Recent Advances and Clinical Potential of Near Infrared Photothermal Conversion Materials for Photothermal Hepatocellular Carcinoma Therapy

Growing concern about photothermal tumor therapy (PTT) as a promising alternative to conventional liver cancer treatment, which is a treatment strategy that utilizes near-infrared (NIR) light-induced photothermal agents (PTAs) to yield photothermal effects to localize thermal damage for tumors. Herein, given the gap between experimental research and clinical application, this review seeks to timely summarize and highlight the recent progress of PTAs used for photothermal treatment of liver cancer in vivo and in vitro in the last five-year. The implications of various PTAs on the multifunctional photothermal conversion capability, the structure-performance correlations of PTT, together with the evaluation of their potential in application are systematically dissected to further dig out what the buried mechanism is. Besides, higher requirements are put forward for the discrepancies and crucial issues faced by different PTAs in PTT with related medical technical obstacles being conquered, which lays a solid theoretical foundation for the medical field of oncology treatment as a whole, especially liver cancer. Finally, it is expected that this review can present valuable guidance for the design of efficient, photostability, and biosafety-aware PTAs for anticancer therapy while stepping into the fast traffic lane for the conversion from bench to bedside in the foreseeable future.     

Injectable Adhesive Hydrogel as Photothermal-Derived Antigen Reservoir for Enhanced Anti-Tumor Immunity

Low vaccine immunogenicity and tumor heterogenicity greatly limit the therapeutic effect of tumor vaccine. In this study, a novel injectable adhesive hydrogel, based on thermosensitive nanogels containing catechol groups and loaded with in situ-forming MnO₂ nanoparticles, is constructed to overcome these issues. The concentrated nanogel dispersion transforms into an adhesive hydrogel in situ after intratumoral injection. The photothermal effect of the loaded MnO₂ nanoparticles induces immunogenic cell death to release mass autologous tumor-derived protein antigens under near-infrared irradiation, which act as ideal immune stimulating substances avoiding the problem of tumor heterogenicity and are captured by the in situ-forming adhesive hydrogel. The antigens-captured adhesive hydrogel acts as an “antigen reservoir” and releases these captured antigens to recruit more dendritic cells to stimulate an intensive and lasting anti-tumor immune response mediated by CD8⁺ T cells. The primary tumors can be almost completely disappeared within 4 days without relapse, and the growth of the distal tumors and rechallenged tumors are also effectively inhibited by the treatment with the injectable adhesive hydrogel-based photothermal therapy. Therefore, the proposed “antigen reservoir” strategy shows the great potential application as an in situ-forming personalized vaccine to enhancing the cancer immune therapy.     

An Acceptor–Donor–Acceptor Structured Small Molecule for Effective NIR Triggered Dual Phototherapy of Cancer

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is regarded as a more effective method for cancer treatment than single PDT or PTT. However, development of single component and near‐infrared (NIR) triggered agents for efficient dual phototherapy remains a challenge. Herein, a simple strategy to develop dual‐functional small‐molecules‐based photosensitizers for combined PDT and PTT treatment is proposed through: 1) finely modulating HOMO–LUMO energy levels to regulate the intersystem crossing (ISC) process for effective singlet oxygen (¹O₂) generation for PDT; 2) effectively inhibiting fluorescence via strong intramolecular charge transfer (ICT) to maximize the conversion of photo energy to heat for PTT or ISC process for PDT. An acceptor–donor–acceptor (A‐D‐A) structured small molecule (CPDT) is designed and synthesized. The biocompatible nanoparticles, FA‐CNPs, prepared by encapsulating CPDT directly with a folate functionalized amphipathic copolymer, present strong NIR absorption, robust photostability, cancer cell targeting, high photothermal conversion efficiency as well as efficient ¹O₂ generation under single 808 nm laser irradiation. Furthermore, synergistic PDT and PTT effects of FA‐CNPs in vivo are demonstrated by significant inhibition of tumor growth. The proposed strategy may provide a new approach to reasonably design and develop safe and efficient photosensitizers for dual phototherapy against cancer.     

Intracellular Bottom-up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX-2 Inactivation

The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia-related inflammation. Intracellular bottom-up synthesis (iBuS) of CuS nanoparticles from small-molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu-meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H₂S inside tumor cells and meanwhile release meloxicam for anti-inflammatory effects. The intracellular bottom-up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam-induced inactivation of the COX-2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.     

A NIR-II AIEgen-Based Supramolecular Nanodot for Peroxynitrite-Potentiated Mild-Temperature Photothermal Therapy of Hepatocellular Carcinoma

Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild-temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild-temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co-deliver nitric oxide (NO) and photothermal agent DCTBT with NIR-II aggregation-induced emission (AIE) characteristic for mild-temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT-based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ-potentiated mild-temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild-temperature PTT, which provides new inspirations to explore ONOOˉ-sensitized tumor therapy strategies.     

Immunotherapeutic Hydrogel with Photothermal Induced Immunogenic Cell Death and STING Activation for Post-Surgical Treatment

Post-surgical tumor recurrence remains a major clinical concern for patients with malignant solid tumors. Herein, an immunotherapeutic hydrogel (SA_PBA/ZMC/ICG) is developed by incorporating metal ion-cyclic dinucleotide (CDN) nanoparticles (Zn-Mn-CDN, ZMC) and a photosensitizer (indocyanine green, ICG) into phenylboronic acid (PBA)-conjugated sodium alginate (SA_PBA) for photothermal therapy (PTT)-triggered in situ vaccination to inhibit post-surgical recurrence and metastasis of malignant tumors. The gelation of SA_PBA/ZMC/ICG in the residual tumors can achieve accurate local PTT and the local sustained release of CDN and Mn²⁺ with minimal detrimental off-target toxic effects. Furthermore, CDN, which is an agonist of the stimulator of interferon genes (STING), along with Mn²⁺ can activate the STING pathway and trigger type-I-IFN-driven immune responses against tumors. Therefore, the immunotherapeutic hydrogel with enhanced immune response by STING agonist and PTT-induced immunogenic cell death (ICD) reprograms the post-surgical immunosuppressive microenvironment, substantially decreasing the post-surgical recurrence and metastasis of solid tumors in multiple murine tumor models when administered during surgical resection. Taken together, PTT-triggered and STING-mediated in situ cancer vaccination is an effective therapeutic intervention for post-surgical recurrence and metastasis of tumors.     

Intracellular Nanoparticle Formation and Hydroxychloroquine Release for Autophagy-Inhibited Mild-Temperature Photothermal Therapy for Tumors

Mild-temperature photothermal therapy (PTT) of tumors has been intensively explored and adopted in preclinical/clinical trials in recent years. Nevertheless, tumor thermoresistance significantly compromises the therapeutic efficacy of mild-temperature PTT, and therefore, the extra addition of anti-thermoresistance agent is needed. Herein, by rational design of a peptide-hydroxychloroquine (HCQ) conjugate Cypate-Phe-Phe-Lys(SA-HCQ)-Tyr(H₂PO₃)-OH (Cyp-HCQ-Yp), a “smart” strategy of enzyme-triggered simultaneously intracellular photothermal nanoparticle formation and HCQ release is proposed for autophagy-inhibited mild-temperature PTT of tumor. In vitro results show that, under sequential catalysis of enzymes alkaline phosphatase and carboxylesterase, Cyp-HCQ-Yp is converted to Cypate-Phe-Phe-Lys(SA)-Tyr-OH (Cyp-Y) which self-assembles into its nanoparticle Cyp-NP and HCQ is released from Cyp-HCQ-Yp. By comparing with two control agents, it is validated that the exceptional therapeutic effect of Cyp-HCQ-Yp on tumor in vivo is achieved by its dual-enzyme-controlled intracellular nanoparticle formation and autophagy inhibition in tumors.     

Schottky Heterojunction Realizes In Situ Vaccine-Like Antitumor Efficacy and Microenvironment Remodeling Upon Near-Infrared Laser Response in Cold Tumors

Cold tumor is one of the most refractory tumors due to its low immunogenicity and absence of T cell infiltration. The immunotherapeutic effect of near-infrared (NIR) responsive nanomaterials on tumors is far from satisfactory. Herein, ultrasmall γ-MnO₂ nanodots are anchored on the intrinsic metallic Ti₃C₂(OH)₂, modified with bovine serum albumin, to realize a Schottky heterojunction (labeled as TC-MnO₂@BSA), which can be utilized to reshape the cold tumor microenvironment (TME) through in situ vaccine-like antitumor effect. The Schottky heterojunction endows TC-MnO₂@BSA with improved photothermal conversion and reactive oxygen species (ROS) generation. Excess ROS and heat lead to tumor immunogenic death (ICD) and abundant damaged double-strain DNA releasing into TME, coordinated with TC-MnO₂@BSA-derived Mn²⁺, magnifying the cGAS-STING signaling pathway, eventually promoting antigen presentation of dendritic cells and infiltration of T cells. Such a NIR-activated nanovaccine can achieve complete ablation of tumors while robust activating systemic antitumor immune response. Furthermore, it inhibits the growth of abscopal tumors through dramatically “heating” their cold TME. This work introduces a universal strategy to magnify the photothermal and immune adjuvant effect through the gain of Schottky heterostructure, as a novel paradigm to construct the multifunctional in situ nanovaccine.     

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria‐targeted near‐infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small‐molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N‐alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic‐anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging‐guided phototherapy and treatment monitoring. This is the first report that a small‐molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small‐molecule‐based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.     

Enzyme‐Mediated Tumor Starvation and Phototherapy Enhance Mild‐Temperature Photothermal Therapy

Compared with conventional tumor photothermal therapy (PTT), mild‐temperature PTT brings less damage to normal tissues, but also tumor thermoresistance, introduced by the overexpressed heat shock protein (HSP). A high dose of HSP inhibitor during mild‐temperature PTT might lead to toxic side effects. Glucose oxidase (GOx) consumes glucose, leading to adenosine triphosphate supply restriction and consequent HSP inhibition. Therefore, a combinational use of an HSP inhibitor and GOx not only enhances mild‐temperature PTT but also minimizes the toxicity of the inhibitor. However, a GOx and HSP inhibitor‐encapsulating nanostructure, designed for enhancing its mild‐temperature tumor PTT efficiency, has not been reported. Thermosensitive GOx/indocyanine green/gambogic acid (GA) liposomes (GOIGLs) are reported to enhance the efficiency of mild‐temperature PTT of tumors via synergistic inhibition of tumor HSP by the released GA and GOx, together with another enzyme‐enhanced phototherapy effect. In vitro and in vivo results indicate that this strategy of tumor starvation and phototherapy significantly enhances mild‐temperature tumor PTT efficiency. This strategy could inspire people to design more delicate platforms combining mild‐temperature PTT with other therapeutic methods for more efficient cancer treatment.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

Mutually Synergistic Nanoparticles for Effective Thermo‐Molecularly Targeted Therapy

Photothermal therapy (PTT) is of particular importance as a highly potent therapeutic modality in cancer therapy. However, a critical challenge still remains in the exploration of highly effective strategy to maximize the PTT efficiency due to tumor thermoresistance and thus frequent tumor recurrence. Here, a rational fabrication of the micelles that can achieve mutual synergy of PTT and molecularly targeted therapy (MTT) for tumor ablation is reported. The micelles generate both distinct photothermal effect from Cypate through enhanced photothermal conversion efficiency and pH‐dependent drug release. The micelles further exhibit effective cytoplasmic translocation of 17‐allylamino‐17‐demethoxygeldanamycin (17AAG) through reactive oxygen species mediated lysosomal disruption caused by Cypate under irradiation. Translocated 17AAG specifically bind with heat shock protein 90 (HSP90), thereby inhibiting antiapoptotic p‐ERK1/2 proteins for producing preferable MTT efficiency through early apoptosis. Meanwhile, translocated 17AAG molecules further block stressfully overexpressed HSP90 under irradiation and thus inhibit the overexpression of p‐Akt for achieving the reduced thermoresistance of tumor cells, thus promoting the PTT efficiency through boosting both early and late apoptosis of Cypate. Moreover, the micelles possess enhanced resistance to photobleaching, preferable cellular uptake, and effective tumor accumulation, thus facilitating mutually synergistic PTT/MTT treatments with tumor ablation. These findings represent a general approach for potent cancer therapy.     

NIR-II Responsive Inorganic 2D Nanomaterials for Cancer Photothermal Therapy: Recent Advances and Future Challenges

Non-invasive cancer photothermal therapy (PTT) is a promising replacement for traditional cancer treatments. The second near-infrared region induced PTT (NIR-II PTT, 1000–1500 nm) with less energy dissipation has been developed for deeper-seated tumor treatment in recent years compared with the traditional first near-infrared light (750–1000 nm). In addition, the use of emerging inorganic 2D nanomaterials as photothermal agents (PTAs) further enhanced PTT efficiency due to their intrinsic photothermal properties. NIR-II light stimulated inorganic 2D nanomaterials for PTT is becoming a hot topic in both academic and clinical fields. This review summarizes the categories, structures, and photothermal conversion properties of inorganic 2D nanomaterials for the first time. The recent synergistic strategies of NIR-II responsive PTT combined with other treatment approaches including chemotherapy, chemodynamic therapy, photodynamic therapy, radiotherapy are summarized. The future challenges and perspectives on these 2D nanomaterials for NIR-II responsive PTT systems construction are further discussed.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

Photothermal Lysis of Engineered Bacteria to Modulate Amino Acid Metabolism against Tumors

Bacterial-mediated synergistic cancer therapy (BMSCT) is used as a promising tumor therapy approach. However, there are some disadvantages of bacterial therapy alone to be resolved, such as low tumor suppression rate in the treatment. In this study, a novel light-controlled engineered bacterial material which synergistically regulates amino acid metabolism to fight tumors is developed. It transcribes l -methionine-γ-lyase (MdeA) into Escherichia coli (E. coli) and loads the approved photothermal agent indocyanine green (ICG), namely E. coli-MdeA@ICG. Using the hypoxic tropism of E. coli, genetically engineered bacteria are first loaded with photothermal agents, then selectively accumulate and replicate in the tumor region. Under laser irradiation, photothermal lysis of E. coli-MdeA is performed to release the MdeA and consume the essential amino acid methionine (Met) in the tumor environment. In vitro cell experiments confirm that the E. coli-MdeA + NIR group can reach 90% of the 4T1 cells killing. In 4T1 tumor-bearing mouse models, E. coli-MdeA@ICG shows enhanced antitumor efficacy, along with 91.8% of the tumor growth inhibited. Apoptosis of tumor cells is induced under the dual action of photothermal therapy (PTT) and amino acid metabolism therapy. This strategy provides new ideas for the combination of synthetic biology and nanotechnology in anti-tumor.     

Ultrafast Synthesis of Ultrasmall Poly(Vinylpyrrolidone)‐Protected Bismuth Nanodots as a Multifunctional Theranostic Agent for In Vivo Dual‐Modal CT/Photothermal‐Imaging‐Guided Photothermal Therapy

To elaborately fabricate real‐time monitoring and therapeutic function into a biocompatible nanoplatform is a promising route in the cancer therapy field. However, the package of diagnosis and treatment into a single‐“element” nanoparticle remains challenge. Herein, ultrasmall poly(vinylpyrrolidone)‐protected bismuth nanodots (PVP‐Bi nanodots) are successfully synthesized through an ultrafacile strategy (1 min only under ambient conditions). The nanodots are easy to synthesize in both laboratory and large scale using low‐cost bismuth ingredients. PVP‐Bi nanodots with ultrasmall size show good biocompatibility. Due to the high X‐ray attenuation ability of Bi element, PVP‐Bi nanodots have prominent performance on X‐ray computed tomography (CT) imaging. Moreover, PVP‐Bi nanodots exhibit a high photothermal conversion efficiency (η = 30%) because of the strong near‐infrared absorbance, which can serve as nanotheranostic agent for photothermal imaging and cancer therapy. The subsequent PVP‐Bi‐nanodot‐mediated photothermal therapy (PTT) result shows highly efficient ablation of cancer cells both in vitro and in vivo. PVP‐Bi nanodots can be almost completely excreted from mice after 7 d. Blood biochemistry and histology analysis suggests that PVP‐Bi nanodots have negligible toxicity. All the positive results reveal that PVP‐Bi nanodots produced through the ultrafacile method are promising single‐“element” nanotheranostic platform for dual‐modal CT/photothermal‐imaging‐guided PTT.     

Imaging‐Guided Combined Photothermal and Radiotherapy to Treat Subcutaneous and Metastatic Tumors Using Iodine‐131‐Doped Copper Sulfide Nanoparticles

Combining different therapeutic strategies to treat cancer by overcoming limitations of conventional cancer therapies has shown great promise in both fundamental and clinical studies. Herein, by adding ¹³¹I when making iodine‐doped CuS nanoparticles, CuS/[¹³¹I]I nanoparticles are obtained, which after functionalization with polyethylene glycol (PEG) are used for radiotherapy (RT) and photothermal therapy (PTT), by utilizing their intrinsic high near‐infrared absorbance and the doped ¹³¹I‐radioactivity, respectively. The combined RT and PTT based on CuS/[¹³¹I]I‐PEG is then conducted, achieving remarkable synergistic therapeutic effects as demonstrated in the treatment of subcutaneous tumors. In the meanwhile, as revealed by bimodal nuclear imaging and computed tomography (CT) imaging, it is found that CuS/[¹³¹I]I‐PEG nanoparticles after being injected into primary solid tumors could migrate to and retain in their nearby sentinel lymph nodes. Importantly, the combined RT and PTT applied on those lymph nodes to assist surgical resection of primary tumors results in remarkably inhibited cancer metastasis and greatly prolonged animal survival. In vivo toxicology studies further reveal that our CuS/I‐PEG is not obviously toxic to animals at fourfold of the treatment dose. This work thus demonstrates the potential of combining RT and PTT using a single nanoagent for imaging‐guided treatment of metastatic tumors.