Nitroreductase-responsive nanoparticles for in situ fluorescence imaging and synergistic antibacterial therapy of bacterial keratitis

doi:10.1016/j.biomaterials.2024.122565

Biomaterials

Volume 308, July 2024, 122565

https://doi.org/10.1016/j.biomaterials.2024.122565 Get rights and content

Abstract

As bacterial keratitis progresses rapidly, prompt intervention is necessary. Current diagnostic processes are time-consuming and invasive, leading to improper antibiotics for treatment. Therefore, innovative strategies for diagnosing and treating bacterial keratitis are urgently needed. In this study, Cu_2-xSe@BSA@NTRP nanoparticles were developed by loading nitroreductase-responsive probes (NTRPs) onto Cu_2-xSe@BSA. These nanoparticles exhibited integrated fluorescence imaging and antibacterial capabilities. In vitro and in vivo experiments showed that the nanoparticles produced responsive fluorescence signals in bacteria within 30 min due to an interaction between the released NTRP and bacterial endogenous nitroreductase (NTR). When combined with low-temperature photothermal therapy (PTT), the nanoparticles effectively eliminated E. coli and S. aureus, achieved antibacterial efficacy above 95% and facilitated the re-epithelialization process at the corneal wound site in vivo. Overall, the Cu_2-xSe@BSA@NTRP nanoparticles demonstrated potential for rapid, noninvasive in situ diagnosis, treatment, and visualization assessment of therapy effectiveness in bacterial keratitis.

Graphical abstract

Introduction

Bacterial keratitis is the most common type of infectious keratitis. As an ocular emergency, the disease progresses rapidly and necessitates urgent intervention [[1], [2], [3]]. The current diagnostic methods for bacterial keratitis, including corneal scraping, bacterial culture, and Gram staining, are traumatic, time-consuming, labor-intensive, and tedious to perform [4,5]. Notably, the percentage of positive culture results is low, ranging from 38% to 66% [6,7]. Clinicians often make empirical diagnoses based on the lesion morphology and clinical manifestations of a patient, then administer tentative treatments with broad-spectrum antibiotics. However, the widespread and indiscriminate use of antibiotics on ocular surfaces leads to increased bacterial resistance [[8], [9], [10]]. Therefore, noninvasive, expeditious, and sensitive in situ diagnostic methods and effective antibacterial strategies for diagnosing and treating bacterial keratitis must be explored to mitigate the issue of drug-resistant bacterial strains.

Fluorescence imaging has emerged as a powerful technique for diagnosing bacterial infections in situ owing to its inherent advantages, such as convenience, high sensitivity, and real-time monitoring capability [[11], [12], [13]]. Various types of fluorescent probes have been developed to improve imaging accuracy [14]. Unlike traditional “always-on” fluorescent probes that always show fluorescence signals under excitation light, activatable fluorescent probes, which consist of fluorophores, linker groups, and recognition groups, are not fluorescent until activated by specific bacterial microenvironments. As a result, these probes demonstrate relatively higher contrast at the targeted site [15,16]. Nitroreductase (NTR) is an endogenous enzyme that is highly expressed in Gram-positive and Gram-negative bacteria [[17], [18], [19]]. Several fluorescent probes responsive to NTR have been reported to exhibit high sensitivity and selectivity and have been successfully used for in vitro bacterial imaging [20,21]. In our previous study, we successfully synthesized a nitroreductase-responsive probe (NTRP) with the chemical formula C₄₃H₅₀IN₃O₃. This approach achieved the desired turn-on fluorescence imaging in response to NTR [22]. Consequently, the synthesized NTRP shows promise for noninvasive fluorescence imaging-based diagnosis of bacterial keratitis in situ.

In order to mitigate the emergence of antimicrobial resistance and simultaneously enhance antibacterial efficiency, a variety of nanoparticles [[23], [24], [25], [26], [27], [28]], including gold (Au), silver (Ag), Zinc oxide (ZnO), and copper (Cu), have emerged as promising antibacterial agents for combating severe bacterial infections [[29], [30], [31], [32]]. Copper-based nanoparticles are widely used as antibacterial agents for the treatment of bacterial infections due to their exceptional antibacterial activity against Gram-positive and Gram-negative bacteria [[33], [34], [35]]. Copper ions released from nanoparticles can be cytotoxic and effective at killing bacteria by disrupting cell membranes, denaturing protein structures, or altering enzymatic functions [36]. Additionally, these nanoparticles demonstrate remarkable photothermal conversion efficiency and can rapidly reach effective temperatures for bacterial elimination [[37], [38], [39], [40]]. It is widely acknowledged that bacteria often develop resistance to antibiotics by blocking or reducing drug absorption, enhancing drug metabolism, or promoting drug excretion. In comparison, bacteria that develop resistance to heat pose a greater challenge [[41], [42], [43]]. Therefore, combining copper-based nanoparticles with photothermal therapy (PTT) can effectively eradicate bacteria. Furthermore, copper ions play a significant role in promoting the generation of nitric oxide (NO) from naturally occurring nitrites in wound exudates, as well as in facilitating the expression of iNOS, thus promoting the production of NO [[44], [45], [46], [47]]. This process significantly alleviates keratitis-related inflammation by simultaneously modulating the expression of toll-like receptor 2 (TLR2) and tumor necrosis factor-α (TNF-α) [48], thereby facilitating the process of corneal regeneration [49].

The application of multifunctional nanoparticles has emerged as a promising approach for the early diagnosis and therapy of bacterial infections. In the present study, copper-based nanoparticles loaded with NTR-responsive probes were designed and constructed. As depicted in Scheme 1, bovine serum albumin (BSA) was used as a template for Cu_2-xSe@BSA synthesis and as a linker to load the NTRP. Through the electrostatic interaction between negatively charged Cu_2-xSe@BSA and positively charged NTRP, the NTRP was successfully loaded onto Cu_2-xSe@BSA, resulting in the formation of Cu_2-xSe@BSA@NTRP nanoparticles. We systematically investigated the NTR- and bacteria-responsive fluorescence imaging capabilities, antibacterial performance, and potential for promoting corneal healing of the Cu_2-xSe@BSA@NTRP nanoparticles in vitro and in vivo. Notably, these nanoparticles exhibited pH-dependent NTRP release behavior and bacteria-responsive fluorescence imaging capability. After the nanoparticles were topically administered to infected corneas in mouse models, increased NTRP release was achieved in a weakly acidic environment; as a result, bacteria-responsive fluorescence imaging was facilitated through an interaction between the released NTRP and the bacterial endogenous NTR. Furthermore, the nanoparticles effectively eliminated bacteria through the synergistic effects of copper ions in combination with low-temperature PTT. Moreover, the presence of copper ions further accelerated re-epithelialization and wound healing in the corneas. Consequently, the application of Cu_2-xSe@BSA@NTRP nanoparticles offers a promising platform for highly responsive imaging diagnosis, efficient treatment and visualization assessment of therapy effectiveness in bacterial keratitis, serving as a supplementary diagnostic and therapeutic tool for this condition.

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Section snippets

Materials

Sodium selenite (Na₂SeO₃) and copper chloride (CuCl₂) were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Bovine serum albumin (BSA), ascorbic acid, dichloromethane (DCM), dimethylformamide (DMF), phosphorus oxychloride, and acetic anhydride (Ac₂O) were purchased from Aladdin Reagent Co., Ltd. (Shanghai, China). All the chemicals were used as received without further purification. S. aureus (ATCC 25923) and E. coli (ATCC 25922) were obtained from Bena Culture Collection

Preparation and characterization of Cu_2-xSe@BSA@NTRP

Cu_2-xSe@BSA@NTRP was prepared by loading NTRP onto Cu_2-xSe@BSA nanoparticles. First, Cu_2-xSe@BSA nanoparticles were obtained using a facile oxidation‒reduction method as described in previous studies [[50], [51], [52]]. In this method, selenium nanoparticles, which were obtained by reducing Na₂SeO₃ with ascorbic acid, served as sacrificial templates and reacted with Cu⁺ to produce copper selenide nanoparticles. The nanoparticles were gradually oxidized upon exposure to air, resulting in the

Conclusion

In summary, NTR-responsive copper-based nanoparticles, denoted as Cu_2-xSe@BSA@NTRP, were successfully developed by loading NTRP onto Cu_2-xSe@BSA through electrostatic interactions. These nanoparticles exhibited several desirable characteristics, including NTR-responsive fluorescence imaging capability, antibacterial properties, and satisfactory biocompatibility. Cu_2-xSe@BSA@NTRP demonstrated greater NTRP release in an acidic environment, which was beneficial for facilitating NTR-responsive

Supporting Information

Supporting Information: Materials; TEM characterizations of Cu_2-xSe@BSA; XRD and XPS characterizations of Cu_2-xSe@BSA; Chemical structure and mass spectrum of the NTRP; UV–Vis Spectra of NTRP; Chemical structure of HQO; The photothermal performance of Cu_2-xSe@BSA; Confocal fluorescence images of bacteria treated with Cu_2-xSe@BSA@NTRP; CFU assay of Cu_2-xSe@BSA@NTRP without laser irradiation; High-resolution images and EDS mapping; Photothermal performance of Cu_2-xSe@BSA@NTRP incubated with

CRediT authorship contribution statement

Jing Xiang: Writing – original draft, Methodology, Investigation, Formal analysis. Ruifen Zou: Methodology, Investigation, Funding acquisition, Formal analysis. Pin Wang: Methodology. Xinfangzi Wang: Methodology. Xuefei He: Funding acquisition, Methodology. Fang Liu: Conceptualization, Funding acquisition, Writing – review & editing. Chen Xu: Writing – review & editing, Writing – original draft, Supervision, Methodology, Funding acquisition, Conceptualization, Formal analysis. Aiguo Wu: Writing

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the National Key R&D Program of China (2023YFC2415700), the National Natural Science Foundation of China (82001890, 32025021), the International Cooperation and Exchange of the National Natural Science Foundation of China (32111540257), the Natural Science Foundation of Zhejiang Province, China (LTGY24H180009, LQ22H180006), the Medical Scientific Research Foundation of Zhejiang Province, China (2023KY1081), the Science and Technology Bureau of Ningbo City, China (

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¹: The first two authors contributed equally to this paper.

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Nitroreductase-responsive nanoparticles for in situ fluorescence imaging and synergistic antibacterial therapy of bacterial keratitis

Abstract

Graphical abstract

Introduction

Access through your organization

Section snippets

Materials

Preparation and characterization of Cu2-xSe@BSA@NTRP

Conclusion

Supporting Information

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgements

Exp. Eye Res.

Lancet Infect. Dis.

Curr. Opin. Chem. Biol.

Coord. Chem. Rev.

Chem. Eng. J.

Chem. Eng. J.

Chem. Eng. J.

Colloids Surf., B

Mater. Sci. Eng. C

J. Colloid Interface Sci.

Chem. Eng. J.

J. Invest. Dermatol.

Biomaterials

Colloids Surf. B Biointerfaces

Biomaterials

Mater. Today Bio

Neurochem. Int.

Crit. Rev. Oncol. Hematol.

Ocul. Surf.

Infectious keratitis in 2021

JAMA

Bacterial ocular surveillance system (BOSS) Sydney, Australia 2017-2018

Comm. Dis. Intell.

Fluorescent silicon nanoparticles-based nanotheranostic agents for rapid diagnosis and treatment of bacteria-induced keratitis

Nano Res.

Bacterial keratitis: identifying the areas of clinical uncertainty

Prog. Retin. Eye Res.

12-year analysis of incidence, microbiological profiles and in vitro antimicrobial susceptibility of infectious keratitis: the Nottingham infectious keratitis study

Br. J. Ophthalmol.

Queensland microbial keratitis database: 2005-2015

Br. J. Ophthalmol.

Super-cationic carbon quantum dots synthesized from spermidine as an eye drop formulation for topical treatment of bacterial keratitis

ACS Nano

Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis

JAMA Ophthalmol.

Fluorescent nanosystems for drug tracking and theranostics: recent applications in the ocular field

Pharmaceutics

Development of a universal fluorescent probe for Gram-positive bacteria

Angew. Chem., Int. Ed. Engl.

Multifunctional nanoagents for ultrasensitive imaging and photoactive killing of Gram-negative and Gram-positive bacteria

Nat. Commun.

Recent progress in fluorescent probes for bacteria

Chem. Soc. Rev.

Activatable fluorescent probes for in situ imaging of enzymes

Chem. Soc. Rev.

Enzyme-responsive turn-on nanoprobes for in situ fluorescence imaging and localized photothermal treatment of multidrug-resistant bacterial infections

J. Mater. Chem. B

In vivo bacterial imaging without engineering; A novel probe-based strategy facilitated by endogenous nitroreductase enzymes

Curr. Gene Ther.

A chalcone-based fluorescent responsive probe for selective detection of nitroreductase activity in bacteria

New J. Chem.

Preparation and characterization of Cu_2-xSe@BSA@NTRP