Citrate-based fluorescent materials for low-cost chloride sensing in the diagnosis of cystic fibrosis

Abstract

Chloride is an essential electrolyte that maintains homeostasis within the body, where abnormal chloride levels in biological fluids may indicate various diseases such as Cystic Fibrosis. However, current analytical solutions for chloride detection fail to meet the clinical needs of both high performance and low material or labor costs, hindering translation into clinical settings. Here we present a new class of fluorescence chloride sensors derived from a facile citrate -based synthesis platform that utilize dynamic quenching mechanisms. Based on this low-cost platform, we demonstrate for the first time a selective sensing strategy that uses a single fluorophore to detect multiple halides simultaneously, promising both selectivity and automation to improve performance and reduce labor costs. We also demonstrate the clinical utility of citrate-based sensors as a new sweat chloride test method for the diagnosis of Cystic Fibrosis by performing analytical validation with sweat controls and clinical validation with sweat from individuals with or without Cystic Fibrosis. Lastly, molecular modeling studies reveal the structural mechanism behind chloride sensing, serving to expand this class of fluorescence sensors with improved chloride sensitivities. Thus citrate-based fluorescent materials may enable low-cost, automated multi-analysis systems for simpler, yet accurate, point-of-care diagnostics that can be readily translated into clinical settings. More broadly, a wide range of medical, industrial, and environmental applications can be achieved with such a facile synthesis platform, demonstrated in our citrate-based biodegradable polymers with intrinsic fluorescence sensing.

Synthesis and characterization of citrate-based fluorescent small molecules and biodegradable polymers

“…Previously, our group has demonstrated the applications of BPLPs in tissue engineering, bioimaging, theranostic drug delivery, and more recently, selective halide (chloride, bromide, iodide) sensing for fluorescence based diagnosis of cystic fibrosis 7, 14, 37, 38 . To establish that the TPA structure is indeed the fluorescent moiety of BPLPs, we synthesized polymers by reacting purified CA-Cys with 1,8-octanediol.…”

Citrate‐Based Fluorescent Biomaterials

“…Kim et al also developed a class of fluorescence chloride sensors based on CA derived fluorophores, utilizing dynamic quenching mechanisms. [48] In detail, a family of citrate-based fluorophores for chloride sensing were synthesized via a simple one-pot reaction of CA and a primary amine (L-cysteine, cysteamine, or methyl serine) in water. Taking CA-Cysteine (CA-Cys), which presented strong fluorescence with a high QY of 81% and a long lifetime of 10.06 ns, as an example, it is generally insensitive to chloride, but dynamic quenching by both protons and chloride happens when pH was below 2.4.…”

“…The developed citrate-based fluorescent materials, which included CDs, BPLPs, and molecular fluorophores, presented favorable biocompatibility/biodegradability, and strong and stable fluorescence, enabling their use in important biomedical applications, such as bioimaging, [31, 33, 37–43] biosensing, [37, 44–48] and nanomedicine. [49–51] For example, NIR-imaging information encryption and in vivo NIR fluorescence imaging of the stomach of a living mouse were achieved using citrate-based CDs synthesized from CA and urea.…”

“…[51] Moreover, molecular fluorophore synthesized from CA and Cysteine (CA-Cys) was applied as selective chloride sensors, and a smartphone operated chloridometer was further designed for the diagnosis of cystic fibrosis (CF). [48, 53] Overall, the development of citrate-based fluorescent materials in current studies has played a significant role in theranostic healthcare and regenerative engineering. This review will provide a comprehensive discussion of the design and synthesis strategies, material properties, fluorescence properties and mechanisms, as well as biomedical applications of various citrate-based fluorescent materials, including CDs, BPLPs, and molecular fluorophores.…”

Flexible biodegradable citrate-based polymeric step-index optical fiber

“…Unlike natural materials (e.g., silk) or traditional synthetic polymers (e.g., poly lactic-co-glycolic acid (PLGA)) that usually have limited tunability for key optical, mechanical, and/or degradation properties, the family of citrate-based biodegradable elastomers possesses tunable mechanical strengths (from tens of Pascal to mega Pascal), programmable degradation rates (from a few days to over a year), reactive nature between citrate-based polymers, multi-functionalities (e.g., adhesive, fluorescent)[14], and as shown in this work, ultrafine tuning of refractive index (~10 −3 )(Figure 1c). Citrate-based elastomers have been used as implant materials for diverse applications such as soft tissue engineering (blood vessel, nerve, and skin)[15–17], bone tissue engineering[18–21], wound healing and bioadhesives[22–26], theranostic nanoparticles for cancer imaging and drug delivery[12,27–33], and biosensing[34]. Therefore, citrate-based elastomers serve as an ideal material platform for the development of fully biodegradable and seamlessly integrated step-index optical fibers for in vivo applications.…”