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Purpose: Our study seeks to develop dual-modal organic-nanoagents for cancer therapy and real-time fluorescence imaging, followed by their pre-clinical evaluation on a murine model. Integrating NIR molecular imaging with nanotechnology, our aim is to improve outcomes for early-stage cutaneous melanoma by offering more effective and less invasive methods. This approach has the potential to enhance both photothermal therapy (PTT) and Sentinel Lymph Node Biopsy (SLNB) procedures for melanoma patients. Methods: NIR-797-isothiocyanate was encapsulated in poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (NPs) using a two-step protocol, followed by thorough characterization, including assessing loading efficiency, fluorescence stability, and photothermal conversion. Biocompatibility and cellular uptake were tested in vitro on melanoma cells, while PTT assay, with real-time thermal monitoring, was performed in vivo on tumor-bearing mice under irradiation with an 808 nm laser. Finally, ex vivo fluorescence microscopy, histopathological assay, and TEM imaging were performed. Results: Our PLGA NPs, with a diameter of 270 nm, negative charge, and 60% NIR-797 loading efficiency, demonstrated excellent stability and fluorescence properties, as well as efficient light-to-heat conversion. In vitro studies confirmed their biocompatibility and cellular internalization. In vivo experiments demonstrated their efficacy as photothermal agents, inducing mild hyperthermia with temperatures reaching up to 43.8 °C. Ex vivo microscopy of tumor tissue confirmed persistent NIR fluorescence and uniform distribution of the NPs. Histopathological and TEM assays revealed early apoptosis, immune cell response, ultrastructural damage, and intracellular material debris resulting from combined NP treatment and irradiation. Additionally, TEM analyses of irradiated zone margins showed attenuated cellular damage, highlighting the precision and effectiveness of our targeted treatment approach. Conclusion: Specifically tailored for dual-modal NIR functionality, our NPs offer a novel approach in cancer PTT and real-time fluorescence monitoring, signaling a promising avenue toward clinical translation.

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OBJECTIVE: To demonstrate the feasibility of using a ring array ultrasound (US) transducer, guided by ultrasound tomography (UST), for generating and monitoring mild hyperthermia (MHTh). METHODS: In silico and in vitro experiments were designed to evaluate the efficacy of a ring array US transducer for generating MHTh and monitoring changes in temperature. In a series of in silico studies, we compared the acoustic focal profiles produced by a ring array US transducer transmitting at different frequencies and further investigated the effectiveness of UST-guidance in implementing aberration correction to enhance the focal profile. In vitro experiments evaluated the capability of using a ring array US transducer to generate and maintain MHTh and the accuracy of using UST to monitor temperature changes. RESULTS: The simulations demonstrated that a ring array US transducer achieves symmetrical and localized acoustic focusing. In a heterogenous tissue model, a ring array US transducer achieved a superior acoustic focus by implementing aberration correction with guidance from UST. In vitro experiments demonstrated the capability of a ring array US transducer to generate MHTh in a tissue-mimicking phantom in an average of 117 ± 18 s and subsequently maintain MHTh. Lastly, a ring array US transducer utilized UST to track temperature changes in a preheated water-filled inclusion while it passively cooled from 45 °C to 25 °C, with a maximum error of 0.58 °C. CONCLUSION: A ring array US transducer can noninvasively generate and monitor MHTh, overcoming many limitations of current clinical systems. The closed geometry of the transducer is optimal for acoustic focusing and UST-guidance allows for improved aberration correction in a heterogenous medium. Utilizing UST thermometry with the same ring array US transducer will allow for implementing an image-guided, temperature-controlled, all-acoustic MHTh system.

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The Enhanced Permeability and Retention (EPR) effect, an elevated accumulation of drugs and nanoparticles in tumors versus in normal tissues, is a widely used concept in the field of cancer therapy. It assumes that the vasculature of solid tumors would possess abnormal, leaky endothelial cell barriers, allowing easy access of intravenous-delivered drugs and nanoparticles to tumor regions. However, the EPR effect is not always effective owing to the heterogeneity of tumor endothelium over time, location, and species. Herein, we introduce a unique nanoparticle-based approach, using MUC18-targeted gold nanorods coupled with mild hyperthermia, to specifically enhance tumor endothelial permeability. This improves the efficacy of traditional cancer therapy including photothermal therapy and anticancer drug delivery by increasing the transport of photo-absorbers and drugs across the tumor endothelium. Using single cell imaging tools and classic analytical approaches in molecular biology, we demonstrate that MUC18-targeted gold nanorods and mild hyperthermia enlarge the intercellular gaps of tumor endothelium by inducing circumferential actin remodeling, stress fiber formation, and cell contraction of adjacent endothelial cells. Considering MUC18 is overexpressed on a variety of tumor endothelium and cancer cells, this approach paves a new avenue to improve the efficacy of cancer therapy by actively enhancing the tumor endothelial permeability.

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While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered self-repairing autophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel (NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundant NO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles (MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtain MNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability to perform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distribution and strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and this process is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over one month and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel at the tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NO effectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronously destroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26 colon tumors are completely eliminated without causing severe side-effects.

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INTRODUCTION: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU). METHODS: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity. RESULTS: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities. CONCLUSION: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

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Aberrant tumor mechanical microenvironment (TMME), featured with overactivated cancer-associated fibroblasts (CAFs) and excessive extracellular matrix (ECM), severely restricts penetration and accumulation of cancer nanomedicines, while mild-hyperthermia photothermal therapy (mild-PTT) has been developed to modulate TMME. However, photothermal agents also encounter the barriers established by TMME, manifesting in limited penetration and heterogeneous distribution across tumor tissues and ending with attenuated efficiency in TMME regulation. Herein, it is leveraged indocyanine green (ICG)-loaded soft nanogels with outstanding deformability, for efficient tumor penetration and uniform distribution, in combination with mild-PTT to achieve potent TMME regulation by inhibiting CAFs and degrading ECM. As a result, doxorubicin (DOX)-loaded stiff nanogels gain greater benefits in tumor penetration and antitumor efficacy than soft counterparts from softness-mediated mild-PTT. This study reveals the crucial role of nanomedicine mechanical properties in tumor distribution and provides a novel strategy for overcoming the barriers of solid tumors with soft deformable nanogels.

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Surgical resection remains the mainstream treatment for malignant melanoma. However, challenges in wound healing and residual tumor metastasis pose significant hurdles, resulting in high recurrence rates in patients. Herein, a bioactive injectable hydrogel (BG-Mngel) formed by crosslinking sodium alginate (SA) with manganese-doped bioactive glass (BG-Mn) is developed as a versatile platform for anti-tumor immunotherapy and postoperative wound healing for melanoma. The incorporation of Mn2+ within bioactive glass (BG) can activate the cGAS-STING immune pathway to elicit robust immune response for cancer immunotherapy. Furthermore, doping Mn2+ in BG endows system with excellent photothermal properties, hence facilitating STING activation and reversing the tumor immune-suppressive microenvironment. BG exhibits favorable angiogenic capacity and tissue regenerative potential, and Mn2+ promotes cell migration in vitro. When combining BG-Mngel with anti-PD-1 antibody (α-PD-1) for the treatment of malignant melanoma, it shows enhanced anti-tumor immune response and long-term immune memory response. Remarkably, BG-Mngel can upregulate the expression of genes related to blood vessel formation and promote skin tissue regeneration when treating full-thickness wounds. Overall, BG-MnGel serves as an effective adjuvant therapy to regulate tumor metastasis and wound healing for malignant melanoma.

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Aims: Preparation and evaluation of nanoparticles for tumor chemotherapy and immunotherapy mild photothermal therapy and oxaliplatin. Methods: The double emulsion method was used for nanoparticle preparations. Polydopamine was deposited on the surface, which was further modified with folic acid. Cytotoxicity assays were carried out by cell counting kit-8. In vivo antitumor assays were carried out on 4T1 tumor-bearing mice. Results: The nanoparticles exhibited a 190 nm-diameter pomegranate-like sphere, which could increase temperature to 43-46°C. In vivo distribution showed enhanced accumulation. The nanoparticles generated stronger immunogenic cell death effects. By stimulating the maturation of dendritic cells, mild photothermal therapy combined with oxaliplatin significantly increased the antitumor effect by a direct killing effect and activation of immunotherapy. Conclusion: This study provided a promising strategy of combination therapy for tumors.

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Second near-infrared (NIR-II) mild photothermal therapy with higher tissue penetration depth and less damage to healthy tissues is emerging as an attractive antitumor modality, but its therapeutic efficiency is dramatically suppressed by the resistance of heat shock proteins (HSPs). As a widely explored photothermal agent, the application of polydopamine (PDA) in the NIR-II region is hampered by low photothermal conversion efficiency (PCE). Herein, its PCE in the NIR-II region is improved by developing novel hollow cavity CaO2 @PDA nanocomposites through chelation-induced diffusion of inner core Ca2+ to the shell PDA to facilitate multiple reflections of laser in the cavity. Upon pH-responsive degradation of CaO2 , its structure is transformed into a stacked "nano-mesh" with excellent light absorption and an enlarged effective irradiation area. Overloading of Ca2+ ions not only induces downregulation of HSPs but also enhances interference of light on membrane potential, which further aggravate mitochondrial dysfunction and reduce the thermotolerance of tumor cells, promoting efficient mild hyperthermia of PDA in the NIR-II region.

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Infected wounds pose a serious threat to public health and pose a significant challenge and financial burden worldwide. The treatment of infected wounds is now an urgent problem to be solved. Herein, mild hyperthermia-assisted hydrogels composed of carboxymethyl chitosan (CMCs), oxidized dextran (Odex), epigallocatechin gallate (EGCG) and PtNPs@PVP (CAT-like nanoenzymes) were proposed for the repair of infected wounds. The incorporation of PtNPs@PVP nanoenzymes give the hydrogels excellent photothermal property and CAT-like activity. When the temperature is maintained at 42-45 °C under 808 nm near infrared (NIR) exposure, the CMCs/Odex/EGCG/Nanoenzymes (COEN2) hydrogel demonstrated highly enhanced antibacterial ability (95.9 % in vivo), hydrogen peroxide (H2O2) scavenging ratio (85.1 % in vitro) and oxygen supply (20.7 mg/L in vitro). Furthermore, this mild-heat stimulation also promoted angiogenesis in the damaged skin area. Overall, this multifunctional hydrogel with antibacterial, antioxidant, oxygen supply, hemostasis, and angiogenesis capabilities has shown great promise in the repair of infected wounds. This study establishes the paradigm of enhanced infected wound healing by mild hyperthermia-assisted H2O2 scavenging, oxygen supplemental, and photothermal antibacterial hydrogels.

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The immune checkpoint blockade (ICB) antibody immunotherapy has demonstrated clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors is suppressed by deficient tumor immunogenicity and immunosuppressive tumor microenvironments. Pyroptosis, a form of programmed cell death, can release tumor antigens, activate effective tumor immunogenicity, and improve the efficiency of ICB, but efficient pyroptosis for tumor treatment is currently limited. Herein, we show a mild hyperthermia-enhanced pyroptosis-mediated immunotherapy based on hollow carbon nanozyme, which can specifically amplify oxidative stress-triggered pyroptosis and synchronously magnify pyroptosis-mediated anticancer responses in the tumor microenvironment. The hollow carbon sphere modified with iron and copper atoms (HCS-FeCu) with multiple enzyme-mimicking activities has been engineered to induce cell pyroptosis via the radical oxygen species (ROS)-Tom20-Bax-Caspase 3-gasdermin E (GSDME) signaling pathway under light activation. Both in vitro and in vivo antineoplastic results confirm the superiority of HCS-FeCu nanozyme-induced pyroptosis. Moreover, the mild photothermal-activated pyroptosis combining anti-PD-1 can enhance antitumor immunotherapy. Theoretical calculations further indicate that the mild photothermal stimulation generates high-energy electrons and enhances the interaction between the HCS-FeCu surface and adsorbed oxygen, facilitating molecular oxygen activation, which improves the ROS production efficiency. This work presents an approach that effectively transforms immunologically "cold" tumors into "hot" ones, with significant implications for clinical immunotherapy.

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Mild-temperature photothermal therapy (mPTT) has shown some advantages over traditional photothermal therapy, such as reducing the damage to surrounding healthy tissues and minimizing side effects. Nevertheless, cancer cells can easily repair damage caused by mild hyperthermia due to heat shock proteins (HSPs). Thus, it is imperative to maximize the mPTT efficiency by down-regulating HSPs overexpression and combining other cancer treatments. Herein, we report the synthesis of phytic acid (PA)-Cu2+ framework/copper sulfide (Cu2-xS) nanocomposites (abbreviated as PA-Cu/Cu2-xS NPs) as the novel therapeutic platform that can down-regulate HSPs overexpression for enhanced multimodal mPTT/chemodynamic therapy (CDT)/chemotherapy. PA-Cu/Cu2-xS NPs were prepared through self-assembly and in-situ vulcanization strategy, resulting in irregular-shaped particles with an approximate size of 100 nm. PA-Cu/Cu2-xS NPs display a plasmon effect from Cu2-xS, which enhances near-infrared (NIR) absorption and possesses excellent photothermal conversion efficiency (41.7%). Moreover, PA-Cu/Cu2-xS NPs exhibit Fenton-like reaction activity resulting from the Cu ions for CDT, and the reaction activity can be further improved 1.3 times due to mild hyperthermia during mPTT. Furthermore, the generated hydroxyl radical (•OH) can effectively decrease HSPs level to enhance mPTT. PA-Cu/Cu2-xS NPs can also serve as a drug delivery system, and they are capable of loading doxorubicin (DOX) with a loading ability (20.7%). Combining mPTT/CDT/chemotherapy exhibits significant inhibition of tumor growth. This approach can serve as a basis for designing more exquisite platforms that combine mPTT with other therapies to achieve more effective cancer treatment.

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PURPOSE: The heating characteristics of water-filtered infrared-A (wIRA) radiation were investigated in vivo in two body regions of healthy humans according to the quality standards of the European Society for Hyperthermic Oncology (ESHO) using an irradiance (infrared-A) of 146 W m-2 as recommended for clinical superficial hyperthermia (HT). METHODS: wIRA was applied to the abdominal wall and lumbar region for 60 min. Skin surface temperature was limited to ≤43 °C. Tissue temperatures were measured invasively at 1-min intervals before, during and after wIRA exposure using five fiber-optical probes at depths of 1-20 mm. RESULTS: Significant differences between body regions occurred during the heating-up phase at depths of 5-15 mm. Thermal steady states were reached at depths ≤5 mm after exposures of 5-6 min, and ≤20 mm after 20 min. On average, the minimum requirements of ESHO were exceeded in both regions by the following factors: ≈3 for the heating rate, ≈2 for the specific absorption rate and ≈1.4 for the temperature rise. Tissue depths with T90 ≥ 40 °C and T50 > 41 °C were ≤10 mm, and ≤20 mm for Tmax ≤ 43 °C. The temperature decay time after termination of irradiation was 1-5 min. Corresponding temperatures were ≤42.2 °C for CEM43 and ≤41.8 °C for CEM43T90, i.e., they are inadequate for direct thermal cell killing. CONCLUSIONS: Thermography-controlled wIRA-HT complies with the ESHO criteria for superficial HT as a radiosensitizer and avoids the risk of thermal skin toxicity.

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BACKGROUND/AIM: Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT. MATERIALS AND METHODS: The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis. RESULTS: Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G2/M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG1 arrest, in a synergistic fashion. CONCLUSION: The combination G2/M blockers and mild-HT can potentially be used for the treatment of OSCC.

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INTRODUCTION: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. AIM: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. METHODS: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis. RESULTS: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. CONCLUSION: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

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Malignant bone tumors result in high rates of disability and death and are difficult to treat in terms of killing tumors and repairing bone defects. Compared with other hyperthermia strategies, magnetic hyperthermia has become an effective therapy for treating malignant bone tumors due to its lack of depth limitations. However, tumor cells express heat shock protein (HSP) to resist hyperthermia, which reduces its curative effect. Competitive ATP consumption can reduce HSP production; fortunately, the basic principle of starvation therapy by glucose oxidase (GOx) is consuming glucose to control ATP production, thereby restricting HSP generation. We developed a triple-functional magnetic gel (Fe3O4/GOx/MgCO3@PLGA) as a magnetic bone repair hydrogels (MBRs) with liquid‒solid phase transition capability to drive magneto-thermal effects to simultaneously trigger GOx release and inhibit ATP production, reducing HSP expression and thereby achieving synergistic therapy for osteosarcoma treatment. Moreover, magnetic hyperthermia improves the effect of starvation therapy on the hypoxic microenvironment and achieves a reciprocal strengthening therapeutic effect. We further demonstrated that in situ MBRs injection effectively suppressed tumor growth in 143B osteosarcoma tumor-bearing mice and an in-situ bone tumor model in the rabbit tibial plateau. More importantly, our study also showed that liquid MBRs could effectively match bone defects and accelerate their reconstruction via magnesium ion release and enhanced osteogenic differentiation to augment the regeneration of bone defects caused by bone tumors, which generates fresh insight into malignant bone tumor treatment and the acceleration of bone defect repair.

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(1) Background: Mild hyperthermia (mHT, 39-42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O2 diffusivities, acidosis- and heat-related enhanced O2 unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O2 tensions in tumors.

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Tumor spheroids as well as multicellular tumor spheroids (MCTSs) are promising 3D in vitro tumor models for drug screening, drug design, drug targeting, drug toxicity, and validation of drug delivery methods. These models partly reflect the tridimensional architecture of tumors, their heterogeneity and their microenvironment, which can alter the intratumoral biodistribution, pharmacokinetics, and pharmacodynamics of drugs. The present review first focuses on current spheroid formation methods and then on in vitro investigations exploiting spheroids and MCTS for designing and validating acoustically mediated drug therapies. We discuss the limitations of the current studies and future perspectives. Various spheroid formation methods enable the easy and reproducible generation of spheroids and MCTSs. The development and assessment of acoustically mediated drug therapies have been mainly demonstrated in spheroids made up of tumor cells only. Despite the promising results obtained with these spheroids, the successful evaluation of these therapies will need to be addressed in more relevant 3D vascular MCTS models using MCTS-on-chip platforms. These MTCSs will be generated from patient-derived cancer cells and nontumor cells, such as fibroblasts, adipocytes, and immune cells.

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As a DNA damaging agent, oxaliplatin (OXA) can induce immunogenic cell death (ICD) in tumors to activate the immune system. However, the DNA damage induced by OXA is limited and the ICD effect is not strong enough to enhance anti-tumor efficacy. Here, we propose a strategy to maximize the ICD effect of OXA through the mild hyperthermia generated by nanoparticles with a platinum (IV) prodrug of OXA (Pt(IV)-C16) and a near-infrared-II (NIR-II) photothermal agent IR1061 upon the irradiation of NIR-II light. The mild hyperthermia (43 °C) holds advantages in two aspects: 1) increase the Pt-DNA cross-linking, leading to enhanced DNA damage and apoptosis; 2) induce stronger ICD effects for cancer immunotherapy. We demonstrated that, compared with OXA and photothermal therapy of IR1061 alone, these nanoparticles under NIR-II light irradiation can significantly improve the anti-cancer efficacy against triple-negative breast cancer 4T1 tumor. This new strategy provides an effective way to improve the therapeutic outcome of OXA. STATEMENT OF SIGNIFICANCE: OXA could induce immunogenic cell death (ICD) via stimulating immune responses by increasing tumor cell stress and death, which triggers tumor-specific immune responses to achieve immunotherapy. However, due to the insufficient Pt-DNA crosslinks, the ICD effect triggered by OXA cannot induce robust immune response. Mild hyperthermia has great potential to maximize the therapeutic outcome of oxaliplatin by increasing the Pt-DNA cross-linking to augment the immunoresponse for enhanced cancer immunotherapy.

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PURPOSE: While radiofrequency catheter ablation (RFCA) creates a lesion consisting of the tissue points subjected to lethal heating, the sublethal heating (SH) undergone by the surrounding tissue can cause transient electrophysiological block. The size of the zone of heat-induced transient block (HiTB) has not been quantified to date. Our objective was to use computer modeling to provide an initial estimate. METHODS AND MATERIALS: We used previous experimental data together with the Arrhenius damage index (Ω) to fix the Ω values that delineate this zone: a lower limit of 0.1-0.4 and upper limit of 1.0 (lesion boundary). An RFCA computer model was used with different power-duration settings, catheter positions and electrode insertion depths, together with dispersion of the tissue's electrical and thermal characteristics. RESULTS: The HiTB zone extends in depth to a minimum and maximum distance of 0.5 mm and 2 mm beyond the lesion limit, respectively, while its maximum width varies with the energy delivered, extending to a minimum of 0.6 mm and a maximum of 2.5 mm beyond the lesion, reaching 3.5 mm when high energy settings are used (25 W-20s, 500 J). The dispersion of the tissue's thermal and electrical characteristics affects the size of the HiTB zone by ±0.3 mm in depth and ±0.5 mm in maximum width. CONCLUSIONS: Our results suggest that the size of the zone of heat-induced transient block during RFCA could extend beyond the lesion limit by a maximum of 2 mm in depth and approximately 2.5 mm in width.

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