RESUMEN

Atherosclerosis is a primary cause of cardiovascular and cerebrovascular diseases, with the unpredictable rupture of vulnerable atherosclerotic plaques enriched with lipid-laden macrophages being able to lead to heart attacks and strokes. Activating macrophage autophagy presents itself as a promising strategy for preventing vulnerable plaque formation and reducing the risk of rupture. In this study, we have developed a novel metal-free nanozyme (HCN@DS) that integrates the functions of multimodal imaging-guided therapy for atherosclerosis. HCN@DS has demonstrated high macrophage-targeting abilities due to its affinity toward scavenger receptor A (SR-A), along with excellent photoacoustic and photothermal imaging capabilities for guiding the precise treatment. It combines mild photothermal effects with moderate reactive oxygen species (ROS) generation to treat atherosclerosis. This controlled approach activates autophagy in atherosclerotic macrophages, inhibiting foam cell formation by reducing the uptake of oxidized low-density lipoproteins (oxLDL) and promoting efferocytosis and cholesterol efflux in macrophages. Additionally, it prevents plaque rupture by inhibiting apoptosis and inflammation within the plaque. Therefore, this metal-free nanozyme holds great potential for reducing the risk of atherosclerosis due to its high biosafety, excellent targeting ability, dual-modality imaging capability, and appropriate modulation of autophagy.

RESUMEN

Photothermal therapy (PTT) shows promise in cancer treatments due to its good spatiotemporal selectivity and minimal invasiveness. However, PTT has some problems such as excessive heat damage to normal tissues, tumor thermo-resistance caused by heat shock proteins (HSPs), and limited efficacy of monotherapy. Here, we construct a patch named "partitioned microneedles" (PMN-SNAP/CuS), which separates the "catalyst" bovine serum albumin-based copper sulfide nanoparticles (CuS@BSA NPs) and the "reactant" S-nitroso-N-acetylpenicillamine (SNAP) into different regions of microneedles, for enhancing mild PTT (mPTT) of melanoma. PMN-SNAP/CuS showed an excellent photothermal effect, Fenton-like catalytic activity, and nitric oxide (NO) generation ability. The combination of NO and reactive oxygen species (ROS) produced by PMN-SNAP/CuS effectively blocked the synthesis of HSPs at the source and enhanced the efficacy of mPTT. Both in vitro and in vivo results proved that PMN-SNAP/CuS significantly enhanced the inhibition of melanoma under 808 nm laser irradiation. In conclusion, our partitioned microneedle strategy based on the combination of enhanced mPTT and gas therapy (GT) provides a promising approach to enhance the therapeutic effect on melanoma.

Asunto(s)

Cobre , Melanoma , Óxido Nítrico , Terapia Fototérmica , Animales , Óxido Nítrico/metabolismo , Cobre/química , Cobre/farmacología , Ratones , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Melanoma/terapia , Agujas , Línea Celular Tumoral , Albúmina Sérica Bovina/química , S-Nitroso-N-Acetilpenicilamina/química , S-Nitroso-N-Acetilpenicilamina/farmacología , Humanos , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Keratitis is the leading cause of blindness worldwide. In refractory cases, it can even lead to eyeball enucleation. The critical challenges of refractory keratitis are the drug-resistant bacteria and bacterial biofilms formation. Therefore, we established an innovative therapeutic approach for keratitis based on mild photothermal loop (MPL) therapy. First, we analyzed the bactericidal effect of methicillin-resistant Staphylococcus aureus (MRSA) under various loops and temperature durations to determine the optimal condition. Then, RAN-seq was applied to explore the underlying mechanisms. Additionally, we formulated a dual-purpose polyvinyl alcohol-polydopamine (PDA/PVA) hydrogel system and explored its effects on the reactive oxygen species (ROS) scavenging capability, antibacterial properties, and anti-inflammatory properties in vitro, as well as its effect in vivo. The results indicated substantial bactericidal properties after exposure in four loops, each lasting 10 min at 45 °C. RNA-seq revealed the altered genes related to virulence and biofilm formation. In addition to good photothermal performance, the PDA/PVA system could effectively eliminate MRSA, reduce ROS, inhibit biofilm formation, and decrease inflammatory factors expression. Moreover, the in vivo results demonstrated the potential of MPL for bacterial keratitis. This study serves as the first attempt to use MPL therapy for refractory keratitis, offering a new approach for clinical practice.

RESUMEN

Background: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities. Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37. Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability. Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.

Asunto(s)

Ferroptosis , Glutatión , Ácido Hialurónico , Nanopartículas , Terapia Fototérmica , ARN Interferente Pequeño , Taninos , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Humanos , Ferroptosis/efectos de los fármacos , Glutatión/metabolismo , Glutatión/química , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Taninos/química , Taninos/farmacología , Nanopartículas/química , Ácido Hialurónico/química , Femenino , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/genética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/genética , Terapia Fototérmica/métodos , Fluorocarburos/química , Fluorocarburos/farmacología , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Terapia Genética/métodos , Terapia Combinada/métodos , Animales , Hierro/química , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/metabolismo

RESUMEN

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Doxorrubicina , Humanos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Lípidos/química , Células MCF-7 , Terapia Fototérmica , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones , Temperatura , Nanopartículas/química , Liberación de Fármacos , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos

RESUMEN

Purpose: Compared with traditional photothermal therapy (PTT, >50°C), mild PTT (≤45°C) is a promising strategy for tumor therapy with fewer adverse effects. Unfortunately, its anti-tumor efficacy is hampered by thermoresistance induced by overexpression of heat shock proteins (HSPs). In our previous study, we found bufalin (BU) is a glycolysis inhibitor that depletes HSPs, which is expected to overcome thermotolerance of tumor cells. In this study, BU-loaded multifunctional nanoparticles (NPs) were developed for enhancing the mild PTT of colorectal cancer (CRC). Methods: Fe3O4 NPs coated with the polydopamine (PDA) shell modified with polyethylene glycol (PEG) and cyclic arginine-glycyl-aspartic peptide (cRGD) for loading BU (Fe3O4@PDA-PEG-cRGD/BU NPs) were developed. The thermal variations in Fe3O4@PDA-PEG-cRGD/BU NPs solution under different conditions were measured. Glycolysis inhibition was evaluated by measuring the glucose uptake, extracellular lactate, and intracellular adenosine triphosphate (ATP) levels. The cellular cytotoxicity of Fe3O4@PDA-PEG-cRGD/BU NPs was analyzed using a cell counting kit-8 assay, Calcein-AM/PI double staining, and flow cytometry in HCT116 cells. The magnetic resonance imaging (MRI) performance and anti-tumor therapeutic efficacy of Fe3O4@PDA-PEG-cRGD/BU NPs were evaluated in HCT116-tumor bearing mice. Results: Fe3O4@PDA-PEG-cRGD/BU NPs had an average diameter of 260.4±3.5 nm, the zeta potential of -23.8±1.6 mV, the drug loading rate of 1.1%, which had good thermal stability, photothermal conversion efficiencies and MRI performance. In addition, the released BU not only killed tumor cells but also interfered with glycolysis by targeting the steroid receptor coactivator 3 (SRC-3)/HIF-1α pathway, preventing intracellular ATP synthesis, and combating HSP-dependent tumor thermoresistance, ultimately strengthening the thermal sensitivity toward mild PTT both in vitro and in vivo. Conclusion: This study provides a highly effective strategy for enhancing the therapeutic effects of mild PTT toward tumors.

Asunto(s)

Bufanólidos , Neoplasias Colorrectales , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Terapia Fototérmica , Animales , Bufanólidos/farmacología , Bufanólidos/química , Bufanólidos/farmacocinética , Humanos , Glucólisis/efectos de los fármacos , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Fototérmica/métodos , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Indoles/química , Indoles/farmacología , Polietilenglicoles/química , Polímeros/química , Ratones Endogámicos BALB C , Línea Celular Tumoral , Ratones Desnudos , Células HCT116 , Nanopartículas de Magnetita/química , Nanopartículas/química , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Considering the profound impact of structure on heterojunction catalysts, the rational design of emerging catalysts with optimized energy band structures is required for antitumor efficiency. Herein, we select titanium nitride (TiN) and Pt to develop a multifunctional Schottky heterojunction named Pt/H-TiN&SRF (PHTS) nanoparticles (NPs) with a narrowed bandgap to accomplish "four birds with one stone" involving enzyo/sono/photo three modals and additional ferroptosis. The in situ-grown Pt NPs acted as electron traps that can cause the energy band to bend upward and form a Schottky barrier, thereby facilitating the separation of electron/hole pairs in exogenous stimulation catalytic therapy. In addition, endogenous catalytic reactions based on peroxidase (POD)- and catalase (CAT)-mimicking activities can also be amplified, triggering intense oxidative stress, in which CAT-like activity decomposes endogenous H2O2 into O2 alleviating hypoxia and provides reactants for sonodynamic therapy. Moreover, PHTS NPs can elicit mild photothermal therapy with boosted photothermal properties as well as ferroptosis with loaded ferroptosis inducer sorafenib for effective tumor ablation and apoptosis-ferroptosis synergistic tumor inhibitory effect. In summary, this paper proposes an attractive design for antitumor strategies and highlights findings for heterojunction catalytic therapy with potential in tumor theranostics.

Asunto(s)

Antineoplásicos , Titanio , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Humanos , Titanio/química , Titanio/farmacología , Ferroptosis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Sorafenib/farmacología , Sorafenib/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Terapia Fototérmica , Nanopartículas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB C

RESUMEN

Mild photothermal therapy (MPTT) generates heat therapeutic effect at the temperature below 45 °C under near-infrared (NIR) irradiation, which has the advantages of controllable treatment efficacy, lower hyperthermia temperatures, reduced dosage, and minimized damage to surrounding tissues. Despite significant progress has been achieved in MPTT, it remains primarily in the stage of basic and clinical research and has not yet seen widespread clinical adoption. Herein, a comprehensive overview of the recent NIR MPTT development was provided, aiming to emphasize the mechanism and obstacles, summarize the used photothermal agents, and introduce various biomedical applications such as anti-tumor, wound healing, and vascular disease treatment. The challenges of MPTT were proposed with potential solutions, and the future development direction in MPTT was outlooked to enhance the prospects for clinical translation.

Asunto(s)

Materiales Biocompatibles , Rayos Infrarrojos , Terapia Fototérmica , Terapia Fototérmica/métodos , Humanos , Materiales Biocompatibles/química , Animales , Rayos Infrarrojos/uso terapéutico , Cicatrización de Heridas , Neoplasias/terapia

RESUMEN

Photothermal therapy (PTT) has attracted attention as a highly effective non-invasive treatment method. However, the high localized temperatures (>50 °C) required for its treatment will inevitably cause damage to the surrounding normal tissues. Therefore, it is important to develop novel and effective strategies to achieve mild photothermal therapy (mPTT). The overexpression of heat shock proteins (HSPs), a widespread heat stress protein, leads to the generation of heat resistance in cancer cells, which seriously affects the therapeutic effect. Thus, inhibiting the expression of HSPs to reduce the heat resistance of tumor cells is expected to enhance the therapeutic effect of mPTT. Here, we successfully synthesized a fluorescent probe bonded with an amphiphilic polypeptide to a cyanine dye and achieved physical encapsulation of the blocker SB705498 through a self-assembly process. SB705498 promotes transient receptor potential vanilloid member 1 (TRPV1) channel blockade that can inhibit the translocation of the heat shock transcription factor 1 (HSF 1) by blocking the influx of calcium and thus affecting the expression of HSPs, which has the potential to enhance the thermotherapy of cancer under mild conditions. In addition, the nanoparticles enabled NIR-II fluorescence imaging with good stability and high photothermal conversion efficiency (48.10 %). Therefore, this study provides a new strategy for realizing precise mPTT(<45 °C) guided by NIR-II imaging. STATEMENT OF SIGNIFICANCE: Inhibition of overexpression of heat shock proteins (HSPs) in cancer photothermal therapy (PTT) is expected to enhance the therapeutic effect of mild photothermal therapy (mPTT). In this study, we synthesized a fluorescent probe bonded to cyanine dyes with amphiphilic polypeptides and physically wrapped the blocker SB705498 through a self-assembly process. As a transient receptor potential vanillin 1 (TRPV1) channel blocker, SB705498 inhibits heat shock transcription factor 1 (HSF1) translocation by blocking calcium ion influx, thereby improving mPTT efficacy by inhibiting the expression of HSPs. The nanoparticles also enable NIR-II fluorescence imaging with good stability and high photothermal conversion efficiency (48.10 %). Thus, this study provides a new strategy for NIR-II mPTT.

Asunto(s)

Rayos Infrarrojos , Nanopartículas , Péptidos , Terapia Fototérmica , Canales Catiónicos TRPV , Nanopartículas/química , Canales Catiónicos TRPV/metabolismo , Humanos , Péptidos/química , Péptidos/farmacología , Nanomedicina Teranóstica/métodos , Animales , Colorantes Fluorescentes/química , Factores de Transcripción del Choque Térmico/metabolismo , Línea Celular Tumoral , Ratones , Ratones Desnudos

RESUMEN

Bacterial keratitis is among the most prevalent causes of blindness. Currently, the abuse of antibiotics in clinical settings not only lacks bactericidal effects but also readily induces bacterial resistance, making the clinical treatment of bacterial keratitis a significant challenge. In this study, we present an injectable hydrogel (GS-PNH-FF@CuS/MnS) containing self-assembled diphenylalanine dipeptide (FF) and CuS/MnS nanocomposites (CuS/MnS NCs) that destroy bacterial cell walls through a synergistic combination of mild photothermal therapy (PTT), chemodynamic therapy (CDT), ion release chemotherapy, and self-assembled dipeptide contact, thereby eliminating Pseudomonas aeruginosa. Under 808 nm laser irradiation, the bactericidal efficiency of GS-PNH-FF@CuS/MnS hydrogel against P. aeruginosa in vitro reach up to 96.97 %. Furthermore, GS-PNH-FF@CuS/MnS hydrogel is applied topically to kill bacteria, reduce inflammation, and promote wound healing. Hematoxylin-eosin (H&E) staining, Masson staining, immunohistochemistry and immunofluorescence staining are used to evaluate the therapeutic effect on infected rabbit cornea models in vivo. The GS-PNH-FF@CuS/MnS demonstrate good biocompatibility with human corneal epithelial cells and exhibit no obvious eyes side effects. In conclusion, the GS-PNH-FF@CuS/MnS hydrogel in this study provides an effective and safe treatment strategy for bacterial keratitis through a multimodal approach.

Asunto(s)

Alginatos , Antibacterianos , Gelatina , Hidrogeles , Queratitis , Pseudomonas aeruginosa , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Hidrogeles/química , Animales , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Conejos , Pseudomonas aeruginosa/efectos de los fármacos , Gelatina/química , Alginatos/química , Humanos , Inyecciones , Terapia Fototérmica/métodos

RESUMEN

Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-ß. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence. This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.

Asunto(s)

Inmunoterapia , Proteínas de la Membrana , Fósforo , Puntos Cuánticos , Puntos Cuánticos/química , Fósforo/química , Inmunoterapia/métodos , Animales , Proteínas de la Membrana/agonistas , Humanos , Ratones , Línea Celular Tumoral , Citocinas/metabolismo , Terapia Fototérmica/métodos , Ratones Endogámicos C57BL , Sistemas de Liberación de Medicamentos , Femenino

RESUMEN

Mild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high-temperature tumor ablation. However, its progress is hindered by the limited availability of high-performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high-performance organic small-molecule PTAs and utilize it to construct a multifunctional nano-theranostic platform. By incorporating additional acceptors and appropriate π-bridges, a diketopyrrolopyrrole-based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near-infrared (NIR) region. Subsequently, BDB is co-coated with the heat shock protein (HSP) inhibitor tanespimycin (17-AAG) using the functional amphiphilic polymers DSPE-Hyd-PEG2000-cRGD to form an all-in-one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real-time through NIR-II fluorescence/photoacoustic/photothermal imaging, and release 17-AAG on demand to enhance mild PTT. Additionally, the mild PTT has been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti-tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

RESUMEN

NIR-II fluorescent photosensitizers as phototheranostic agents hold considerable promise in the application of mild photothermal therapy (MPTT) for tumors, as the reactive oxygen species generated during photodynamic therapy can effectively disrupt heat shock proteins. Nevertheless, the exclusive utilization of these photosensitizers to significantly augment the MPTT efficacy has rarely been substantiated, primarily due to their insufficient photodynamic performance. Herein, the utilization of high-performance NIR-II fluorescent type I/II photosensitizer (AS21:4) is presented as a simple but effective nanoplatform derived from molecule AS2 to enhance the MPTT efficacy of tumors without any additional therapeutic components. By taking advantage of heavy atom effect, AS21:4 as a type I/II photosensitizer demonstrates superior efficacy in producing 1O2 (1O2 quantum yield = 12.4%) and O2 •- among currently available NIR-II fluorescent photosensitizers with absorption exceeding 800 nm. In vitro and in vivo findings demonstrate that the 1O2 and O2 •- generated from AS21:4 induce a substantial reduction in the expression of HSP90, thereby improving the MPTT efficacy. The remarkable phototheranostic performance, substantial tumor accumulation, and prolonged tumor retention of AS21:4, establish it as a simple but superior phototheranostic agent for NIR-II fluorescence imaging-guided MPTT of tumors.

RESUMEN

Stable organic radicals have emerged as a promising option to enhance fluorescence quantum yield (QY), gaining traction in medical treatment due to their unique electronic transitions from the ground state (D0) to the doublet excited state (D1). We synthesized a stable dicyanomethyl radical with a NIR-II fluorescence QY of 0.86 %, surpassing many NIR-II organic dyes. Subsequently, amphiphilic polymer-encapsulated nanoparticles (NPs) containing the radical were created, achieving a NIR-II fluorescence QY of 0.32 %, facilitating high-contrast bio-imaging. These CNPPs exhibit self-enhanced photothermal properties, elevating photothermal conversion efficiency (PCE) from 43.5 % to 57.5 % under 915 nm laser irradiation. This advancement enables more efficient photothermal therapy (PTT) with lower dye concentrations and reduced laser power, enhancing both feasibility and safety. Through regular fractionated mild photothermal therapy, we observed the release of damage-associated molecular patterns (DAMPs) and an increase in cytokine expression, culminating in combined mild phototherapy (m-PTT)-mediated immunogenic cell death (ICD). Consequently, we developed an immunostimulatory tumor vaccine, showcasing a novel approach for refining photothermal agents (PTA) and optimizing the PTT process.

Asunto(s)

Rayos Infrarrojos , Nanopartículas , Péptidos , Nanopartículas/química , Péptidos/química , Péptidos/farmacología , Animales , Humanos , Ratones , Nanomedicina Teranóstica , Tamaño de la Partícula , Terapia Fototérmica , Fototerapia , Radicales Libres/química , Propiedades de Superficie , Supervivencia Celular/efectos de los fármacos

RESUMEN

Mild photothermal therapy (PTT) is a spatiotemporally controllable method that utilizes the photothermal effect at relatively low temperatures (40-45 °C) to especially eliminate tumor tissues with negligible side effects on the surrounding normal tissues. However, the overexpression of heat shock protein 70 (HSP70) and limited effect of single treatment drastically impede the therapeutic efficacy. Herein, the constructed multifunctional core-shell structured Ag-Cu@SiO2-PDA/GOx nanoreactors (APG NRs) that provide a dual inhibition of HSP70 strategy for the second near-infrared photoacoustic (NIR-II PA) imaging-guided combined mild PTT/chemodynamic therapy (CDT). The Ag-Cu cores can convert endogenous H2O2 to hydroxyl radical (•OH), which can induce lipid peroxidation (LPO) and further degrade HSP70. The polydopamine (PDA)/glucose oxidase (GOx) shells are utilized as the NIR-II photothermal agent to generate low temperature, and the GOx can reduce the energy supplies and inhibit energy-dependent HSP70 expression. Furthermore, both the generation of •OH and GOx-mediated energy shortage can reduce HSP70 expression to sensitize mild PTT under 1064 nm laser, and in turn, GOx and laser self-amplify the catalytic reactions of APG NRs for more production of •OH. The multifunctional nanoreactors will provide more potential possibilities for the clinical employment of mild PTT and the advancement of tumor combination therapies.

RESUMEN

NIR-IIa fluorescence imaging (FI) and NIR-II photothermal therapy (PTT) have gained popularity due to the advantages of high temporal and spatial resolution and deep penetration. However, the hyperthermia (>48 °C) of conventional PTT with nonspecific warming and thermal diffusion may inevitably cause damage to healthy tissues or organs surrounding the tumor. Therefore, it is highly desirable to provide effective cancer treatment by implementing mild photothermal therapy (mPTT) at mild temperatures with lower laser power density. Here, the nanotheranostic platform FN@P-GA NPs with NIR-II absorption and NIR-IIa emission was developed by constructing J-aggregates. FN@P-GA possesses good biocompatibility, favorable NIR-IIa FI performance, decent stability, and high photothermal conversion efficiency (57.6 %), which lays a solid foundation for FI-guided mPTT. Due to its ability to effectively down-regulate the expression of HSP90 and reduce cellular thermoresistance to kill cancer cells, FN@P-GA successfully achieved NIR-IIa FI-guided mPTT and demonstrated its potent anti-tumor effect under 1064 nm laser irradiation at mild temperature and low power density (0.3 W/cm2).

Asunto(s)

Carbocianinas , Colorantes Fluorescentes , Rayos Infrarrojos , Terapia Fototérmica , Humanos , Carbocianinas/química , Carbocianinas/farmacología , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Animales , Ratones , Imagen Óptica , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Antineoplásicos/química , Antineoplásicos/farmacología , Propiedades de Superficie , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Nanopartículas/química , Fluorescencia , Línea Celular Tumoral

RESUMEN

Although photothermal therapy (PTT) is effective at killing tumor cells, it can inadvertently damage healthy tissues surrounding the tumor. Nevertheless, lowering the treatment temperature will reduce the therapeutic effectiveness. In this study, we employed 2,2'-((2Z,2'Z)-((4,4,9,9-Tetrahexyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-2,7-diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1-diylidene)) dimalononitrile (IDIC), a molecule possessing a conventional acceptor-donor-acceptor (A-D-A) structure, as a photothermal agent (PTA) to facilitate effective mild photothermal therapy (mPTT). IDIC promotes intramolecular charge transfer under laser irradiation, making it a promising candidate for mPTT. To enhance the therapeutic potential of IDIC, we incorporated quercetin (Qu) into IDIC to form IDIC-Qu nanoparticles (NPs), which can inhibit heat shock protein (HSP) activity during the process of mPTT. Moreover, IDIC-Qu NPs exhibited exceptional water dispersibility and passive targeting abilities towards tumor tissues, attributed to its enhanced permeation and retention (EPR) effect. These advantageous properties position IDIC-Qu NPs as a promising candidate for targeted tumor treatment. Importantly, the IDIC-Qu NPs demonstrated controllable photothermal effects, leading to outstanding in vitro cytotoxicity against cancer cells and effective in vivo tumor ablation through mPTT. IDIC-Qu NPs nano-system enriches the family of organic PTAs and holds significant promise for future clinical applications of mPTT.

Asunto(s)

Nanopartículas , Terapia Fototérmica , Humanos , Animales , Ratones , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Quercetina/química , Quercetina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Tamaño de la Partícula , Estructura Molecular , Ratones Endogámicos BALB C , Propiedades de Superficie , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Experimentales/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/terapia

RESUMEN

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

RESUMEN

Rapid propagation of tumor cells requires plenty of energy, which is adenosine triphosphate (ATP) dependent. ATP inhibition in tumors not only results in the starvation of tumor cells but also down-regulation of the level of heat shock proteins (HSPs), which usually increase during traditional photothermal therapy (PTT), especially when the temperature is up 50 °C. 2-deoxy-D-glucose (2DG) is an anti-glycolytic reagent and can be used as an efficient agent for ATP inhibition in tumors. Compared with typical PTT, low-temperature mild photothermal therapy (MPTT) is receiving more and more attention because it avoids the high temperatures causing damage to the normal tissue, and the increase of HSPs which decrease PTT. Here, multifunctional polypeptide nanoparticles pDG@Ahx conjugating both a NIR probe Ahx-BDP and 2DG into the side chain of the amphiphilic polypeptide have been prepared. In vitro and in vivo studies reveal that the as-prepared nanoparticles achieve a synergistic effect of starvation/MPTT/PDT (photodynamic therapy), and it provides a new strategy to NIR-I/II fluorescence imaging-guided starvation/MPTT/PDT synergy therapy for tumors.

RESUMEN

Combined mild-temperature photothermal/chemotherapy has emerged as a highly promising modality for tumor therapy. However, its therapeutic efficacy is drastically compromised by the heat-induced overexpression of heat shock proteins (HSPs) by the cells, which resist heat stress and apoptosis. The purpose of this study was to downregulate HSPs and enhance the mild-temperature photothermal/chemotherapy effect. In detail, the colon cancer cell membrane (CT26M)-camouflaged HSP90 inhibitor ganetespib and the chemotherapeutic agent doxorubicin (DOX)-coloaded hollow mesoporous Prussian blue (HMPB) nanoplatform (named PGDM) were designed for synergistic mild photothermal/chemotherapy via HSP inhibition. In addition to being a photothermal agent with a high efficiency of photothermal conversion (24.13%), HMPB offers a hollow hole that can be filled with drugs. Concurrently, the cancer cell membrane camouflaging enhances tumor accumulation through a homologous targeting mechanism and gives the nanoplatform the potential to evade the immune system. When exposed to NIR radiation, HMPB's photothermal action (44 °C) not only causes tumor cells to undergo apoptosis but also causes ganetespib to be released on demand. This inhibits the formation of HSP90, which enhances the mild photothermal/chemotherapy effect. The results confirmed that the combined treatment regimen of mild photothermal therapy (PTT) and chemotherapy showed a better therapeutic efficacy than the individual treatment methods. Therefore, this multimodal nanoparticle can advance the development of drugs for the treatment of malignancies, such as colon cancer, and has prospects for clinical application.