like receptors and negative surface charge allows uptake of Me‐ANPs by infected macrophages/monocytes through positively charged, lysozyme‐rich membrane scars created during staphylococcal engulfment. Me‐ANPs are not engulfed by more negatively charged sterile cells possessing less lysozyme at their surface. The Me‐ANPs kill staphylococci internalized in macrophages in vitro. Me‐ANPs likewise kill staphylococci more effectively than ANPs without membrane‐encapsulation or clinically used ciprofloxacin in a mouse peritoneal infection model. Similarly, organ infections in mice created by dissemination of infected macrophages through circulation in the blood are better eradicated by Me‐ANPs than by ciprofloxacin. These unique antimicrobial properties of macrophage‐monocyte Me‐ANPs provide a promising direction for human clinical application to combat persistent infections.
A novel amphiphilic conjugate composed of triclosan and ciprofloxacin self‐assembles into antimicrobial nanoparticles (ANPs) and is stabilized through encapsulation in a macrophage–monocyte membrane. These membrane‐encapsulated ANPs exclusively enter bacterially infected macrophages. Accordingly, membrane‐encapsulated ANPs kill staphylococci internalized in macrophages in vitro. Staphylococcal killing in mouse peritoneal and organ infection models by membrane‐encapsulated ANPs is more effective than clinically applied ciprofloxacin.
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