Engineering of copper sulfide mediated by phototherapy performance.

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, Cu2-x S based phototherapy is more efficient and has fewer side effects. However, considering the dose-dependent toxicity of Cu2-x S, the performance of Cu2-x S based phototherapy still cannot meet the requirement of the clinical application to now. To overcome this limitation, engineering of Cu2-x S to improve the phototherapy performance by increasing light absorption has attracted extensive attention. For better guidance of Cu2-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 Cu2-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 Cu2-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.

Tumor microenvironment-mediated NIR-I-to-NIR-II transformation of Au self-assembly for theranostics.

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.

Engineering of an endogenous hydrogen sulfide responsive smart agent for photoacoustic imaging-guided combination of photothermal therapy and chemotherapy for colon cancer.

INTRODUCTION: Photothermal therapy can be synergistically combined with chemotherapy to improve the therapeutic effect for colon cancer. However, conventional therapeutic agents have side effects in normal tissues, limiting their application. OBJECTIVES: To reduce these side effects, a smart agent (Cur@HKUST-1@PVP) whose functionality is triggered by the high content of endogenous hydrogen sulfide in colon tumors was engineered for photoacoustic imaging-guided combination of photothermal therapy and chemotherapy for colon tumors. METHODS: After reacting with hydrogen sulfide, Cur@HKUST-1@PVP simultaneously generates CuS and releases curcumin. The generated CuS serves as an imaging agent for both photothermal therapy and photoacoustic imaging, while the released curcumin is used for chemotherapy. RESULTS: In vivo photoacoustic imaging experiments demonstrated that Cur@HKUST-1@PVP can be used for selectively imaging colon cancer tumors. In vivo experiments in mice for treatment suggested that the endogenous hydrogen sulfide-activated combination of photothermal therapy and chemotherapy has a better treatment effect that photothermal therapy or chemotherapy treatment alone. CONCLUSION: The endogenous hydrogen sulfide-activated Cur@HKUST-1@PVP agent developed herein shows great potential for the accurate diagnosis and effective treatment of colon cancer.

2D Cu-Bipyridine MOF Nanosheet as an Agent for Colon Cancer Therapy: A Three-in-One Approach for Enhancing Chemodynamic Therapy.

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 (H2S), 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 H2S to inhibit the consumption of generated hydroxyl radicals. Second, the ultrasmall CuS generated after H2S 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.

Hyaluronic acid-coated Bi:Cu2O: an H2S-responsive agent for colon cancer with targeted delivery and enhanced photothermal performance.

BACKGROUND: Endogenous hydrogen sulfide (H2S)-responsive theranostic agents have attracted extensive attention due to their specificity for colon cancer. However, the development of such agents with high enrichment in tumors and excellent photothermal performance remains challenging. RESULTS: We prepared hyaluronic acid (HA)-coated Bi-doped cuprous oxide (Bi:Cu2O@HA) via a one-pot method. The HA specifically targets colon cancer tumor cells to improve the enrichment of Bi:Cu2O@HA at tumor sites, while the doped Bi both enhances the photothermal performance of the H2S-triggered Cu2O and serves as an agent for tumor imaging. The results in this work demonstrated that the Bi:Cu2O@HA nanoparticles exhibit good biocompatibility, target colon cancer tumor cells, facilitate computed tomography imaging, and enhanced H2S-responsive photothermal therapy performance, resulting in an excellent therapeutic effect in colon cancer. CONCLUSIONS: The novel Bi:Cu2O@HA nanoparticles exhibit excellent tumor targeting and photothermal therapeutic effects, which provide new strategies and insights for colon cancer therapy.

Magnetic-Photoacoustic Dual-Mode Probe for the Visualization of H2S in Colorectal Cancer.

Techniques for the qualitative and quantitative detection of H2S in vivo have attracted considerable attention due to the key role of H2S in various physiological and pathological processes. However, in vivo detection strategies for H2S are mainly based on fluorescence imaging, which is limited by its poor tissue penetration. Moreover, the limitations of single-mode probes are amplified in complex physiological environments. Herein, a core-shell Fe3O4@Cu2O nanoparticle was constructed as a magnetic-photoacoustic dual-mode probe for H2S detection in vitro and in vivo based on the in situ response of Cu2O to endogenous H2S in colon tumors. This probe is expected to greatly improve the accuracy of H2S detection in vivo because it employs two detection methods with complementary advantages. The new probe was experimentally applied to the in vivo and in vitro visualization of H2S in mice with colorectal cancer, validating the in situ reaction-activated dual-detection method. This work establishes a simple and efficient dual-mode imaging method based on a novel trigger mechanism. The findings provide a new strategy for colon cancer detection based on the in situ reactions at tumor sites.

A smart theranostic platform for photoacoustic and magnetic resonance dual-imaging-guided photothermal-enhanced chemodynamic therapy.

The use of smart theranostic agents in multimodal imaging and treatment is a promising strategy to overcome the limitations of single mode diagnosis and treatment, and can greatly improve the diagnosis and effects of treatment. In this study, a gold@manganese dioxide (Au@MnO2) core-shell nanostructure was designed as a glutathione (GSH)-triggered smart theranostic agent for photoacoustic and magnetic resonance (MR) dual-imaging-guided photothermal-enhanced chemodynamic therapy. Both in vitro and in vivo experiments demonstrated not only that the photoacoustic and MR imaging function of Au@MnO2 could be activated by a high endogenous GSH concentration, but also that after being triggered by the endogenous GSH, Au@MnO2 had an excellent synergistic treatment effect in photothermal-enhanced chemodynamic therapy under the guidance of photoacoustic and MR imaging. This study demonstrated that the use of GSH-triggered Au@MnO2 in photoacoustic and MR dual-imaging-guided photothermal-enhanced chemodynamic therapy is a smart theranostic nanoplatform for the accurate diagnosis and efficient treatment of cancer.

pH and Glutathione Synergistically Triggered Release and Self-Assembly of Au Nanospheres for Tumor Theranostics.

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.

Mn-Porphyrin-Based Metal-Organic Framework with High Longitudinal Relaxivity for Magnetic Resonance Imaging Guidance and Oxygen Self-Supplementing Photodynamic Therapy.

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 Zr4+ ions. Because of the good dispersibility of Mn3+ 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 T1-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.

Surface Plasmon Resonance-Enhanced Photoacoustic Imaging and Photothermal Therapy of Endogenous H2 S-Triggered Au@Cu2 O.

Smart theranostics agents triggered by endogenous H2 S with combined activated photoacoustic imaging and photothermal therapy can improve the diagnosis and treatment of colon cancer. However, the low theranostic performance of the current smart theranostics agents after the triggering step has limited their further application. In this work, the theranostic performance of endogenous H2 S-triggered Au@Cu2 O for the diagnosis and treatment of colon cancer, which is generated from the localized surface plasmon resonance coupling effect between a noble metal (Au) and a semiconductor (Cu2 O), is investigated. Compared with Cu2 O, the prepared H2 S-triggered Au@Cu2 O shows a significantly stronger absorption at the near-infrared region, such as a ≈2.1 times change at 808 nm, giving a photothermal conversion efficiency increase of ≈1.2 times. More importantly, Au@Cu2 O still exhibits good photoacoustic imaging contrast and photothermal properties for treatment of colon cancer in vivo even at very low injection doses. This work not only investigates an endogenous H2 S-triggered Au@Cu2 O theranostic agent with enhanced theranostic performance for colon cancer but also provides a novel strategy for designing high-performance theranostic agents.

Tumor pH-Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy.

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.

Macrophages-Mediated Delivery of Small Gold Nanorods for Tumor Hypoxia Photoacoustic Imaging and Enhanced Photothermal Therapy.

Macrophage-mediated delivery of drugs or nanoparticles has great potential in cancer treatment because it can avoid interception by the immune system and cross the blood-vessel barriers to reach the hypoxic regions of tumors. However, macrophage-based delivery system still faces some great challenges such as low theranostics agent loading capacity and hypoxic regions tendency in vivo. Herein, small gold nanorods (AuNRs) were used as the model theranostics agent to design a macrophage-mediated delivery system with high loading quantity for tumor hypoxia photoacoustic (PA) imaging and enhanced photothermal therapy (PTT). AuNRs modified with various thiolated poly(ethylene glycol)s (HS-PEG) via ligand exchange were investigated for toxicity and cell uptake by macrophages. The tumor hypoxic regions tendency of macrophage-loaded Anionic-AuNRs (Anionic-AuNRs@RAW) were verified by in vivo PA imaging and tumor sections. In vivo systemic PTT demonstrated enhanced tumor inhibition of anionic-AuNRs@RAW. This macrophage-mediated delivery system with high loading capacity could be used to enhance the effectiveness of cancer treatment.

Ultrasmall WO3- x@γ-poly-l-glutamic Acid Nanoparticles as a Photoacoustic Imaging and Effective Photothermal-Enhanced Chemodynamic Therapy Agent for Cancer.

Synergistic treatment strategies for cancer have attracted increasing attention owing to their enhanced therapeutic effects compared with monotherapy. Chemodynamic therapy (CDT) is an emerging and thriving in situ treatment for cancer owing to its high regioselectivity and activation only by endogenous substances. However, the therapeutic effects of CDT are hindered by low reaction speeds. Here, ultrasmall WO3- x@γ-poly-l-glutamic acid (WO3- x@γ-PGA) nanoparticles (NPs) with good photoacoustic and photothermal properties were prepared, and their chemodynamic performance based on a Fenton-like reaction was explored due to its good catalytic effect. The synergistic treatment effect was also investigated by photothermal-enhanced CDT based on single WO3- x@γ-PGA NPs using a penetrating near-infrared-II laser both in vitro and in vivo. This work provides an effective treatment for cancer and further develops the CDT.

Concentration effect on large scale synthesis of high quality small gold nanorods and their potential role in cancer theranostics.

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 ±â€¯5 nm) × (5 ±â€¯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.

Functionalized Cu3BiS3 nanoparticles for dual-modal imaging and targeted photothermal/photodynamic therapy.

Multifunctional nano-biomaterials with the integration of diagnostic and therapeutic functions have shown great promise in improving the efficacy of cancer therapy. Herein, a new nanoplatform based on functionalized Cu3BiS3 nanoparticles (NPs) is fabricated for tumour-targeted combination phototherapy. The as-synthesized hydrophobic Cu3BiS3 NPs are modified with DSPE-PEG/DSPE-PEG-NH2, followed by the conjugation of the photosensitizer chlorin e6 (Ce6) and the target ligand folic acid (FA). The introduced Ce6 can further form a chelate complex with Gd3+. The rationally designed Cu3BiS3-PEG-(Ce6-Gd3+)-FA NPs, which have high physiological stability and good biocompatibility, can specifically target FA-receptor over-expressed tumour cells. The Cu3BiS3-PEG-(Ce6-Gd3+)-FA NPs exhibit effective dual-modal CT and MR imaging in the xenografted HeLa tumours. Importantly, excellent in vivo anti-tumour effects have been achieved by synergistic photothermal/photodynamic therapy using the multifunctional NPs. We expect that this versatile nanoplatform will play a role in exploring precise cancer diagnosis and therapy.

BSA-assisted synthesis of ultrasmall gallic acid-Fe(III) coordination polymer nanoparticles for cancer theranostics.

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 r2:r1 ratio (1.06), and strong absorption in the visible near-infrared region. T1-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.

Dynamically tuning near-infrared-induced photothermal performances of TiO2 nanocrystals by Nb doping for imaging-guided photothermal therapy of tumors.

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 TiO2 as an example, we report the tuning from UV-responsive TiO2 nanocrystals to blue TiO2 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 Nb5+ ions (<15.5%). Interestingly, under the irradiation of a 1064 nm laser, Nb-doped TiO2 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 TiO2 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 TiO2 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.

Multifunctional polypyrrole@Fe(3)O(4) nanoparticles for dual-modal imaging and in vivo photothermal cancer therapy.

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.

Sub-10 nm Fe3O4@Cu(2-x)S core-shell nanoparticles for dual-modal imaging and photothermal therapy.

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.