RESUMEN
Hollow silica spheres have been widely studied for drug delivery because of their excellent biosecurity and high porosity. However, difficulties with degradation in the tumor microenvironment (TME) and premature leaking during drug delivery limit their clinical applications. To alleviate these problems, herein, hollow organosilica spheres (HOS) were initially prepared using a "selective etching strategy" and loaded with a photothermal drug: new indocyanine green (IR820). Then, the Cu2+-tannic acid complex (Cu-TA) was deposited on the surface of the HOS, and a new nanoplatform named HOS@IR820@Cu-TA (HICT) was finally obtained. The deposition of Cu-TA can gate the pores of HOS completely to prevent the leakage of IR820 and significantly enhance the loading capacity of HOS. Once in the mildly acidic TME, the HOS and outer Cu-TA decompose quickly in response, resulting in the release of Cu2+ and IR820. The released Cu2+ can react with the endogenous glutathione (GSH) to consume it and produce Cu+, leading to the enhanced production of highly toxic ·OH through a Fenton-like reaction due to the overexpressed H2O2 in the TME. Meanwhile, the ·OH generation was remarkably enhanced by the NIR light-responsive photothermal effect of IR820. These collective properties of HICT enable it to be a smart nanomedicine for dually enhanced chemodynamic therapy through GSH depletions and NIR light-triggered photothermal effects.
Asunto(s)
Complejos de Coordinación , Nanopartículas , Neoplasias , Polifenoles , Humanos , Peróxido de Hidrógeno , Sistemas de Liberación de Medicamentos , Glutatión , Microambiente Tumoral , Línea Celular TumoralRESUMEN
The efficiency of photodynamic therapy (PDT) is related to the subcellular localization of photosensitizers (PSs) because organelles are associated with many fundamental life-sustaining activities. In this work, we synthesized a PS (CN) based on curcumin (CUR) and obtained enhanced PDT efficiency by simultaneously targeting lipid droplets (LDs) and the endoplasmic reticulum (ER). Compared with CUR, CN with a D-π-A-π-D structure possessed stronger intramolecular charge transfer features, resulting in longer absorption and emission wavelengths. In cell imaging experiments of CN using a confocal laser scanning microscope, a bright green emission in LDs and a weak orange emission in the ER were simultaneously observed due to its sensitivity to polarity. Surprisingly, CN with low singlet oxygen yields (0.13) exhibited an excellent photodynamic effect. Further experimental results showed that the phototoxicity of CN resulted in apoptosis by destroying the ER and ferroptosis by oxidizing polyunsaturated fatty acids (PUFAs) in LDs. This work paves the way for developing more effective photosensitizers with superior dual-targeting specificity.
Asunto(s)
Curcumina , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Curcumina/farmacología , Fotoquimioterapia/métodos , Retículo Endoplásmico , Oxígeno SingleteRESUMEN
Developing nanoplatforms integrating superior fluorescence imaging ability in second near-infrared (NIR-II) window and tumor microenvironment responsive multi-modal therapy holds great potential for real-time feedback of therapeutic efficacy and optimizing tumor inhibition. Herein, we developed a pH-sensitive pyrrolopyrrole aza-BODIPY-based amphiphilic molecule (PTG), which has a balanced NIR-II fluorescence brightness and photothermal effect. PTG is further co-assembled with a vascular disrupting agent (known as DMXAA) to prepare PTDG nanoparticles for combined anti-vascular/photothermal therapy and real-time monitoring of the tumor vascular disruption. Each PTG molecule has an active PT-3 core which is linked to two PEG chains via pH-sensitive ester bonds. The cleavage of ester bonds in the acidic tumor environment would tricker releases of DMXAA for anti-vascular therapy and further assemble PT-3 cores into micrometer particles for long term monitoring of the tumor progression. Furthermore, benefiting from the high brightness in the NIR-II region (119.61 M-1 cm-1) and long blood circulation time (t1/2 = 235.6 min) of PTDG nanoparticles, the tumor vascular disrupting process can be in situ visualized in real time during treatment. Overall, this study demonstrates a self-assembly strategy to build a pH-responsive NIR-II nanoplatform for real-time monitoring of tumor vascular disruption, long-term tracking tumor progression and combined anti-vascular/photothermal therapy.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Terapia Fototérmica , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neoplasias/patología , Nanopartículas/química , Concentración de Iones de Hidrógeno , Ésteres , Línea Celular Tumoral , Fototerapia/métodos , Microambiente TumoralRESUMEN
Lipid droplets (LDs) are crucial organelles used to store lipids and participate in lipid metabolism in cells. The abnormal aggregation and polarity change of LDs are associated with the occurrence of diseases, such as steatosis. Herein, the polarity-sensitive probe TBPCPP with a donor-acceptor-π-acceptor (D-A-π-A) structure was designed and synthesized. The TBPCPP has a large Stokes shift (â¼220 nm), excellent photostability, high LD targeting, and considerable two-photon absorption (TPA) cross-section (â¼226 GM), enabling deep two-photon imaging (â¼360 µm). In addition, the fluorescence lifetime of TBPCPP decreases linearly with increasing solvent polarity. Therefore, with the assistance of two-photon fluorescence lifetime imaging microscopy (TP-FLIM), TBPCPP has successfully achieved not only the visualization of polarity changes caused by LD accumulation in HepG-2 cells but also lipid-specific imaging and visualization of different polarities in lipid-rich regions in zebrafish for the first time. Furthermore, TP-FLIM revealed that the polarity gradually decreases during steatosis in HepG-2 cells, which provided new insights into the diagnosis of steatosis.
Asunto(s)
Gotas Lipídicas , Pez Cebra , Animales , Gotas Lipídicas/química , Microscopía Fluorescente/métodos , Fotones , Lípidos/análisis , Colorantes Fluorescentes/químicaRESUMEN
As a class of highly dynamic organelles, lipid droplets (LDs) are involved in numerous physiological functions, and the changes in polarity of LDs are closely related to a variety of diseases. In this work, we developed two polarity-sensitive fluorescent probes (CC-CH and CC-Cl) based on curcumin analogs. CC-CH and CC-Cl with a donor-acceptor-donor (D-A-D) structure exhibited the property of intramolecular charge transfer (ICT); thus, their fluorescence emissions were significantly attenuated with increasing ambient polarity. Cell experiments indicated that CC-CH and CC-Cl showed excellent photostability, a low cytotoxicity, and a superior targeting ability regarding LDs. After treatment with oleic acid (OA) and methyl-ß-cyclodextrin (M-ß-CD), the polarity changes of LDs in living cells could be visualized by using CC-CH and CC-Cl. In addition, CC-CH and CC-Cl could monitor polarity changes of LDs in different pathological processes, including inflammatory responses, nutrient deprivation, and H2O2-induced oxidative stress. Therefore, CC-CH and CC-Cl are promising potential fluorescent probes for tracking intracellular LD polarity changes.
RESUMEN
Pyroptosis is increasingly considered a new weathervane in cancer immune therapy. However, triggering specific pyroptotic tumor cell death while preserving normal cells still remains a major challenge. Herein, a brand-new pyroptosis inducer, copper-bacteriochlorin nanosheet (Cu-TBB), is designed. The synthesized Cu-TBB can be activated to an "on" state in the tumor microenvironment with glutathione (GSH) overexpression, leading to the release of Cu+ and TBB, respectively. Intriguingly, the released Cu+ can drive cascade reactions to produce O2 -⢠and highly toxic ·OH in cells. Additionally, the released TBB can also generate O2 -⢠and 1 O2 upon 750 nm laser irradiation. Encouragingly, both Cu+ -driven cascade reactions and photodynamic therapy pathways result in potent pyroptosis along with dendritic cell maturation and T cell priming, thus simultaneously eliminating the primary tumors and inhibiting the distant tumor growth and metastases. Conclusively, the well-designed Cu-TBB nanosheet is shown to trigger specific pyroptosis in vitro and in vivo, leading to enhanced tumor immunogenicity and antitumor efficacy while minimizing systemic side effects.
Asunto(s)
Neoplasias , Porfirinas , Humanos , Piroptosis , Cobre , Inmunoterapia , Glutatión , Microambiente Tumoral , Línea Celular Tumoral , Neoplasias/terapiaRESUMEN
Real-time monitoring vascular responses is crucial for evaluating the therapeutic effects of vascular-targeted photodynamic therapy (V-PDT). Herein, we developed a highly-stable and bright aggregation induced emission (AIE) fluorophore (PTPE3 NP) for dynamic fluorescence (FL) imaging of vascular dysfunction beyond 1300 nm window during V-PDT. The superior brightness (ϵmaxΦf>1000 nm ≈ 180.05 M-1 cm-1) and high resolution of PTPE3 NP affords not only high-clarity images of whole-body and local vasculature (hindlimbs, mesentery, and tumor) but also high-speed video imaging for tracking blood circulation process. By virtue of the NPs' prolonged blood circulation time (t1/2 ≈ 86.5 min) and excellent photo/chemical (pH, RONS) stability, mesenteric and tumor vascular dysfunction (thrombosis formation, vessel occlusion, and hemorrhage) can be successfully visualized during V-PDT by FL imaging for the first time. Furthermore, the reduction of blood flow velocity (BFV) can be monitored in real time for precisely evaluating efficacy of V-PDT. These provide a powerful approach for assessing vascular responses during V-PDT and promote the development of advanced fluorophores for biological imaging.
Asunto(s)
Neoplasias , Fotoquimioterapia , Animales , Humanos , Fotoquimioterapia/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/irrigación sanguínea , Imagen Óptica/métodosRESUMEN
The development of photosensitizers (PSs) with subcellular targeting capability has raised interest for photodynamic therapy (PDT) research. In this work, two coumarin-based photosensitizers (C-S-2 and C-S-3) were designed and synthesized via expanding their π-conjugation, introducing strong electron-donor and acceptor groups, and adopting sulfur substitution strategy. These sulfured-coumarins exhibited near-infrared emission (greater than 650 nm), lipid droplet-targeting ability and obvious photocytotoxicity under laser irradiation. In particular, C-S-3 exhibited better photostability, superior lipid droplet-targeting capability, and stronger photodynamic effect on cancer cells than C-S-2.
Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Gotas Lipídicas , Cumarinas/farmacologíaRESUMEN
Recently, photodynamic therapy (PDT) based on the generation of cytotoxic reactive oxygen species (ROS) has drawn great attention in tumor treatment. However, the hypoxia tumor microenvironment (TME) inhibits the generation efficacy of ROS, and the high glutathione (GSH) level in TME could neutralize the generated ROS, both of which strongly reduce the therapeutic efficiency of PDT. In this work, we first constructed the porphyrinic metal-organic framework PCN-224. Then Au nanoparticles were decorated on the PCN-224 to obtain the PCN-224@Au. The decorated Au nanoparticles could not only produce O2 through the decomposition of H2O2 in tumor sites for enhancing the generation of 1O2 in PDT but also deplete glutathione through the strong interactions between Au and sulfhydryl groups on glutathione to weaken the antioxidant ability of tumor cells, thus amplifying the 1O2 damage to cancer cells. The in vitro and in vivo experiments totally exhibited that the as-prepared PCN-224@Au nanoreactor can be used as an oxidative stress amplifier for enhanced PDT, which provides a promising candidate to conquer the limitation of intratumor hypoxia and high GSH level on PDT of cancer.
Asunto(s)
Estructuras Metalorgánicas , Neoplasias , Fotoquimioterapia , Humanos , Estructuras Metalorgánicas/farmacología , Especies Reactivas de Oxígeno , Peróxido de Hidrógeno , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estrés Oxidativo , Hipoxia/tratamiento farmacológico , Glutatión/metabolismo , Nanotecnología , Microambiente TumoralRESUMEN
Two photosensitizers (CCOH and CCN) were designed and synthesized by introducing coumarin into the curcumin (CUR) structure. Compared with CUR, more reactive oxygen species (ROS) were generated by CCOH and CCN in type I and II synergy upon light irradiation. Cell experiments indicated that CCN with an excellent LD-targeting effect could be used to monitor the changes in the morphology and number of LDs in tumor cells during PDT.
Asunto(s)
Curcumina , Fotoquimioterapia , Curcumina/farmacología , Curcumina/química , Gotas Lipídicas , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno , Línea Celular TumoralRESUMEN
Carbon dots (CDs) have emerged as promising nanomaterials for bioimaging-guided photodynamic therapy (PDT). However, designing red-emissive CDs (RCDs) with tunable type I and type II reactive oxygen species (ROS) generation to simultaneously meet PDT applications in aerobic and hypoxic scenarios still remain major challenges. Herein, three types of RCDs with maximum emission at approximately 680 nm are successfully prepared. It is noteworthy that they exhibit the adjustable ROS production with equal superoxide anion (via type I PDT) and incremental singlet oxygen (via type II PDT). Detailed structural and optical characterizations along with theoretical calculation reveal that the unique type I/II ROS formation mainly depends on the core sizes and surface states of RCDs, which determine their identical redox potentials and tapering energy gaps between singlet- and triplet states, respectively. Additionally, due to the inherent mitochondria targeting capability, RCDs enable themselves to induce cell programmed death via activating mitochondrion-mediated apoptotic pathways. This work exploits the unprecedented RCDs with tunable type I and type II ROS generation that could ensure highly efficient tumor eradication both in vitro and in vivo, even under the harsh tumor microenvironment, providing a new prospect for CDs as nanophotosensitizers to conquer the limitations of single type PDT.
Asunto(s)
Neoplasias , Fotoquimioterapia , Humanos , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno/metabolismo , Carbono/química , Neoplasias/tratamiento farmacológico , Mitocondrias/metabolismo , Fármacos Fotosensibilizantes/química , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Benzopyran nitrile dyes cannot be used as qualified photosensitizers due to the low quantum yield of triplet state. The benzopyran derivatives containing selenium instead of oxygen atom based on the heavy atom effect are expected to become potential agents for photodynamic therapy. In this paper, a series of selenium-containing photosensitizers (PSX) were prepared according to this strategy. PSX can effectively produce both singlet oxygen and superoxide anions upon laser irradiation. PSX exhibited the emission wavelength at 500-800 nm and near-infrared (NIR) fluorescence imaging in HeLa cells. Excellent biocompatibility and phototoxicity further indicated that PSX could be used as efficient photosensitizers for NIR fluorescence imaging and photodynamic therapy.
Asunto(s)
Fotoquimioterapia , Selenio , Benzopiranos , Células HeLa , Humanos , Imagen Óptica , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéuticoRESUMEN
γ-Glutamyl transpeptidase (GGT) is one of the biomarker of cancer, hepatitis, and numerous other diseases. The accurate analysis of GGT is useful for the early diagnosis of these diseases. In this work, Probe 1, a ratiometric fluorescent probe based on 2,3,5,6-tetrafluoroterephthalonitrile, was designed for GGT detection. The results indicated that Probe 1 can sensitively and selectively detect GGT in phosphate buffered solution and complex biological systems (e.g., blood serum). Furthermore, Probe 1 has been successfully applied for ratiometric imaging of GGT in cancer cells and normal cells.
Asunto(s)
Colorantes Fluorescentes , gamma-Glutamiltransferasa , Colorantes Fluorescentes/análisis , Células Hep G2 , Humanos , Suero/química , gamma-Glutamiltransferasa/análisisRESUMEN
Based on coumarin and benzopyran derivatives, a dual-wavelength excitation ratiometric fluorescent probe, HABA, was prepared to detect H2S. The HABA probe showed good selectivity and anti-interference abilities during H2S detection. Fluorescence co-localization experiments showed that HABA had excellent localization abilities toward mitochondria and lysosomes. More importantly, HABA can not only detect exogenous H2S, but it can also detect endogenous H2S, indicating that HABA has high application potential and value in the biological field.
Asunto(s)
Sulfuro de Hidrógeno , Colorantes Fluorescentes , Sulfuro de Hidrógeno/metabolismo , Lisosomas/metabolismo , MitocondriasRESUMEN
The design and synthesis of single-molecule amphiphilic and multifunctional phototherapeutic agents are important to cancer diagnosis and therapy. In this work, we developed three amphiphilic diketopyrrolopyrrole derivatives (TPADPP, DTPADPP, and TPADDPP) with different donor-acceptor structures and poly(ethylene glycol) side chains. The corresponding nanoparticles (NPs) were obtained via a self-assembly from three amphiphilic DPP derivatives and used as smart phototherapeutic agents for tumor diagnosis and treatment. The three amphiphilic DPP NPs exhibited near-infrared (NIR) emissions and good biocompatibility. Thus, they could be used as fluorescence (FL) imaging agents for guided therapy. DTPADPP NPs and TPADDPP NPs also displayed excellent photothermal performance and high accumulation in the tumor. Owing to these beneficial features, the DTPADPP NPs and TPADDPP NPs synthesized herein are suitable for NIR FL imaging and effective photothermal therapy against the tumor in vivo.
RESUMEN
Hydrophobic photosensitizers greatly affect cell permeability and enrichment in tumors, but they cannot be used directly for clinical applications because they always aggregate in water, preventing their circulation in the blood and accumulation in tumor cells. As a result, amphiphilic photosensitizers are highly desirable. Although nanomaterial-based photosensitizers can solve water solubility, they have the disadvantages of complicated operation, poor reproducibility, low drug loading, and poor stability. In this work, an efficient synthesis strategy is proposed that converts small molecules into nanoparticles in 100 % aqueous solution by molecular assembly without the addition of any foreign species. Three photosensitizers with triphenylphosphine units and ethylene glycol chains of different lengths, TPP-PPh3 , TPP-PPh3 -2PEG and TPP-PPh3 -4PEG, were synthesized to improve amphiphilicity. Of the three photosensitizers, TPP-PPh3 -4PEG is the most efficient (singlet oxygen yield: 0.89) for tumor photodynamic therapy not only because of its definite constituent, but also because its amphiphilic structure allows it to self-assemble in water.
Asunto(s)
Nanopartículas , Fotoquimioterapia , Porfirinas , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
Peroxalate CL as an energy source to excite photosensitizers has attracted tremendous attention in photodynamic therapy (PDT). In this work, peroxyoxalate CPPO and hypocrellin B (HB)-based nanoparticles (CBNPs) for ultrasound (US)-enhanced self-exciting PDT were designed and prepared. CBNPs showed an excellent therapeutic effect against cancer cells with the assistance of US. This US-enhanced-chemiluminescence system avoids the dependence on external light and provides an example for inspiring more effective and precise strategies for cancer treatment.
Asunto(s)
Antineoplásicos/farmacología , Estructuras Metalorgánicas/farmacología , Perileno/análogos & derivados , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Quinonas/farmacología , Ondas Ultrasónicas , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Modelos Moleculares , Tamaño de la Partícula , Perileno/química , Perileno/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Quinonas/químicaRESUMEN
Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600-900â nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near-infrared (NIR) region, NIR emission (peaked at 805â nm), and singlet oxygen quantum yields of 0.27/0.31. HE-PEG-NPs were also prepared using 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE-PEG-NPs not only retained their 1 O2 -generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and inâ vivo therapeutic results revealed that the synergetic effect of HE-PEG-NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE-PEG-NPs could be regarded as a promising phototheranostic agent.
Asunto(s)
Antineoplásicos/farmacología , Perileno/análogos & derivados , Fenol/farmacología , Fármacos Fotosensibilizantes/farmacología , Terapia Fototérmica , Quinonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Rayos Infrarrojos , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Ratones , Imagen Óptica , Perileno/síntesis química , Perileno/química , Perileno/farmacología , Fenol/síntesis química , Fenol/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Quinonas/síntesis química , Quinonas/química , Nanomedicina TeranósticaRESUMEN
FTC dye with a D-π-A structure showed outstanding stability, high extinction coefficient, and good photothermal performance. Thus, nanoparticles based on FTC dye were first fabricated by a nanoprecipitation method for photothermal therapy (PTT) which was guided by photoacoustic imaging (PAI). The prepared FTC NPs showed a photothermal conversion efficiency of â¼52.71%, good photoacoustic performance, and excellent stability in in vitro experiments. Moreover, FTC NPs showed good performance in tumor ablation under a 635 nm laser irradiation and low cytotoxicity to the mice model without laser treatment. Histopathological analysis further confirmed that FTC NPs did not harm the major organs of mice. Given the abovementioned features, FTC NPs have great potential to be effective phototheranostic materials for PAI and PTT.
RESUMEN
Dopamine modified hypocrellin B (DAHB) derivative-loaded calcium phosphate nanorods (DAHB@CaP NRs) were prepared as a novel phototheranostic agent for effective tumor imaging and therapy. DAHB@CaP NRs were obtained through microwave treatment using DAHB, CaCl2 , NH3 â H2 O, and H3 PO4 as precursors. The DAHB@CaP NRs possessed the following advantages: 1) efficient absorption in the near-infrared (NIR) region from 650â nm to 800â nm; 2) maximum NIR emission at approximately 735â nm; 3) enhanced cellular uptake efficiency inâ vitro and inâ vivo; and 4) efficient inhibition of tumor growth and low biotoxicity. These properties indicate the high capability of DAHB@CaP NRs for NIR fluorescence (FL) imaging-guided photodynamic therapy of cancer, thus offering promising new prospects for clinical applications.