| Cancer was a major chronic disease worldwide that continued to pose a persistent threat to the survival and health of mankind.Early detection and diagnosis facilitated an increased success rate of treatment and cure.In view of its advantages in non-invasive diagnosis,strong visualization,and high spatial resolution,bioluminescent imaging has become an important medical diagnostic imaging approach compared with traditional visualization techniques for diagnosing tumors.However,single bioluminescent imaging could not achieve functional and structural imaging simultaneously in the diagnostic imaging of tumors,which had limitations in generating more accurate and reliable biological information.Moreover,the performance of optical imaging and pathological detection based on the intrinsic optical properties of biological tissues alone could be restricted due to the lack of endogenous chromophores in the majority of biological tissues and structures.The urgent need to design dual-modal imaging that combines high-penetration depth and high-resolution features to profile deep-seated tumors and to develop a multifunctional nano-platform for "Theranostics" that could be used for dual-modal imaging and photodynamic therapy(PDT)of tumors was highlighted.Consequently,this study conducted a comprehensive investigation into near-infrared-II fluorescence imaging/photoacoustic imaging(NIR-II FLI/PAI)dual-modal imaging.The purpose was to integrate the advantageous features of NIR-II FLI,such as high signal-to-noise ratio and high sensitivity,with the high-resolution and deep tissue penetration capabilities of PAI.Furthermore,a multifunctional nanocluster was also designed for "Theranostics" under the guidance of dual-modal imaging simultaneously as an exogenous contrast agent,which could further improve the diagnostic performance of tumors and enhance the effect of imaging-guided PDT.The main research content of this article was as follows:(1)The problems of existing exogenous contrast agents,such as weak fluorescence emission properties,frequent photobleaching,and obvious biological toxicity,were addressed in this study.Palladium-doped bimetallic gold-palladium nanoclusters(Au Pd NCs)were proposed and synthesized.The nanoclusters prepared in this study showed the ideal ultra-small size and good dispersibility.The UV-visible absorption spectrum at 300–1000-nm wavelength exhibited excellent near-infrared absorption.Meanwhile,combined with fluorescence emission spectroscopy,the fluorescence emission center exhibited a redshift to1250-nm,and the fluorescence intensity increased by about 2.1 times,showing a positive correlation with the concentration of Au Pd NCs,similar to the intensity of photoacoustic signals.As a result,it could serve as a Nanoprobe for dual-modal imaging-guided tumor tracing and diagnosis.The above experiment supported that Au Pd NCs had excellent NIR-II fluorescence emission,broad infrared absorption,and biosafety.It provided a basic performance guarantee and the possibility for subsequent construction of a multifunctional nano-platform for tumor diagnosis and treatment under the guidance of NIR-II FLI/PAI dual-modal imaging.(2)To overcome limitations of drug resistance induced by traditional intravesical instillation,as well as the poor selectivity and short retention time of existing exogenous contrast agents in the bladder,a novel temperature-responsive bidirectional nano-delivery system(Au Pd-PNIPAM-FA Nanoprobe Bidirectional Delivery Systems,Au Pd-P-FA NBDs)was proposed and constructed in this study.The prepared Au Pd-P-FA NBDs could bind poly-(N-isopropylacrylamide)and folic acid on the surface of Au Pd NCs through EDC/NHS coupling reaction,revealing excellent NIR-II fluorescence emission and photoacoustic absorption performance.After injecting Au Pd-P-FA NBDs into nude mice with bladder cancer via the tail vein,laser irradiation was applied when the maximum aggregation in the bladder was reached(1.0 h).This led to a local temperature rise that activated the reversible phase transition of Au Pd-P-FA NBDs and prolonged their retention time in the bladder.At the 6.0-h time point after injection,strong NIR-II FLI/PAI signals were clearly observed in the cancerous area of the bladder.This type of exogenous Nanoprobe combines the "Perfusion-like" and "Active Targeting" delivery modes,offering a potential solution to the problem of drug resistance associated with the traditional invasive mode of intravesical instillation.Furthermore,it has the potential to extend the retention time and achieve high-specificity targeting of the exogenous Nanoprobe at the tumor site within the bladder,providing a new opportunity for NIR-II FLI/PAI-guided early non-invasive diagnosis and real-time imaging of bladder cancer.(3)In hypoxic areas of tumor tissue,PDT exhibits limited killing power against tumor cells and consumes a significant amount of oxygen,potentially causing damage to vascular structures and exacerbating tumor tissue hypoxia,leading to an unsatisfactory therapeutic effect.To address this issue,a novel multifunctional cluster nano-platform(Au Pd-BSA Cluster Nanotheranostics,Au Pd-BSA CNs)was proposed and developed for the diagnosis and treatment of tumors.The corresponding results indicated that the prepared Au Pd-BSA CNs,which were bound to bovine serum albumin(BSA),exhibited good biocompatibility and an excellent fluorescence emission spectrum(at 1250 nm).Additionally,their photoacoustic signal intensity was approximately 15 times higher than that in blood samples from the modeled nude mice.Thus,they can be utilized for NIR-II FLI with high contrast and PAI with high spatial resolution in vivo.Importantly,further detection of in vitro free-radical markers and experiments on cell killing by PDT confirmed the ability of Au Pd-BSA CNs to achieve a successful PDT process under both hypoxic and normoxic conditions.Moreover,after injecting Au Pd-BSA CNs into the tail vein for 10 h,the tumor site was illuminated,facilitating accurate localization of the tumor tissue’s position and morphology.This illumination also aided in determining the optimal time point for treatment.By utilizing Type I/Type II PDT and the catalytic activity of synergistic glucose oxidase,efficient tumor killing was achieved under the guidance of NIR-II FLI/PAI dual-modal imaging in hypoxic environments.Consequently,this approach effectively addresses the issue of poor efficacy in type II PDT,which heavily relies on oxygen.Overall,the proposal of this type of Nanoprobe offers a promising design strategy for NIR-II FLI/PAI-guided PDT in hypoxic environments.The results presented in this paper provide a novel direction and idea for the design and development of the multifunctional "Theranostic" nanoplatform.The focus is on the superiority and feasibility of alloy nanoclusters and alloy nanocluster complexes as a multifunctional nanotheranostic platform.Additionally,the findings provide a realistic theoretical basis and a solid experimental foundation for the future development and advancement of NIR-II FLI/PAI/PDT "Theranostics."... |
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