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Pancreatic cancer, a prevalent malignancy of the digestive system, has a poor 5-year survival rate of around 10%. Although numerous minimally invasive alternative treatments, including photothermal therapy and photodynamic therapy, have shown effectiveness compared with traditional surgical procedures, radiotherapy, and chemotherapy. However, the application of these alternative treatments is constrained by their depth of penetration, making it challenging to treat pancreatic cancer situated deep within the tissue. Sonodynamic therapy (SDT) has emerged as a promising minimally invasive therapy method that is particularly potent against deep-seated tumors such as pancreatic cancer. However, the unique characteristics of pancreatic cancer, including a dense surrounding matrix, high reductivity, and a hypoxic tumor microenvironment, impede the efficient application of SDT. Thus, to guide the evolution of SDT for pancreatic cancer therapy, this review addresses these challenges, examines current strategies for effective SDT enhancement for pancreatic cancer, and investigates potential future advances to boost clinical applicability. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2024 Wiley Periodicals LLC.)

Copper sulfide based phototherapy, including photothermal therapy and photodynamic therapy, is an emerging minimally invasive treatment of tumor, which the light was converted to heat or reactive oxygen to kill the tumor cells. Compared with conventional chemotherapy and radiation therapy, Cu 2-x S based phototherapy is more efficient and has fewer side effects. However, considering the dose-dependent toxicity of Cu 2-x S, the performance of Cu 2-x S based phototherapy still cannot meet the requirement of the clinical application to now. To overcome this limitation, engineering of Cu 2-x S to improve the phototherapy performance by increasing light absorption has attracted extensive attention. For better guidance of Cu 2-x S engineering, we outline the currently engineering method being explored, including (1) structural engineering, (2) compositional engineering, (3) functional engineering, and (4) performance engineering. Also, the relationship between the engineering method and phototherapy performance was discussed in this review. In addition, the further development of Cu 2-x S based phototherapy is prospected, including smart materials based phototherapy, phototherapy induced immune microenvironment modulation et al. This review will provide new ideas and opportunities for engineering of Cu 2-x S with better phototherapy performance. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2023 Wiley Periodicals LLC.)

The misdiagnosis of tumors due to insufficient penetration depth or signal interference and damage to normal tissues due to indiscriminate treatment are the biggest challenges in using photothermal agents for clinical translation. To overcome these limitations, a strategy of switching from the near-infrared (NIR)-I region to the NIR-II region was developed based on tumor microenvironment (TME)-mediated gold (Au) self-assembly. Using zeolitic imidazolate framework-8 (ZIF-8) metal-organic framework-coated gold nanorods (AuNRs@ZIF-8) as a model photothermal agent, we demonstrated that only a NIR-I photoacoustic imaging signal was observed in normal tissue because ZIF-8 could prevent the aggregation of AuNRs. However, when ZIF-8 dissociated in the TME, the AuNRs aggregated to activate NIR-II photoacoustic imaging and attenuate the NIR-I signal, thereby allowing an accurate diagnosis of tumors based on signal transformation. Notably, TME-activated NIR-II photothermal therapy could also inhibit tumor growth. Therefore, this TME-activated NIR-I-to-NIR-II switching strategy could improve the accuracy of deep-tumor diagnoses and avoid the injury caused by undifferentiated treatment. STATEMENT OF SIGNIFICANCE: Photothermal agents used for photoacoustic imaging and photothermal therapy have garnered great attention for tumor theranostics. However, always "turned on" near-infrared (NIR)-I laser (700-1000 nm)-responsive photothermal agents face issues of penetration depth and damage to normal tissues. In contrast, tumor microenvironment-activated NIR-II "smart" photothermal agents exhibit deeper penetration depth and tumor selectivity. Therefore, a NIR-I-to-NIR-II switching strategy was developed based on tumor microenvironment-mediated Au self-assembly. This work provides a new strategy for developing tumor microenvironment-activated NIR-II smart photothermal agents., Competing Interests: 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., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Frequency upconversion optical imaging has attracted great attention due to its remarkable advantages over traditional down-conversion optical imaging. However, the development of frequency upconversion optical imaging is extremely limited. Herein, five derivatives with BODIPY structure (B1-B5) were developed to investigate its frequency upconversion luminescence (FUCL) performance by introducing electron-donating and electron-withdrawing groups. Except for the nitro group decorated derivative, the other derivatives have strong and stable FUCL around 520 nm under 635 nm light excitation. More importantly, B5 retains FUCL ability after self-assembly. When applied to FUCL imaging of cells, B5 nanoparticles can be enriched in the cytoplasm and show a good signal-to-noise ratio. Meanwhile, FUCL tumor imaging can be achieved after 1 h of injection. This study not only provides a potential agent for FUCL biomedical imaging but also develops a new strategy for designing FUCL agents that exhibit excellent performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chemodynamic therapy (CDT) is a highly tumor-specific and minimally invasive treatment that is widely used in cancer therapy. However, its therapeutic effect is limited by the poor efficiency of hydroxyl radical generation. In colon cancer in particular, the high expression of hydrogen sulfide (H 2 S), which has strong reducibility, results in the consumption of generated hydroxyl radicals, further weakening the efficacy of CDT. To overcome this problem, we developed a novel two-dimensional (2D) Cu-bipyridine metal-organic framework (MOF) nanosheet [Cu(bpy) 2 (OTf) 2 ] for colon cancer CDT. The therapeutic effect of Cu(bpy) 2 (OTf) 2 is enhanced based on three factors. First, the developed 2D Cu-MOF rapidly consumes H 2 S to inhibit the consumption of generated hydroxyl radicals. Second, the ultrasmall CuS generated after H 2 S depletion facilitates Fenton-like reactions. Third, the generated CuS exhibits good photothermal performance in the second near-infrared window, allowing for photothermal-enhanced CDT. The ability of Cu(bpy) 2 (OTf) 2 to improve the CDT effect was demonstrated through both in vitro and in vivo experiments. This work demonstrates the applicability of 2D Cu-MOF in the CDT of colon cancer and provides a novel strategy for constructing CDT agents for colon cancer.

Combinations of immune checkpoint therapies show encouraging results in the treatment of many human cancers. However, the higher costs and greater side effects of such combinations compared with single-agent immunotherapies limit their further applications. In this work, a novel smart agent, KN046@ 19 F-ZIF-8, is developed to overcome these limitations. KN046 is a novel recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody-Fc fusion protein, which can bind to both PD-L1 and CTLA-4 effectively. ZIF-8 is a smart delivery system, which can safely and effectively deliver KN406 to a tumor. In vitro and in vivo results demonstrate that the smart agent KN046@ 19 F-ZIF-8 not only improves the immune response rate of the antibody drug in treatment of tumors but also reduces its toxic side effects, thereby achieving excellent antitumor efficacy. This study provides an engineering strategy for clinical applications of a more effective immunotherapy., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Although multimethod therapy has shown great promise for effective cancer treatment, it is still a great challenge to develop simple and effective strategies to construct multifunctional therapeutic reagents. According to the characteristics of the tumor microenvironment, such as a mild acidic environment and overexpression of H 2 O 2 , an intelligent therapeutic reagent with photoacoustic (PA) imaging-guided photothermal therapy, chemodynamic therapy, and in situ chemotherapy was constructed by simply loading disulfiram (DSF) in a Cu-based porous metal-organic framework (HKUST-1). The resultant material DFS@HKUST-1 shows near-infrared adsorption around 600-900 nm and effective photoacoustic imaging properties and photothermal conversion efficiency upon 808 nm irradiation. Besides, after DFS@HKUST-1 is enriched in the tumor, the acidic environment of the tumor will slowly trigger the decomposition of HKUST-1, leading to the release of Cu 2+ ions to react with DSF and endogenous H 2 O 2 to generate the Cu/DSF complex (CuET) and cytotoxic •OH for chemotherapy and chemodynamic therapy, respectively. Therefore, DFS@HKUST-1 can serve as a promising tumor microenvironment response therapeutic reagent for photoacoustic imaging-guided multimethod therapy.

Targeted T 1 -T 2 MRI contrast agents, which can eliminate the difficulty of image matching across multiple imaging instruments and permit specific localization of lesions, are promising candidates for more accurate diagnosis of tumors. In this study, ultrasmall Fe@Fe 3 O 4 nanoparticles were designed and synthesized as T 1 -T 2 dual-mode MRI contrast agents for accurate tumor imaging. First, to investigate the influence of nanoparticle size, Fe@Fe 3 O 4 nanoparticles with diameters of 4, 8, and 12 nm were prepared, among which the 8 nm 3-(3,4-dihydroxyphenyl)propionic acid (DHCA)-modified nanoparticles exhibited the optimal T 1 -T 2 dual-mode MRI performance. Next, to develop a tumor-targeted contrast agent, the DHCA-Fe@Fe 3 O 4 nanoparticles were conjugated with the F56 peptide, which targets the vascular endothelial growth factor receptor, and the resulting F56-DHCA-Fe@Fe 3 O 4 nanoparticles were found to exhibit good T 1 -T 2 dual-mode imaging and tumor-targeting performance both in vitro and in vivo, indicating the nanoparticles represent a new research tool for accurate tumor diagnosis., Competing Interests: Declaration of competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Second near-infrared window (NIR-II, 1000-1700 nm) absorption and fluorescent agents have attracted great attention because they can overcome the penetration limitation of the first near-infrared window (NIR-I, 750-1000 nm). However, these always "on" agents face the severe problem of being susceptible to retention and phagocytosis by the reticuloendothelial system after intravenous administration, which results in signal interference during diagnosis and side effects during treatment. Accordingly, tumor microenvironment-responsive smart agents (smart NIR-II agents), whose imaging and therapeutic functions can only be triggered in tumors, can overcome this limitation. Thus, NIR-II smart agents, which exhibit a combined response to the tumor microenvironment and NIR-II, make full use of the advantages of both triggers and improve the precision diagnosis and effective treatment of cancer. This review summarizes the recent advances in tumor microenvironment-activated NIR-II agents for tumor diagnosis and treatment, including smart NIR-II fluorescence imaging, photoacoustic imaging, photothermal therapy and photodynamic therapy. Finally, the challenges and perspectives of NIR-II smart agents for tumor diagnosis and treatment are proposed.

Theranostic agents based on near-infrared absorption which integrate both imaging and therapeutic functions have attracted considerable attention. However, because of the interference signal, indiscriminate treatment usually causes side effects on normal tissues during tumor treatment. To address this limitation, we propose a new synergistically triggered mechanism, release and self-assembly of Au nanospheres, for tumor theranostics based on the synergistic effect of H + and glutathione on the tumor microenvironment. In vitro experiments reveal that Au nanospheres release from Au@ZIF-8 at a high concentration of H + or glutathione. Importantly, Au aggregation only appears in the synergistic effect of glutathione and lower pH and exhibits strong coupling plasmonic resonance absorption in the near-infrared region and can be used as the theranostics agent. This statement was further verified by biological transmission electron microscopy and in vivo imaging. Au@ZIF-8 is stable and produces no photoacoustic signal in normal tissue; in contrast, in the presence of overexpressed glutathione and H + , Au nanospheres release from Au@ZIF-8, assemble to aggregates, and exhibit a strong signal at the tumor site for imaging and efficient photothermal therapy. This work provides a new strategy for designing theranostic agents with sequentially responsive steps to avoid interference diagnosis signals from normal tissues and reduce damage to normal tissue during treatment.

A nanoplatform for magnetic resonance imaging guidance and oxygen self-supplementing photodynamic therapy (PDT) was constructed on the basis of a porous metal-organic framework (PCN-222(Mn)), which was built by simple Mn-porphyrin ligands and biocompatible Zr 4+ ions. Because of the good dispersibility of Mn 3+ in the open framework and the high water affinity of the channel, PCN-222(Mn) exhibits a high longitudinal relaxivity of ∼35.3 mM -1 s -1 (1.0 T). In addition, it shows good catalytic activity for the conversion of endogenous hydrogen peroxide into oxygen, thereby improving tumor hypoxia during photodynamic therapy. The intravenous injection of PCN-222(Mn) into tumor-bearing mice mode provided good T 1 -weighted contrast of the tumor site and effectively inhibited tumor growth upon a single-laser irradiation. The findings provide insights for the development of multifunctional theranostic nanoplatforms based on simple components.

Tumor-microenvironment-responsive theranostics have great potential for precision diagnosis and effective treatment of cancer. Polyaniline (PANI) is the first reported pH-responsive organic photothermal agent and is widely used as a theranostic agent. However, tumor pH-responsive PANI-based theranostic agents are not explored, mainly because the conversion from the emeraldine base (EB) to emeraldine salt (ES) state of PANI requires pH < 4, which is lower than tumor acidic microenvironment. Herein, a tumor pH-responsive PANI-based theranostic agent is designed and prepared for amplified photoacoustic imaging guided augmented photothermal therapy (PTT), through intermolecular acid-base reactions between carboxyl groups of bovine serum albumin (BSA) and imine moieties of PANI. The albumin/PANI assemblies (BSA-PANI) can convert from the EB to ES state at pH < 7, accompanied by the absorbance redshift from visible to near-infrared region. Both in vitro and in vivo results demonstrate that tumor acidic microenvironment can trigger both the photoacoustic imaging (PAI) signal amplification and the PTT efficacy enhancement of BSA-PANI assemblies. This work not only highlights that BSA-PANI assemblies overcome the limitation of low-pH protonation, but also provides a facile assembly strategy for a tumor pH-responsive PANI-based nanoplatform for cancer theranostics., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Effective tumor diagnosis and therapy have always been a significant but challenging issue. Although nanomedicine has shown great potential for improving the outcomes of tumor diagnosis and therapy, the nonspecial targeted distribution of nanomedicine agents in the whole body causes a low diagnosis signal-to-noise ratio and a potential risk of systemic toxicity. Recently, the development of smart nanomedicine agents with diagnosis and therapy functions that can only be activated by the tumor microenvironment (TME) is regarded as an effective strategy to improve the theranostic sensitivity and selectivity, as well as reduce the potential side effects during treatment. This article will introduce and summarize the latest achievements in the design and fabrication of TME-responsive smart nanomedicine agents, and highlight their prospects for enhancing tumor diagnosis and therapy., Competing Interests: The authors report no conflicts of interest in regard to this work.

By exploiting the amorphous-crystalline transition of CuS, which results in greatly increased absorption throughout the entire near-infrared region, a novel smart off-on CuS photoacoustic imaging agent with good photostability and low cost is developed. More importantly, the photoacoustic imaging ability of CuS can be effectively activated by body temperature for in vivo cancer imaging.

Ultrasmall nanoparticles have attracted great attention because of their efficient renal clearance. However, their bioapplication is still severely hampered by the poor performance derived from low tumor accumulation. Here, a large, self-assembled nanoparticle was designed for cancer theranostics and used with paclitaxel (PTX) to assemble bovine serum albumin-coated ultrasmall gallic acid-Fe(III) (GA-Fe@BSA-PTX) nanoparticles by the hydrophobic effect. The GA-Fe@BSA-PTX self-assembled nanoparticles featured appropriate size (∼115 nm), high water dispersity and stability, and low cell toxicity. Importantly, the magnetic resonance imaging performance and tumor accumulation of GA-Fe@BSA-PTX self-assembled nanoparticles were much better than those of the ultrasmall GA-Fe@BSA nanoparticles. Furthermore, the GA-Fe@BSA-PTX self-assembled nanoparticles exhibited an excellent therapeutic effect on tumors, owing to the combined chemo- and photothermal effects. This work highlights the great potential of the as-synthesized GA-Fe@BSA-PTX self-assembled nanoparticles as a multifunctional theranostic nanoplatform, offering compelling opportunities for theranostic applications in the clinic.

Cancer theranostics agents, such as gold nanorods, represent great potential in cancer therapy . However, the big size and the low yield of the gold nanorods reported previously have limited their clinical translation. Therefore, it is significant to develop a new method to prepare the small gold nanorods (width <8 nm) at larger scale. In this report, a modified seedless method was proposed based on the effect of precursor concentration assisted synthesis of high quality small gold nanorods at large scale. The obtained small gold nanorods exhibit high quality and dimension of (18 ± 5 nm) × (5 ± 1 nm). After modified with biological compatibility reagents, the small gold nanorods behave excellent photoacoustic imaging and photo-thermal therapy ability. These results manifest that the obtained small gold nanorods not only realize the improvements of previously limitations, also are thus supposed to pave the way to cancer theranostics in clinic application., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Protein-related nanotheranostic agents hold great promise as tools to serve many clinical applications. Proteins such as BSA are used to regulate the synthesis of nondegradable inorganic nanoparticles (NPs). To fully employ the potential of such proteins, a new type of biosafe nanotheranostic agent must be designed to optimize BSA as a biomineralization agent. Here, a straightforward BSA-assisted biomineralization method was developed to prepare gallic acid (GA)-Fe(III) coordination polymer NPs. BSA-coated GA-Fe (GA-Fe@BSA) NPs were ultrasmall (3.5 nm) and showed good biocompatibility, a lower r 2 : r 1 ratio (1.06), and strong absorption in the visible near-infrared region. T 1 -weighted magnetic resonance imaging of tumor-bearing mice before and after intratumoral injection with GA-Fe@BSA NPs definitively demonstrated positive change. In a subsequent in vivo study, antitumor activity was precipitated by intratumoral injection of GA-Fe@BSA NPs combined with laser treatment, suggesting excellent outcomes with this treatment method. These results describe a successful protocol in which BSA regulated the synthesis of benign organic polymer NPs. GA-Fe@BSA NPs have the potential to be ideal agents to be used in clinical theranostic nanoplatforms., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Conventional wide bandgap semiconductors can absorb UV/visible light but have no photoabsorption band in the near-infrared (NIR) region, leading to difficulty in their use as NIR-responsive agents. With TiO 2 as an example, we report the tuning from UV-responsive TiO 2 nanocrystals to blue TiO 2 nanocrystals with newly appeared NIR absorption band through the Nb-doping strategy. A strong NIR band should result from the localized surface plasmon resonances due to the considerable free electrons originating from the efficient incorporation of Nb 5+ ions (<15.5%). Interestingly, under the irradiation of a 1064 nm laser, Nb-doped TiO 2 nanocrystals can convert laser energy into heat, and higher Nb-doping content can lead to higher NIR-induced temperature elevation, highlighting that the photothermal performances of TiO 2 nanocrystals can be dynamically modulated by adjusting the Nb-doping levels. After coating with PEGylated phospholipid, the resulting nanocrystals display water dispersibility, high photothermal conversion efficiency and cytocompatibility. Therefore, these Nb-doped TiO 2 nanocrystals can be used as efficient and heavy-metal-free nanoagents for the simultaneous NIR/photoacoustic imaging and photothermal therapy of tumors using a 1064 nm laser in the second biological window.

Magnetic Fe3 O4 crystals are produced in situ on preformed polypyrrole (PPY) nanoparticles by rationally converting the residual Fe species in the synthetic system. The obtained PPY@Fe(3)O(4)composite nanoparticles exhibit good photostability and biocompatibility, and they can be used as multifunctional probes for MRI, thermal imaging, and photothermal ablation of cancer cells., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Photothermal nanomaterials have recently attracted significant research interest due to their potential applications in biological imaging and therapeutics. However, the development of small-sized photothermal nanomaterials with high thermal stability remains a formidable challenge. Here, we report the rational design and synthesis of ultrasmall (<10 nm) Fe3O4@Cu2-xS core-shell nanoparticles, which offer both high photothermal stability and superparamagnetic properties. Specifically, these core-shell nanoparticles have proven effective as probes for T2-weighted magnetic resonance imaging and infrared thermal imaging because of their strong absorption at the near-infrared region centered around 960 nm. Importantly, the photothermal effect of the nanoparticles can be precisely controlled by varying the Cu content in the core-shell structure. Furthermore, we demonstrate in vitro and in vivo photothermal ablation of cancer cells using these multifunctional nanoparticles. The results should provide improved understanding of synergistic effect resulting from the integration of magnetism with photothermal phenomenon, important for developing multimode nanoparticle probes for biomedical applications.