Simultaneously Enhancing NIR-II Emission, Type-I, and Type-II Photosensitization Through Acceleration of Charge-Separated-State Formation for Tumor Phototheranostics.

Photothermal therapy (PTT) uses near-infrared (NIR) light and a photothermal agent (PTA) to generate heat to kill tumor cells. PTT is an attractive therapy for highly metastatic tumors─such as triple-negative breast cancer (TNBC)─because PTT is a potent activator of immunogenic cell death (ICD). ICD is characterized by the production of damage-associated molecular patterns (DAMPs) that help the immune system recognize cancer cells as "nonself." This generates an immune response against the tumor cells and helps to combat both primary and metastatic tumors. However, an unknown thermal window remains in which ICD is most prevalent. Here, we conjugate an NIR-absorbing dye to the surface of bacteriophage Qβ to generate a viral-based PTA. Additionally, we demonstrate that mild PTT (<45 °C) is not enough to cause significant apoptosis in the murine TNBC model. In comparison, hot PTT (>60 °C) effectively eliminates cancer cells but is less likely to induce ICD. An optimal temperature range is moderate PTT (50-60 °C), where effective cell killing and ICD occur. We show an increased surface expression of DAMPs within this range, along with an increased ratio of pro- to anti-inflammatory cytokines by dendritic cells.

Aggregation-Induced Fluorogens in Bio-Detection, Tumor Imaging, and Therapy: A Review

Advances in Immunogenic Cell Death for Cancer Immunotherapy

Photothermal therapy (PTT) can reprogram the immunosuppressive "cold" tumor microenvironment (TME) by releasing heat shock protein (HSP)-related danger-associated molecular patterns (DAMPs) into an immunoreactive "hot" TME for immunogenic cell death (ICD). However, PTT is hampered by a lack of irradiation laser power with obvious energy loss at the tumor site, which results in a limited ICD effect. To overcome this obstacle, chemotherapy-based doxorubicin hydrochloride (DOX) can evoke an antitumor immune response by expressing DAMPs, such as calreticulin (CRT), high-mobility-group box 1 (HMGB1), and adenosine triphosphate (ATP) to initiate intra-tumoral ICD, which also can induce DNA damage to promote cellular apoptosis undoubtedly improving the PTT effect for cascaded amplified tumor ablation outcome. Herein we prepare near-infrared nanoadjuvant CA DOX NPs, which are constructed using near-infrared (NIR) phototherapeutic agent CA and clinical chemotherapeutic drug DOX to cooperatively fight cancer. The CA DOX NPs display enhanced PTT efficiency owing to the strengthened apoptosis and ICD with DNA damage based on DOX. More importantly, the chemotherapeutic effects of DOX can also be specifically promoted during cellular heat stress. Hence, the multimodal NIR CA DOX NPs can initiate synergistic therapeutic outcomes to augment the cancer ablation effect, which provides a promising avenue in cancer therapy for further preclinical investigation.

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.

D-A-D-structured boron-dipyrromethene with aggregation-induced enhanced phototherapeutic efficiency for near-infrared fluorescent and photoacoustic imaging-guided synergistic photodynamic and photothermal cancer therapy

Herein, we have developed a composite antibacterial hydrogel with photodynamic therapy (PDT) and photothermal therapy (PTT) antibacterial capabilities, triggered by white light and NIR light irradiation. A water-insoluble conjugated polymer (PDPP) with photothermal ability was prepared into nanoparticles by the nanoprecipitation method, and the cell-penetrating peptide TAT was grafted on the surface of the nanoparticles. Based on our previous work that developed a hybrid hydrogel with an enhanced PDT effect from polyisocyanide (PIC) hydrogel and cationic conjugated polythiophene (PMNT), PDPP nanoparticles (CPNs-TAT) with photothermal ability are introduced to realize the synergistic antibacterial effect of PDT and PTT. Using the PIC hydrogel to combine PIC and CPNs-TAT has the following advantages. First, the PIC hydrogel can regulate the aggregation state of PMNT, making it better dispersed and improving its capacity of reactive oxygen species (ROS) production. Second, CPNs-TAT can be uniformly dispersed in the PIC hybrid, thereby avoiding the toxicity caused by too high local concentration, achieving a uniform increase in system temperature, and enhancing the therapeutic effect of PTT. Third, the PIC hybrid has the synergistic treatment effect of PDT and PTT. The PIC hybrid intelligently regulates its antibacterial ability through white light and NIR light, which can be used in the white light and NIR light areas. When irradiated with white light and NIR light sequentially, synergistic PDT and PTT exhibit stronger antibacterial ability than PDT or PTT alone. The combination of two antibacterial methods realizes the dual-control antibacterial hydrogel of PDT and PTT and provides an antibacterial mode based on PIC hybrids. Therefore, the PIC hybrids are promising as an antibacterial excipient for clinical wounds.

Nanoparticle-based photothermal therapy (PTT) has been widely investigated in cancer therapy as a rapid and minimally invasive tumor ablation technique. In this treatment modality, the intrinsic photothermal conversion property of synthesized nanoparticles allows the conversion of incident light into heat, which generates cell temperature increases, thereby killing cancer cells in contact with the nanoparticles. Here, Prussian blue nanoparticles (PBNPs) are used as photothermal agents, as they exhibit strong absorbance at near-infrared (NIR) wavelengths, are stable, non-toxic, and have 20.5% photothermal conversion efficiencies. In studies using PBNPs to administer photothermal therapy (PBNP-PTT) to localized tumors in a neuroblastoma model, PBNP-PTT generates local heating, resulting in decreased tumor growth and significantly improved survival. Importantly, we have shown that under certain conditions, PBNP-PTT generates immunogenic cell death (ICD), a favorable cell death phenotype characterized by concurrent cytotoxicity and immune cell engagement, enabling a potentially robust and long-lasting immune response and allowing for immunological memory against recurrent or metastatic disease. ICD is defined by the release or exposure of danger-associated molecular patterns (DAMPs), such as calreticulin, adenosine triphosphate (ATP), and high mobility group box 1 (HMGB1) from dying cancer cells. DAMPs are critical for the maturation, antigen uptake, and presentation of dendritic cells, and serve as powerful immunological adjuvants to activate a cytotoxic T lymphocyte response; these markers must be present for a cell to be classified as undergoing ICD. Previous studies in our lab show that the PBNP-PTT-stimulated release of DAMPs from dying cancer cells is both disease- and stimulus-specific; that is, depending on the cell type and conditions of PBNP-PTT, DAMPs may or may not be released sufficiently to generate downstream responses. To ensure that PBNP-PTT induces the release and expression of the correct DAMPs to induce ICD, we synthesized DAMPs-coated PBNPs to use in PBNP-PTT. Our hypothesis is that PBNP-PTT allows to heat cancer cells, causing exposure of some DAMPs, while simultaneously releasing other DAMPs from the PBNPs, augmenting the immunogenic effect. Here, we show the synthesis strategy for coating PBNPs with DAMPs, the number of DAMPs bound to PBNPS using the Bio-Red Protein Assay, and the stability of the DAMPs-PBNPs over several days. We present consistent data showing the cytotoxic capability of DAMPs-PBNP-based PTT using CellTiter-Glo® Luminescent Cell Viability Assay. Additionally, we compare the effects of applying PBNP-based PTT on the surface versus interstitially, to further optimize our photothermal nanoimmunotherapy. Support or Funding Information UPR-Ponce RISE (NIH-NIGMS R25GM096955) Hypothesis The stability of PBNPs and PBNPs-DAMPs measured over 7 days using a Dynamic Light Scattering. Cytotoxicity capabilities of PBNPs and DAMPs-PBNPs.The viability of treated neuroblastoma cells with PBNPs and DAMPs-PBNPs at different concentrations using CellTiter-Glo® Luminescent Cell Viability Assay. Cytotoxicity capabilities of PBNP-PTT and DAMPs-PBNP-PTTThe viability of tumor cells of neuroblastoma under PBNPs-PTT and DAMPs-PBNPs-PTT, after 24h of incubation, treated at different concentrations of the nanoparticles (0–0.1 mg/mL) using a 0.75W (A) and 1.00W laser power (B). Reached temperatures at 0.75W (C) and 1.00W (D) laser power for the treated tumor cells under PTT for 10 min. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

NIR II light-driven nanomotor synergistically enhances immunogenic cell death through photothermal and chemodynamic therapy for melanoma immunotherapy.

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an ‘eat me’ signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8+ T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.

Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

Indocyanine green (ICG) is a promising near-infrared (NIR) dye for tumor imaging and photothermal therapy; however, the poor stability and lack of targeting limit its application. In this study, ICG was encapsulated into folate-conjugated poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) micelles to overcome these problems. ICG-loaded micelles were prepared by solvent evaporation method. Cell uptake and in vitro photothermal cytotoxicity were evaluated on KB cells. In vivo NIR imaging and photothermal therapy were conducted on KB tumor-bearing mice. ICG-loaded micelles with favorable sizes and stable NIR optical properties were successfully prepared. These micelles could target to KB tumors and enabled high-resolution NIR imaging. Moreover, they could effectively convert the absorbed NIR laser energy into heat, resulting in significant tumor damage and inhibition. This novel micellar system, integrating stable NIR properties, excellent tumor targeting and photothermal capability, showed great potential in tumor imaging and therapy.

With the continuous discovery of new materials and a deeper understanding of tumor diseases, more possibilities have been identified for the delivery of antitumor drugs and the treatment of tumors. Currently, the treatment of tumors is not limited to traditional chemotherapy and radiotherapy. Photothermal therapy (PTT) is a new type of noninvasive therapeutic strategy that has aroused widespread concern. PTT can generate a large amount of heat in a specific external environment to achieve the purpose of tumor ablation. Notably, PTT produces heat to kill tumors. In addition, tumor tissues produce many related molecules, which can submit antigens to stimulate T cells and cause antitumor immunity, a process known as the immunogenic cell death (ICD) effect of the tumor environment. However, relying solely on PTT to induce the ICD effect in tumor tissues is challenging, and the immunosuppressive character of the tumor microenvironment weakens the curative effect. Therefore, it is necessary to combine therapy with PTT to achieve the desired efficacy. Here, this review summarizes recent nanomaterial-based PTT and its concomitant ICD, discusses how to amplify the effect of ICD and combines immunotherapy with cotherapy to carry out antitumor research, and finally looks forward to the prospect of PTT combination therapy for tumor treatment.

High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment

Due to the immunosuppressive tumor microenvironment (TME) and potential systemic toxicity, chemotherapy often fails to elicit satisfactory anti-tumor responses, so how to activate anti-tumor immunity to improve the therapeutic efficacy remains a challenging problem. Photothermal therapy (PTT) serves as a promising approach to activate anti-tumor immunity by inducing the release of tumor neoantigens in situ. In this study, we designed tetrasulfide bonded mesoporous silicon nanoparticles (MSNs) loaded with the traditional drug doxorubicin (DOX) inside and modified their outer layer with polydopamine (DOX/MSN-4S@PDA) for comprehensive anti-tumor studies in vivo and in vitro. The MSN core contains GSH-sensitive tetrasulfide bonds that enhance DOX release while generating hydrogen sulfide (H2S) to improve the therapeutic efficacy of DOX. The polydopamine (PDA) coating confers acid sensitivity and mild photothermal properties upon exposure to near-infrared (NIR) light, while the addition of hyaluronic acid (HA) to the outermost layer enables targeted delivery to CD44-expressing tumor cells, thereby enhancing drug accumulation at the tumor site and reducing toxic side effects. Our studies demonstrate that DOX/MSN@PDA-HA can reverse the immunosuppressive tumor microenvironment in vivo, inducing potent immunogenic cell death (ICD) of tumor cells and improving anti-tumor efficacy. In addition, DOX/MSN@PDA-HA significantly suppresses tumor metastasis to the lung and liver. In summary, DOX/MSN@PDA-HA exhibits controlled drug release, excellent biocompatibility, and remarkable tumor inhibition capabilities through synergistic chemical/photothermal combined therapy.