A biodegradable multifunctional nanoplatform based on antimonene nanosheets for synergistic cancer phototherapy and dual imaging.

Recently, nanomaterials have been well-studied in cancer therapy, but some of them often experience difficulties with degradation in vivo, which could cause severe damage to the human body. Among numerous biodegradable nanomaterials, antimonene nanosheets (AMNSs) are versatile, and possess photothermal and photodynamic properties and photoacoustic imaging (PAI) and drug loading ability. Herein, we employed a clearable multifunctional system. The small molecule photosensitizer IR820 and the gold nanoparticles (AuNPs) at small sizes of approximately 5 nm were loaded onto AMNSs coated with biodegradable chitosan (CS). This nanoplatform showed excellent photothermal and photodynamic properties, satisfactory degradability and photoacoustic imaging ability, good biocompatibility and effective NIR light triggered intracellular synergistic treatment. It also displayed good fluorescence imaging ability in the experiment of cell uptake. These suggested that this versatile nanoplatform was able to significantly enhance the therapeutic efficiency based on synergistic phototherapy, and could also be applied in fluorescence and photoacoustic dual imaging for integrating diagnosis and treatment.

Photothermal hydrogel platform for prevention of post-surgical tumor recurrence and improving breast reconstruction.

BACKGROUND: As one of the leading threats for health among women worldwide, breast cancer has high morbidity and mortality. Surgical resection is the major clinical intervention for primary breast tumor, nevertheless high local recurrence risk and breast tissue defect remain two main clinical dilemmas, seriously affecting survival and quality of life of patients. EXPERIMENTAL: We developed a thermoresponsive and injectable hybrid hydrogel platform (IR820/Mgel) by integration of co-loaded porous microspheres (MPs) and IR820 for preventing postoperative recurrence of breast cancer via photothermal therapy and promoting subsequent breast reconstruction. RESULTS: Our results suggested that IR820/Mgel could quickly heated to more than 50.0 â„ƒ under NIR irradiation, enabling killing effect on 4T1 cells in vitro and prevention effect on post-surgical tumor recurrence in vivo. In addition, the hydrogel platform was promising for its minimal invasion and capability of filling irregularly shaped defects after surgery, and the encapsulated MPs could help to increase the strength of gel to realize a long-term in situ function in vivo, and promoted the attachment and anchorage property of normal breast cells and adipose stem cells. CONCLUSIONS: This photothermal hydrogel platform provides a practice paradigm for preventing locally recurrence of breast cancer and a potential option for reconstruction of breast defects.

A mitochondrial-metabolism-regulatable carrier-free nanodrug to amplify the sensitivity of photothermal therapy.

The oxidative phosphorylation inhibitor atovaquone (ATO) and the photosensitizer new indocyanine green (IR820) were self-assembled into carrier-free nanodrugs (IR820/ATO NPs) to achieve superior photothermal therapy (PTT), offering an attractive mitochondrial metabolism-regulatable approach for breast cancer treatment, where adenosine triphosphate (ATP) was downregulated along with downregulating the expression of heat shock proteins (HSPs) to amplify the sensitivity of PTT.

Cyanine Dyes for Photo-Thermal Therapy: A Comparison of Synthetic Liposomes and Natural Erythrocyte-Based Carriers.

Cyanine fluorescent dyes are attractive diagnostic or therapeutic agents due to their excellent optical properties. However, in free form, their use in biological applications is limited due to the short circulation time, instability, and toxicity. Therefore, their encapsulation into nano-carriers might help overcome the above-mentioned issues. In addition to indocyanine green (ICG), which is clinically approved and therefore the most widely used fluorescent dye, we tested the structurally similar and cheaper alternative called IR-820. Both dyes were encapsulated into liposomes. However, due to the synthetic origin of liposomes, they can induce an immunogenic response. To address this challenge, we proposed to use erythrocyte membrane vesicles (EMVs) as "new era" nano-carriers for cyanine dyes. The optical properties of both dyes were investigated in different biological relevant media. Then, the temperature stability and photo-stability of dyes in free form and encapsulated into liposomes and EMVs were evaluated. Nano-carriers efficiently protected dyes from thermal degradation, as well as from photo-induced degradation. Finally, a hemotoxicity study revealed that EMVs seem less hemotoxic dye carriers than clinically approved liposomes. Herein, we showed that EMVs exhibit great potential as nano-carriers for dyes with improved stability and hemocompatibility without losing excellent optical properties.

Shortwave-Infrared Fluorescent Molecular Imaging Probes Based on π-Conjugation Extended Indocyanine Green.

Recently, shortwave-infrared (SWIR) fluorescence imaging for the optical diagnostics of diseases has attracted much attention as a new noninvasive imaging modality. For this application, the development of SWIR molecular imaging probes with high biocompatibility is crucial. Although many types of biocompatible SWIR fluorescent probes based on organic dyes have been reported, there are no SWIR-emitting molecular imaging probes that can be used for the detection of specific biomolecules in vivo. To apply SWIR-emitting molecular imaging probes to biomedical fields, we developed a biocompatible SWIR fluorescent dye based on π-conjugation extended indocyanine green (ICG), where ICG is the only approved near-infrared dye by the US Food and Drug Administration (FDA) for use in the clinic. Using the π-conjugation extended ICG, we prepared SWIR molecular imaging probes that can be used for in vivo tumor imaging. Herein, we demonstrate noninvasive SWIR fluorescence imaging of human epidermal growth factor receptor 2 (HER2)-positive and epidermal growth factor receptor (EGFR)-positive breast tumors using π-conjugation extended ICG and monoclonal antibody conjugates. The presented π-conjugation extended ICG analog probes will be a breakthrough to apply SWIR fluorescence imaging in biomedical fields.

Near-infrared emissive polymer-coated IR-820 nanoparticles assisted photothermal therapy for cervical cancer cells.

Photothermal therapy (PTT) has attracted wide attention due to its noninvasiveness and its thermal ablation ability. As photothermal agents are crucial factor in PTT, those with the characteristics of biocompatibility, non-toxicity and high photothermal stability have attracted great interest. In this work, new indocyanine green (IR-820) was utilized as a photothermal agent and near-infrared (NIR) fluorescence imaging nanoprobe. To improve the biocompatibility, poly(styrene-co-maleic anhydride) (PSMA) was utilized to encapsulate the IR-820 molecules to form novel IR-820@PSMA nanoparticles (NPs). Then, the optical and thermal properties of IR-820@PSMA NPs were studied in detail. The IR-820@PSMA NPs showed excellent photothermal stability and biocompatibility. The cellular uptaking ability of the IR-820@PSMA NPs was further confirmed in HeLa cells by the NIR fluorescent confocal microscopic imaging technique. The IR-820@PSMA NPs assisted PTT of living HeLa cells was conducted under 793 nm laser excitation, and a high PTT efficiency of 73.3% was obtained.

Curcumin-Microsphere/IR820 Hybrid Bifunctional Hydrogels for In Situ Osteosarcoma Chemo-co-Thermal Therapy and Bone Reconstruction.

Conventional biomaterial-mediated osteosarcoma therapy mainly focuses on its antitumor effect yet often fails to overcome the problem of post-treatment bone tissue defect repair. Simultaneously, minimally invasive drug delivery methods are becoming spotlights for normal tissue preservation. Herein, an injectable curcumin-microsphere/IR820 coloaded hybrid methylcellulose hydrogel (Cur-MP/IR820 gel) platform was designed for osteosarcoma therapy and bone regeneration. In vitro, the K7M2wt osteosarcoma cells were eradicated by hyperthermia and curcumin. Later, the sustained release of curcumin promoted alkaline phosphatase expression and calcium deposition of bone mesenchymal stem cells. In vivo, this hybrid hydrogel could reach tumor site via injection and turned into hydrogel due to heat sensitivity. Under the irradiation of an 808 nm laser, localized hyperthermia (∼51 °C) generated in 5 min to ablate the tumor. Meanwhile, the thermal-accelerated curcumin release and thermal-increased cell membrane permeability led to tumor cell apoptosis. Tumors in photothermal-co-chemotherapy group were successfully restrained from day 2 after treatment. After that, bone reconstruction was promoted because of sustained released curcumin. The chemo-co-thermal efficacy and osteogenic capacity of Cur-MP/IR820 hydrogel suggest a promising approach to the treatment of osteosarcoma and provide provoking inspiration for treating bone tumors and repairing bone tissue.

A carrier-free nanoparticle with dual NIR/acid responsiveness by co-assembly of enediyne and IR820 for combined PTT/chemotherapy.

Combined photothermal therapy/chemotherapy by co-delivery of a photosensitizer (PS) and a chemotherapeutic drug has demonstrated great potential for cancer treatment. The intrinsic drawbacks of traditional drug delivery systems (DDSs), such as tedious synthetic procedures, side effects originated from the carrier materials, low loading efficiency, and uncontrolled drug release, however, have impaired their further advancement. On the other hand, enediyne antibiotics are highly cytotoxic toward cancer cells through the generation of lethal carbon radicals via thermal-induced cyclization, endowing them with great potential to achieve enhanced synergistic anticancer performance by incorporation with the photothermal effect of PS. To this end, a carrier-free and NIR/acid dual-responsive DDS was constructed for combined photothermal therapy/chemotherapy. The facile co-assembly of maleimide-based enediyne and PS IR820 was achieved in aqueous solution to give nanoparticles (EICN) with a hydrodynamic diameter of 90 nm and high stability. In vitro study confirmed the acid/NIR dual-responsive degradation and drug release, free radical generation and DNA-cleaving ability of EICN, which was accomplished by the corporation of enediyne and IR820 moieties. Further tests on HeLa cells verified the excellent synergistic anticancer performance of EICN including the improved cellular uptake, NIR-enhanced drug release, DNA damage and histone deacetylase inhibitor capacity. Overall, this carrier-free DDS with dual acid/NIR-responsivity would potentially provide new insights for the development of combined photothermal/chemotherapy.

Unexpected Binding of Tozuleristide "Tumor Paint" to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery.

BACKGROUND: Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as "Tumor Paint," is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green. OBJECTIVE: To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations. METHODS: Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection. RESULTS: Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations. CONCLUSION: This finding deserves further investigation to determine if tozuleristide "Tumor Paint" may have a wider role in the identification of non-neoplastic intracranial pathologies.

Fluorescence Imaging of Tumor-Accumulating Antibody-IR700 Conjugates Prior to Near-Infrared Photoimmunotherapy (NIR-PIT) Using a Commercially Available Camera Designed for Indocyanine Green.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses antibody-IRDye700DX (IR700) conjugates and was recently approved in Japan for patients with inoperable head and neck cancer. Exposure of the tumor with NIR light at a wavelength of 690 nm leads to physicochemical changes in the antibody-IR700 conjugate-cell receptor complex, resulting in increased hydrophobicity and damage to the integrity of the cell membrane. However, it is important that the tumor be completely exposed to light during NIR-PIT, and thus, a method to provide real-time information on tumor location would help clinicians direct light more accurately. IR700 is a fluorophore that emits at 702 nm; however, there is no clinically available device optimized for detecting this fluorescence. On the other hand, many indocyanine green (ICG) fluorescence imaging devices have been approved for clinical use in operating rooms. Therefore, we investigated whether LIGHTVISION, one of the clinically available ICG cameras, could be employed for NIR-PIT target tumor detection. Due to the limited benefits of adding IR700 molecules, the additional conjugation of IRDye800CW (IR800) or ICG-EG4-Sulfo-OSu (ICG-EG4), which has an overlapping spectrum with ICG, to trastuzumab-IR700 conjugates was performed. Conjugation of second NIR dyes did not interfere the efficacy of NIR-PIT. The dual conjugation of IR800 and IR700 to trastuzumab clearly visualized target tumors with LIGHTVISION by detecting emission light of IR800. We demonstrated that the conjugation of second NIR dyes enables us to provide a real-time feedback of tumor locations prior to NIR-PIT.

CD44-Targeting Oxygen Self-Sufficient Nanoparticles for Enhanced Photodynamic Therapy Against Malignant Melanoma.

OBJECTIVE: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy. MATERIALS AND METHODS: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect. RESULTS: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly. CONCLUSION: The present study presents a novel nanoplatform for melanoma treatment.

Inclusion of IR-820 into Soybean-Phosphatides-Based Nanoparticles for Near-Infrared-Triggered Release and Endolysosomal Escape in HaCaT Keratinocytes at Insignificant Cytotoxic Level.

PURPOSE: The degradation of drugs within endolysosomes has been widely addressed as a cause of poor bioavailability. One of the strategies to allow molecules to escape from a destructive fate is to introduce a photosensitizing moiety into a drug carrier enabling the permeabilization of endosomes and endolysosomes upon irradiation. This paper presents an alternative delivery nanosystem composed of cost-effective soybean phosphatides mixed with IR-820, a near-infrared (NIR) sensitizer, to load various active compounds and trigger an endolysosomal escape with a low cytotoxic effect. METHODS: IR-820-incorporated phosphatides-based nanoparticles were formulated using a thin-film hydration method to encapsulate different molecular probes and a drug model. The nanoparticles were characterized in vitro using dynamic light scattering, transmission electron microscopy, as well as ultraviolet-visible and fluorescence spectroscopy techniques. The NIR-corresponding generation of the photochemical products, the content release, and the cytotoxicity toward the HaCaT keratinocyte cell line were evaluated. The cellular internalization and endolysosomal escape were monitored using a cytochemical marker and fluorescent probes with a colocalization analysis. RESULTS: The IR-820-combined nanoparticles revealed the NIR-triggered changes in the singlet oxygen presence, nanoparticle architecture, and release rate without being cytotoxic. Additionally, the nanoplatform appeared to enhance cellular uptake of the macromolecules. The localization of the cytochemical marker and the colocalization analysis on the fluorescence signals of the encapsulated fluorophore and the lysosome-labeling reporter implied the transient endolysosomal escape of the cargo within the HaCaT cells after NIR irradiation. CONCLUSION: The inclusion of IR-820 into a soybean-phosphatides base ingredient provides NIR responsiveness, particularly the endolysosomal escape of the payload, to the formulated nanoparticles, while preserving the beneficial properties as a drug carrier. This alternative delivery nanomedicine system has future potential to provide high bioavailability of cytosolic drugs utilizing time- and spatial-controllable NIR triggerability as well as the synergistic therapeutic effects with NIR-biomodulation.

The microneedles carrying cisplatin and IR820 to perform synergistic chemo-photodynamic therapy against breast cancer.

BACKGROUNDS: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. METHODS: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. RESULTS: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. CONCLUSIONS: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.

Lactosylated IR820/DOX Co-Assembled Nanodrug for Synergetic Antitumour Therapy.

INTRODUCTION: Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used photothermal agent, IR820, and chemotherapeutic drug, doxorubicin hydrochloride (DOX), are both hydrophilic molecules that suffer from the drawbacks of a short circulation time, rapid elimination and off-target effects. METHODS AND RESULTS: Herein, a novel nanodrug that combined HCC-targeted IR820 and DOX was developed based on excipient-free co-assembly. First, lactosylated IR820 (LA-IR820) was designed to target HCC. Then, the LA-IR820/DOX nanodrug (LA-IR820/DOX ND) was purely self-assembled without excipient assistance. The physicochemical properties and the chemo-photothermal antitumour activity of the excipient-free LA-IR820/DOX ND were evaluated. More importantly, the obtained LA-IR820/DOX ND exhibited 100% drug loading, remarkable HCC targeting and excellent antitumour efficacy. CONCLUSION: This excipient-free LA-IR820/DOX ND may be a promising candidate for the synchronous delivery and synergistic targeting of IR820 and DOX as a combined chemo-photothermal therapy.

Rapidly dissolving microneedle patch for synergistic gene and photothermal therapy of subcutaneous tumor.

The synergistic combination of gene therapy and photothermal therapy (PTT) has been widely investigated as a promising strategy for cancer treatment. To deliver genes and photothermal agents simultaneously and accurately to a tumor site, a microneedle (MN) patch co-loaded with p53 DNA and IR820 was fabricated by a two-step casting method. Hyaluronic acid was chosen as a matrix and p53 DNA and IR820 were mainly loaded into the tips to enhance utilization and reduce waste. The MN patch could efficiently penetrate the stratum corneum, and dissolve rapidly to release p53 DNA and IR820 in the subcutaneous tumor site. Due to the efficient photothermal efficacy of IR820, the temperature of the tumor site where the MN patch was applied increased by 14.7 °C under near-infrared light irradiation. The MN patch showed excellent antitumor effects in vivo owing to the synergistic effect of gene therapy and PTT. Consequently, the p53 DNA/IR820 MN patch may be a promising synergistic strategy for subcutaneous tumor treatments.

A nanoplatform with tumor-targeted aggregation and drug-specific release characteristics for photodynamic/photothermal combined antitumor therapy under near-infrared laser irradiation.

Due to their high biocompatibility, high spatial resolution, chromatographic capability, and adjustable size and morphology, magnetic nanoparticles have become the most promising nanomaterials for clinical application in noninvasive imaging and drug delivery for the treatment of malignant tumors. Herein, a novel magnetic nanoparticle coated with calcium carbonate was prepared and loaded with near-infrared drugs to be used as a multifunctional theranostic nanoplatform for the diagnosis and treatment of malignant tumors. Then, these drug-loaded nanoparticles were used for combined photodynamic/photothermal therapy by intravenous administration that was simultaneously guided by fluorescence/MR imaging. Due to the targeted induction of the external magnetic field and tumor response degradation of the calcium carbonate layer, the nanoprobe demonstrated excellent tumor targeting and greatly improved drug aggregation at the tumor site. Finally, single wavelength-mediated photothermal/photodynamic therapy was applied to liver cancer model mice, ultimately achieving an exciting antitumor therapeutic effect. This study may promote further exploration of nanoplatforms based on magnetic nanoparticles for clinical application in the treatment of malignant tumors.

CD133 antibody targeted delivery of gold nanostars loading IR820 and docetaxel for multimodal imaging and near-infrared photodynamic/photothermal/chemotherapy against castration resistant prostate cancer.

Due to the lack of effective strategies on the treatment of castration resistant prostate cancer (CRPC), we established a multifunctional nanoplatform (GNS@IR820/DTX-CD133) for the synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy (CT) under the monitoring of multimodal near-infrared (NIR) fluorescence/photoacoustic (PA) imaging. Benefiting from the guided effect of CD133 antibody, GNS@IR820/DTX-CD133 can targetedly deliver the loaded drug to the tumor tissues, which can further contribute to the combined therapeutic effect. Our experimental results prove that the bio-distribution of GNS@IR820/DTX-CD133 can be monitored with NIR fluorescence and PA imaging. In addition, the application of GNS@IR820/DTX-CD133 for in vitro and in vivo therapy achieves the excellent antitumor effects of the synergistic PTT/PDT/CT strategies under the NIR-light irradiation. Therefore, as a multifunctional nanoplatform integrating the PTT/PDT/CT strategies with tumor multimodal imaging or drug tracing, GNS@IR820/DTX-CD133 has the great potential for clinical applications in the antitumor therapy of CRPC.

Infracyanine Green vs. Brilliant Blue G in Inverted Flap Surgery for Large Macular Holes: A Long-Term Swept-Source OCT Analysis.

Background and Objectives: To compare the long-term toxicity of infracyanine green (IFCG) to brilliant blue G (BBG) in inverted internal limiting membrane flap surgery (I-ILMFS) for large, full-thickness macular holes (FTMHs). Materials and Methods: Prospective randomized study including 39 eyes with ≥ 400 µm idiopathic FTMH who underwent I-ILMFS with either IFCG or BBG. Postoperative 6- and 12-month corrected distance visual acuity (CDVA), closure rate, and swept-source optical coherence tomography parameters, including ellipsoid zone (EZ) and external limiting membrane (ELM) mean defect length, central foveal thicknesses (CFT), parafoveal macular thickness (MT), ganglion cells and inner plexiform layer (GCL++) thickness, and peripapillary nerve fiber layer (pRNFL) thickness, were compared. Results: Nineteen eyes were included in the IFCG group and 20 eyes in the BBG group. In all cases a FTMH closure was found. CDVA improved at 6 and 12 months in both groups (p < 0.0005); the increase at 12 months was greater in the BBG group (p = 0.036). EZ and ELM defects did not differ between groups at either follow-up time. CFT at 12 months was greater in the BBG group (p = 0.041). A 12-months compared to 6-months MT decrease was present in both groups (p < 0.01). The GCL++ superior inner sector was thicker in the BBG group at 12 months (p = 0.036), as were the superior outer sector (p = 0.039 and p = 0.027 at 6 and 12 months, respectively) and inferior outer sector (p = 0.011 and p = 0.009 at 6 and 12 months, respectively). Conclusion: In our study BBG in I-ILMFS exhibits better long-term CDVA and retinal thickness than does IFCG, suggesting a lesser toxicity from BBG. These findings support the use of BBG over IFCG in I-ILMFS.

Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy.

One of the main challenges for immune checkpoint blockade antibodies lies in malignancies with limited T-cell responses or immunologically "cold" tumors. Inspired by the capability of fever-like heat in inducing an immune-favorable tumor microenvironment, mild photothermal therapy (PTT) is proposed to sensitize tumors to immune checkpoint inhibition and turn "cold" tumors "hot." Here we present a combined all-in-one and all-in-control strategy to realize a local symbiotic mild photothermal-assisted immunotherapy (SMPAI). We load both a near-infrared (NIR) photothermal agent IR820 and a programmed death-ligand 1 antibody (aPD-L1) into a lipid gel depot with a favorable property of thermally reversible gel-to-sol phase transition. Manually controlled NIR irradiation regulates the release of aPD-L1 and, more importantly, increases the recruitment of tumor-infiltrating lymphocytes and boosts T-cell activity against tumors. In vivo antitumor studies on 4T1 and B16F10 models demonstrate that SMPAI is an effective and promising strategy for treating "cold" tumors.

Tumor-Microenvironment-Activatable Nanoreactor Based on a Polyprodrug for Multimodal-Imaging-Medicated Enhanced Cancer Chemo/Phototherapy.

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPTSS/IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPTSS/IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPTSS/IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPTSS/IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.