NIR-triggered on-site NO/ROS/RNS nanoreactor:Cascade-amplified photodynamic/photothermal therapy with local and systemic immune responses activation

Photothermal and photodynamic therapies(PTT/PDT)hold promise for localized tumor treatment,yet their full potential is hampered by limitations such as the hypoxic tumor microenvironment and inadequate systemic immune activation.Addressing these challenges,we present a novel near-infrared(NIR)-triggered RNS nanoreactor(PBNO-Ce6)to amplify the photodynamic and photothermal therapy efficacy against triple-negative breast cancer(TNBC).The designed PBNOCe6 combines sodium nitroprusside-doped Prussian Blue nanoparticles with Chlorin e6 to enable on-site RNS production through NIR-induced concurrent NO release and ROS generation.This not only enhances tumor cell eradication but also potentiates local and systemic antitumor immune responses,protecting mice from tumor rechallenge.Our in vivo evaluations revealed that treatment with PBNO-Ce6 leads to a remarkable 2.7-fold increase in cytotoxic T lymphocytes and a 62%decrease in regulatory T cells in comparison to the control PB-Ce6(Prussian Blue nanoparticles loaded with Chlorin e6),marking a substantial improvement over traditional PTT/PDT.As such,the PBNO-Ce6 nanoreactor represents a transformative approach for improving outcomes in TNBC and potentially other malignancies affected by similar barriers.

Isoindigo nanoparticles for photoacoustic imaging-guided tumor photothermal therapy

The key factor in photothermal therapy lies in the selection of photothermal agents.Traditional photothermal agents generally have problems such as poor photothermal stability and low photothermal conversion efficiency.Herein,we have designed and synthesized an isoindigo(IID)dye.We used isoindigo as the molecular center and introduced common triphenylamine and methoxy groups as rotors.In order to improve the photothermal stability and tumor targeting ability,we encapsulated IID into nanoparticles.As a result,the nanoparticles exhibited high photothermal stability and photothermal conversion efficiency(67%)upon 635 nm laser irradiation.Thus,the nanoparticles demonstrated a significant inhibitory effect on live tumors in photothermal therapy guided by photoacoustic imaging and provided a viable strategy to overcome the treatment challenges.

Temperature-feedback two-photon-responsive metal-organic frameworks for efficient photothermal therapy

The realization of real-time thermal feedback for monitoring photothermal therapy(PTT)under near-infrared(NIR)light irradiation is of great interest and challenge for antitumor therapy.Herein,by assembling highly efficient photothermal conversion gold nanorods and a temperature-responsive probe((E)-4-(4-(diethylamino)styryl)-1-methylpyridin-1-ium,PyS)within MOF-199,an intelligent nanoplatform(AMPP)was fabricated for simultaneous chemodynamic therapy and NIR light-induced temperature-feedback PTT.The fluorescence intensity and temperature of the PyS probe are linearly related due to the restriction of the rotation of the characteristic monomethine bridge.Moreover,the copper ions resulting from the degradation of MOF-199 in an acidic microenvironment can convert H_(2)O_(2)into•OH,resulting in tumor ablation through a Fenton-like reaction,and this process can be accelerated by increasing the temperature.This study establishes a feasible platform for fabricating highly sensitive temperature sensors for efficient temperature-feedback PTT.

RBC Membrane Camouflaged Semiconducting Polymer Nanoparticles for Near-Infrared Photoacoustic Imaging and Photothermal Therapy

Semiconducting conjugated polymer nanoparticles(SPNs)represent an emerging class of phototheranostic materi-als with great promise for cancer treatment.In this report,low-bandgap electron donoracceptor(DA)-conjugated SPNs with sur-face cloaked by red blood cell membrane(RBCM)are developed for highly e ective photoacoustic imaging and photothermal therapy.The resulting RBCM-coated SPN(SPN@RBCM)displays remarkable near-infrared light absorption and good photosta-bility,as well as high photothermal conver-sion e ciency for photoacoustic imaging and photothermal therapy.Particularly,due to the small size(<5 nm),SPN@RBCM has the advantages of deep tumor penetration and rapid clearance from the body with no appreciable toxicity.The RBCM endows the SPNs with prolonged systematic circulation time,less reticuloendothelial system uptake and reduced immune-recognition,hence improving tumor accumulation after intravenous injection,which provides strong photoacoustic signals and exerts excellent photothermal therapeutic e ects.Thus,this work provides a valuable paradigm for safe and highly e cient tumor pho-toacoustic imaging and photothermal therapy for further clinical translation.

Deep-Tissue Photothermal Therapy Using Laser Illumination at NIR-Ⅱa Window

Photothermal therapy(PTT)using near-infrared(NIR)light for tumor treatment has triggered extensive attentions because of its advantages of noninvasion and convenience.The current research on PTT usually uses lasers in the first NIR window(NIR-I;700–900 nm)as irradiation source.However,the second NIR window(NIR-II;1000–1700 nm)especially NIRIIa window(1300–1400 nm)is considered much more promising in diagnosis and treatment as its superiority in penetration depth and maximum permissible exposure over NIR-I window.Hereby,we propose the use of laser excitation at 1275 nm,which is approved by Food and Drug Administration for physical therapy,as an attractive technique for PTT to balance of tissue absorption and scattering with water absorption.Specifically,CuS-PEG nanoparticles with similar absorption values at 1275 and 808 nm,a conventional NIR-I window for PTT,were synthesized as PTT agents and a comparison platform,to explore the potential of 1275 and 808 nm lasers for PTT,especially in deep-tissue settings.The results showed that 1275 nm laser was practicable in PTT.It exhibited much more desirable outcomes in cell ablation in vitro and deep-tissue antitumor capabilities in vivo compared to that of 808 nm laser.NIR-IIa laser illumination is superior to NIR-I laser for deep-tissue PTT,and shows high potential to improve the PTT outcome.

Crushed Gold Shell Nanoparticles Labeled with Radioactive Iodine as a Theranostic Nanoplatform for Macrophage-Mediated Photothermal Therapy

Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.

Advances in biodegradable nanomaterials for photothermal therapy of cancer

Photothermal cancer therapy is an alternative to chemotherapy, radiotherapy, and surgery. With the development of nanophotothermal agents, this therapy holds immense potential in clinical translation. However, the toxicity issues derived from the fact that nanomaterials are trapped and retained in the reticuloendothelial systems limit their biomedical application.Developing biodegradable photothermal agents is the most practical route to address these concerns. In addition to the physicochemical properties of nanomaterials, various internal and external stimuli play key roles on nanomaterials uptake,transport, and clearance. In this review, we summarized novel nanoplatforms for photothermal therapy; these nanoplatforms can elicit stimuli-triggered degradation. We focused on the recent innovative designs endowed with biodegradable photothermal agents under different stimuli, including enzyme, p H, and near-infrared(NIR) laser.

Biomedical overview of melanin.1.Updating melanin biology and chemistry,physico-chemical properties,melanoma tumors,and photothermal therapy

Melanins(eumelanin,pheomelanin,and allomelanin)represent a very,if not themost,important group of biological pigments.Their biological roles are multiple,from photoprotection to antioxidant activity,heavy metal disposal or the myriad uses of color in organisms across all Phyla.In the first part of this review,eumelanin biology and some chemical aspects will be presented,as well as key physico-chemical features that make this biological pigment so interesting.The principal characteristics of the melanocyte,the melanin-synthesizing cell in mammals,will also be introduced.Transformed melanocytes are the cause of one of the most devastating known cancers:the malignant melanoma.Epidemiology and molecular signaling aspects will be presented next,as well as the principal advances in promising oncotherapies designed and applied for the treatment of melanoma.In particular,on account of the photo-physical properties of melanin,special details will be provided regarding the use of photothermal therapy for melanoma treatment.

Multifunctional magnetic nanoparticles for magnetic resonance image-guided photothermal therapy for cancer

Key advances in multifunctional magnetic nanoparticles （MNPs） for magnetic resonance （MR） image-guided pho- tothermal therapy of cancer are reviewed. We briefly outline the design and fabrication of such multifunctional MNPs. Bimodal image-guided photothermal therapies （MR/fluorescence and MR/ultrasound） are also discussed.

Targeted Micellar Phthalocyanine for Lymph Node Metastasis Homing and Photothermal Therapy in an Orthotopic Colorectal Tumor Model

Tumor lymph node(LN)metastasis seriously affects the treatment prognosis.Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration.Here,we speculate through introducing targeting capacity,the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy.Trastuzumabtargeted micelles(<50 nm)were formulated using a unique surfactantstripping approach that yielded concentrated phthalocyanines with strong near-infrared absorption.Targeted micellar phthalocyanine(T-MP)was an effective photothermal transducer and ablated HT-29 cells in vitro.A HER2-expressing colorectal cancer cell line(HT-29)was used to establish an orthotopic mouse model that developed metastatic disease in mesenteric sentinel LN.T-MP accumulated more in the LN metastases compared to the micelles conjugated with control IgG.Following surgical resection of the primary tumor,minimally invasive photothermal treatment of the metastatic LN with T-MP,but not the control micelles,extended mouse survival.Our findings demonstrate for the first time that targeted small-sized nanoparticles have potential to enable superior paradigms for dealing with LN metastases.

Fluorescence life-time imaging microscopy(FLIM)monitors tumor cell death triggered by photothermal therapy with MoS_(2) nanosheets

Recently,photothermal therapy(PTT)has been proved to have great potential in tumor therapy.In the last several years,MoS_(2),as one novel member of nanomaterials,has been applied into PTT due to its excellent photothermal conversion efficacy.In this work,we applied fuorescence lifetime imaging microscopy(FLIM)techniques into monitoring the PPT-triggered cell death under MoS_(2) nanosheet treatment.Two types of MoS_(2) nanosheets(single layer nanosheets and few layer nanosheets)were obtained,both of which exhibited presentable photothermal conversion fficacy,leading to high cell death rates of 4T1 cells(mouse breast cancer cells)under PTT.Next,live cell images of 4T1 cells were obtained via directly labeling the mitochondria with Rodamine123,which were then continuously observed with FLIM technique.FLIM data showed that the fuorescence lifetimes of mitochondria targeting dye in cells treated with each type of MoS_(2) nanosheets significantly increased during PTT treatment.By contrast,the fuorescence lifetime of the same dye in control cells(without nanomaterials)remained constant after laser irradiation.These findings suggest that FLIM can be of great value in monitoring cell death process during PTT of cancer cells,which could provide dynamic data of the cellular microenvironment at single cell level in multiple biomedical applications.

Preparation of vapreotide-templated silver nanocages and their photothermal therapy efficacy

Vapreotide acetate （Vap） was used as a biotemplate to synthesize silver nanocages through direct co-incubation of a AgNO3 solution, following by reduction using fresh NaBH4. The characterized vapreotide-templated silver nanocages （Vap-AgNCs） presented a wide and red shifted absorption band with a maximum between 480 nm and 800 nm and possessed a uniform structure with a face-centered cubic crystal structure. The biocompatibiliW of Vap-AgNCs was assessed using the MTT method, indicating Vap-AgNCs had better biocompatibility when its concentration was lower than 2,5 × 10-4 mmol. L- 1. The photothermal characteristics of Vap-AgNCs were analyzed with laser irradiation （808 nm, 1,5 W, cm-2） and the results showed that the temperature of the Vap- AgNCs solution reached 45 ℃ starting from 25 ℃ within 5 min. Additionally, Vap-AgNCs with a laser led to HeLa cell death. Therefore, the prepared Vap-AgNCs is expected to be an effective photothermal therapy agent.

Zinc-doped Prussian blue nanoparticles for mutp53-carrying tumor ion interference and photothermal therapy

Quite a great proportion of known tumor cells carry mutation in TP53 gene,expressing mutant p53 proteins(mutp53)missing not only original genome protective activities but also acquiring gain-of-functions that favor tumor progression and impede treatment of cancers.Zinc ions were reported as agents cytocidal to mutp53-carrying cells by recovering p53 normal functions and abrogating mutp53.Meanwhile in a hyperthermia scenario,the function of wild type p53 is required to ablate tumors upon heat treatment hence the effects might be hindered in a mutp53 background.We herein synthesized zinc-doped Prussian blue(ZP)nanoparticles(NPs)to combine Zn 2+based and photothermal therapeutic effects.An efficient release of Zn 2+in a glutathione-enriched tumor intracellular microenvironment and a prominent photothermal conversion manifested ZP NPs as zinc ion carriers and photothermal agents.Apoptotic death and autophagic mutp53 elimination were found to be induced by ZP NPs in R280K mutp53-containing MDA-MB-231 cells and hyperthermia was rendered to ameliorate the treatment in vitro through further mutp53 elimination and increased cell death.The combinatorial therapeutic effect was also confirmed in vivo in a mouse model.This study might expand zinc delivery carriers and shed a light on potential interplay of hyperthermia and mutp53 degradation in cancer treatment.

Multifunctional conjugated polymer nanoparticles for photoacoustic-based multimodal imaging and cancer photothermal therapy

Photoacoustic imaging(PAI)is a hybrid imaging method based on photoacoustic(PA)effects,which is able to capture the structure,function,and molecular information of biological tissues with high resolution.To date,therapeutic techniques under the guidance of PAI have provided new strategies for accurate diagnosis and precise treatment of tumors.In particular,conjugated polymer nanoparticles have been extensively inspected for PA-based cancer theranostics largely due to their superior optical properties such as tunable spectrum and large absorption coefficient and their good biocompatibility,and abundant functional groups.This mini-review mainly focuses on the recent advances toward the development of novel conjugated polymer nanoparticles for PA-based multimodal imaging and cancer photothermal therapy.

The morpho-functional assessment of plasmonic photothermal therapy effects on transplanted liver tumor

The antitumor efficiency of gold nanorod plasmonic photothermal therapy(PPTT)was evalu-ated experimentally.The rat cholangiocarcinoma line PC-1 was used as a tumor model.Exposureof tumors to S08-nm laser radiation was performed,and the noninvasive temperature monitoring of the tumor tissue was carried out using infrared imager.The growth rate kinetics and mor-phological alterations of transplanted liver tumors,as wll as indicators of lipid peroxidation activity and autointoxication in rat serum,were studied,The activation of lipid peroxidation andthe development of autointoxication were detected after PPTT.The results not only demonstratethe antitumor ficacy of the proposed therapeutic technology but also reveal the side effectsin the presence of peroxidation products in systemic circulation.

Porous Pt nanoparticles for cancer photothermal therapy

OBJECTIVE Plasmonic nanostructures act as a type of promising candidate for cancer photothermal therapy.These photothermal agents with good biocompatibility and high photothermal conversion efficiency are highly desirable.In the present study,we synthesized poly(diallyldimethylammonium chloride)(PDDAC)coated porous platinum(Pt)nanoparticles for photothermal therapy.METHODS Biocompatibility and cellular uptake of Pt nanoparticles were studied in human glioblastoma U-87 MG cells.Cell viability was evaluated by ATP assay and calcein AM staining.The photothermal therapeutic effect of the Pt nanoparticles was studied under 808-nm laser irradiation.In addition,the synergistic anti-cancer effect of the Pt nanoparticle-based photothermal therapy and doxorubicinwas investigated.RESULTS The as-prepared Pt nanoparticles exhibited considerable photothermal conversion efficiency under 809 nm and 980 nm laser irradiation.In vitro study indicated that the Pt nanoparticles displayed good biocompatibility and high cellular uptake efficiency.In the presence of the Pt nanoparticles,808-nm laser irradiation at 8.4 W·cm-2for3 min induces significant cytotoxicity,and cell necrosis is involved in the photothermal injury.Furthermore,simultaneousapplication of photothermal therapy synergistically enhances the cytotoxicity of anticancer drug doxorubicin.CONCLUSION Therefore,PDADMAC-coated Pt nanoparticles will have great potential in cancer photothermal therapy.

Polydopamine Modified Biomimetic Gold Nanoparticles for Dual Photothermal Therapy

Our study producted Polydopamine modified gold nanoflowers with controlled morphology for anti-tumor photothermal therapy.The branch structure containsabundant(Au NFs).By adjusting the reduction rate,the dosage of reducing agent(sodium borohydride)and the reduction temperature,we can adjust tthe morphology and particle size of Au NFs.We found that the lower reaction temperature is,the more abundant the surface branching structure of gold nanoflowers is,by adjusting the reaction temperature.and the largest specific surface area of golden nanopowder was found at 0℃.The results of TEM indicated that with the increase of sodium borohydride,the diameter of gold nano flowers gold nanoflowers decreased and was in the range of 60~100nm,and it has good EPR effect After that,we modify poly(dopamine)(PDA)biomimetic layer on the surface of golden nanoparticles to obtain Au NFS@PDA.Poly(dopamine)has the ability,of photothermal conversion,which can enhance the plasma resonance ability and biocompatibility of gold nanoflowers in the near infrared region.We can control the thickness of polydopamine layer on the surface of gold nanoflowers between 7~15nm by adjusting dopamine DA concentrationgold nanoflowers.Au NFS@PDA was characterized by its morphology and physical properties.We detect(UV-Vis)spectra in the near infrared region.And it showed obvious absorption peaks in the near infrared region of 575~650nm.Under the 808nm irradiation laser,the photothermal conversion of gold nanoflowers and polydopamine can be rapidly increased to 57°C.Fourier Transform Infrared Absorption Spectroscopy(FTIR)and X-ray Diffraction(XRD)analysis showed that polydopamine was modified successfully,Au NFS@PDA and Au NFs had no obvious difference in crystal form.The cell viability test showed that the bionic Au NFS@PDA had good biocompatibility and showed good antitumor activity against HeLa cells under NIR irradiation.The cell viability was only 12%.Therefore,we can use Au NFS@PDA with good biocompatibility as a promising photothermal conversion agent in tumor therapy.

Fe3O4-based Nanoparticles for pH-responsive Dual-modality Imaging and Photothermal Therapy

The study designed a polyacrylic acid(PAA)modified Fe3O4@MnO2 nanoparticles(Fe3O4@MnO2@PAA)for T1/T2 dualmode imaging.In addition,this nano-drug has pH response and anti-tumor photothermal therapy.First,using Fe3O4 as the core can significantly reduce the signal of Fe3O4@MnO2@PAA nanoparticles.MnO2 nanoshells can be decomposed into paramagnetic Mn2+under the acidic environment in the tumor,which enhanced the T1 signal.The pH-responsive T1/T2 dual-mode magnetic resonance imaging(MRI)contrast agent had good sensitivity and specificity,providing more comprehensive and detailed information for tumor diagnosis.In addition,Fe3O4@MnO2@PAA nanoparticles showed excellent absorption capacity in the near-infrared region(NIR),which could be used as a good photothermal conversion material to mediate photothermal treatment of tumors.Therefore,the pHresponsive dual-mode MRI nanoparticle-mediated photothermal therapy showed good application potential in tumor treatment and diagnosis.

Hyaluronic Acid-RGD Peptide Conjugated Mesoporous Silica-coated Gold Nanorods for Cancer Dual-targeted Chemo-photothermal Therapy

A multifunctional drug delivery system（GNRs@mSiO_2-HA-RGD） was developed by conjugating targeting ligand hyaluronic acid（HA） and RGD with mesoporous silica-coated gold nanorods（GNRs@mSiO_2） for dual-targeted chemo-photothermal therapy. The physiochemical properties of the prepared nanoparticles were characterized by FTIR, UV-vis spectra, and ~1H NMR. Doxorubicin hydrochloride（DOX）, an anticancer drug, was used as the model drug to investigate the drug loading, in vitro drug release profiles and cytotoxicity. The experimental results show that DOX-GNRs@mSiO_2-HA-RGD is synthesized with a mean diameter of 116 nm and a sufficient load capacity of about 19.8%. It also has p H-enzyme sensitive and NIRtriggered drug release manner. Cellular uptake indicates that DOX-GNRs@mSiO_2-HA-RGD exhibits a higher cellular uptake via CD44 receptor and integrin receptor mediated endocytosis compared with the GNRs@mSiO_2 modified with one receptor or no receptor. In comparison with chemotherapy or photothermal therapy alone, DOX-GNRs@mSiO_2-HA-RGD displayes the synergistic effects and achieves a higher therapeutic efficacy. It can be expected that DOX-GNRs@mSiO_2-HA-RGD is a potential dual-targeted chemo-photothermal therapeutic platform for effective cancer treatment.

Silicon dioxide-protection boosting the peroxidase-like activity of Fe single-atom catalyst for combining chemo-photothermal therapy

Carbon-based single-atom catalysts(SACs)have been widely studied in the field of biomedicine due to their excellent catalytic performance.However,carbon-based SACs usually aggregate during pyrolysis,which leads to the reduction of catalytic activity.Here,we describe a method to improve the monodispersion of SACs using silicon dioxide as a protective layer.The decoration of silicon dioxide serves as a buffer layer for individual nanoparticles,which is not destroyed during the pyrolysis process,ensuring the single-particle dispersion of the nanoparticles after etching.This approach increased the hydroxyl groups on the surface of Fe-SAC(Fe-SAC-SE)and improved its water solubility,resulting in a four times enhancement of the peroxidase(POD)-like activity of Fe-SAC-SE(58.4 U/mg)than that of non-protected SACs(13.9 U/mg).The SiO_(2)-protection approach could also improve the catalytic activities of SACs with other metals such as Mn,Co,Ni,and Cu,indicating its generality for SACs preparation.Taking advantage of the high POD-like activity,photothermal properties,and large specific surface area of Fe-SAC-SE,we constructed a synergistic therapeutic system(Fe-SAC-SE@DOX@PEG)for combining the photothermal therapy,catalytic therapy,and chemotherapy.It was verified that the photothermal properties of Fe-SAC-SE@DOX@PEG could effectively improve its POD-like activity,exhibiting excellent tumor-killing performance at the cellular level.This work may provide a general approach to improve the performances of SACs for disease therapy and diagnosis.