RESUMO
Designing reactive calcium-based nanogenerators to produce excess calcium ions (Ca2+ ) in tumor cells is an attractive tumor treatment method. However, nanogenerators that introduce exogenous Ca2+ are either overactive incapable of on-demand release, or excessively inert incapable of an overload of calcium rapidly. Herein, inspired by inherently diverse Ca2+ -regulating channels, a photo-controlled Ca2+ nanomodulator that fully utilizes endogenous Ca2+ from dual sources was designed to achieve Ca2+ overload in tumor cells. Specifically, mesoporous silica nanoparticles were used to co-load bifunctional indocyanine green as a photodynamic/photothermal agent and a thermal-sensitive nitric oxide (NO) donor (BNN-6). Thereafter, they were coated with hyaluronic acid, which served as a tumor cell-targeting unit and a gatekeeper. Under near-infrared light irradiation, the Ca2+ nanomodulator can generate reactive oxygen species that stimulate the transient receptor potential ankyrin subtype 1 channel to realize Ca2+ influx from extracellular environments. Simultaneously, the converted heat can induce BNN-6 decomposition to generate NO, which would open the ryanodine receptor channel in the endoplasmic reticulum and allow stored Ca2+ to leak. Both in vitro and in vivo experiments demonstrated that the combination of photo-controlled Ca2+ influx and release could enable Ca2+ overload in the cytoplasm and efficiently inhibit tumor growth.
Assuntos
Nanopartículas , Neoplasias , Humanos , Cálcio , Fototerapia , Neoplasias/tratamento farmacológico , Verde de Indocianina , Retículo EndoplasmáticoRESUMO
Photothermal therapy (PTT) using near-infrared (NIR) conjugated polymers as photosensitizers has exhibited enormous potential for tumor treatment. However, most NIR conjugated polymers have poor therapeutic efficacy due to their faint absorbance in the NIR region and low photothermal conversion efficiency (PCE). Herein, a valuable strategy for designing NIR polymeric photosensitizer PEKBs with an enhanced PCE accompanied by strong NIR absorbance is proposed by means of inserting TPA-AQ as a thermally activated delayed fluorescence unit into a polymeric backbone. In these PEKBs, PEKB-244 with the appropriate molar content of the TPA-AQ unit displays the strongest NIR absorbance and the highest PCE of 64.5%. Theoretical calculation results demonstrate that the TPA-AQ unit in the polymeric backbone can modulate the intramolecular charge transfer effects and the excited energy decay routes for generating higher heat. The prepared nanoparticles (PEKB-244 NPs) exhibit remarkable photothermal conversion capacities and great biocompatibility in aqueous solutions. Moreover, PEKB-244 NPs also show outstanding photothermal stability, displaying negligible changes in the absorbance within 808 nm irradiation of 1 h (800 mW cm-2). Both in vitro and in vivo experimental results further indicate that PEKB-244 NPs can substantially kill cancer cells under NIR laser irradiation. We anticipate that this novel molecular design strategy can be employed to develop excellent NIR photosensitizers for cancer photothermal therapy.
Assuntos
Nanopartículas , Terapia Fototérmica , Fármacos Fotossensibilizantes , Polímeros/farmacologia , Fluorescência , FototerapiaRESUMO
Developing effective therapies to fight against biofilm-associated infection is extremely urgent. The complex environment of biofilm forces the bacteria to evade the elimination of antibiotics, resulting in recalcitrant chronic infections. To address this issue, a cationic antibacterial agent based on phosphindole oxide (ß-PM-PIO) is designed and prepared. The unique molecular structure endows ß-PM-PIO with aggregation-induced emission feature and efficient singlet oxygen generation ability. ß-PM-PIO shows excellent visual diagnostic function to planktonic bacteria and biofilm. In addition, owing to the synergistic effect of phototoxicity and dark toxicity, ß-PM-PIO can achieve superb antibacterial and antibiofilm performance against Gram-positive bacteria with less potential of developing drug resistance. Notably, ß-PM-PIO also holds excellent anti-infection capacity against drug-resistant bacteria in vivo with negligible side effects. This work offers a promising platform to develop advanced antibacterial agents against multidrug-resistant bacterial infection.
Assuntos
Infecções Bacterianas , Fármacos Fotossensibilizantes , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias , Biofilmes , Cátions , Humanos , Testes de Sensibilidade Microbiana , Óxidos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , PlânctonRESUMO
Synergistic phototherapy provides a promising strategy to conquer the hypoxia and heterogeneity of tumors and realize a better therapeutic effect than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). The development of efficient multifunctional organic phototheranostic systems still remains a challenging task. Herein, 9,10-phenanthrenequinone (PQ) with strong electron-withdrawing ability is conjugated with the rotor-type electron-donating triphenylamine derivatives to create a series of tailor-made photosensitizers. The highly efficient Type I reactive oxygen species generation and outstanding photothermal conversion capacity are tactfully integrated into these PQ-cored photosensitizers. The underlying photophysical and photochemical mechanisms of the combined photothermal and Type I photodynamic effects are deciphered by experimental and theoretical methods and are closely associated with the active intramolecular bond stretching vibration, facilitated intersystem crossing, and specific redox cycling activity of the PQ core. Both in vitro and in vivo evaluations demonstrate that the nanoagents fabricated by these PQ-based photosensitizers are excellent candidates for Type I photodynamic and photothermal combined antitumor therapy. This study thus broadens the horizon for the development of high-performance PTT/Type I PDT nanoagents for synergistic phototheranostic treatments.
Assuntos
Nanopartículas , Fotoquimioterapia , Fenantrenos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Terapia FototérmicaRESUMO
Multimodal therapy is attracting increasing attention to improve tumor treatment efficacy, but generally requires various complicated ingredients combined within one theranostic system to achieve multiple functions. Herein, a multifunctional theranostic nanoplatform based on a single aggregation-induced-emission luminogen (AIEgen), DDTB, is designed to integrate near-infrared (NIR) fluorescence, photothermal, photodynamic, and immunological effects. Intravenously injected AIEgen-based nanoparticles can efficiently accumulate in tumors with NIR fluorescence to provide preoperative diagnosis. Most of the tumors are excised under intraoperative fluorescence navigation, whereafter, some microscopic residual tumors are completely ablated by photodynamic and photothermal therapies for maximally killing the tumor cells and tissues. Up to 90% of the survival rate can be achieved by this synergistic image-guided surgery and photodynamic and photothermal therapies. Importantly, the nanoparticles-mediated photothermal/photodynamic therapy plus programmed death-ligand 1 antibody significantly induce tumor elimination by enhancing the effect of immunotherapy. This theranostic strategy on the basis of a single AIEgen significantly improves the survival of cancer mice with maximized therapeutic outcomes, and holds great promise for clinical cancer treatment.
Assuntos
Fotoquimioterapia , Nanomedicina Teranóstica , Animais , Linhagem Celular Tumoral , Humanos , Hipertermia Induzida , CamundongosRESUMO
Semiconducting polymers (SPs)-based dual photothermal therapy (PTT) obtained better therapeutic effect than single PTT due to its higher photothermal conversion efficiency. However, most dual PTT need to use two lasers for heat generation, which brings about inconvenience and limitation to the experimental operations. Herein, we report the development of "nanococktail" nanomaterials (DTPR) with 808 nm-activated image-guided dual photothermal properties for optimized cancer therapy. Methods: In this work, we co-encapsulated AIEgens (TPA-BDTO, T) and SPs (PDPPP, P) by using maleimide terminated amphiphilic polymer (DSPE-PEG2000-Mal, D), then further conjugated the targeting ligands (RGD, R) through "click" reaction. Finally, such dual PTT nanococktail (termed as DTPR) was constructed. Results: Once DTPR upon irradiation with 808 nm laser, near-infrared fluorescence from T could be partially converted into thermal energy through fluorescence resonance energy transfer (FRET) between T and P, coupling with the original heat energy generated by the photothermal agent P itself, thus resulting in image-guided dual PTT. The photothermal conversion efficiency of DTPR reached 60.3% (dual PTT), much higher as compared to its inherent photothermal effect of only 31.5% (single PTT), which was further proved by the more severe photothermal ablation in vitro and in vivo upon 808 nm laser irradiation. Conclusion: Such smart "nanococktail" nanomaterials could be recognized as a promising photothermal nanotheranostics for image-guided cancer treatment.
Assuntos
Transferência Ressonante de Energia de Fluorescência/instrumentação , Terapia Fototérmica/métodos , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/efeitos da radiação , Sistemas de Liberação de Medicamentos/métodos , Fluorescência , Hipertermia Induzida/métodos , Lasers , Ligantes , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros , SemicondutoresRESUMO
Nanochannels with functional elements have shown promise for DNA sequencing, single-molecule sensing, and ion gating. Ionic current measurement is currently a benchmark, but is focused solely on the contribution from nanochannels' inner-wall functional elements (NIWFE); the attributes of functional elements at nanochannels' outer surface (NOSFE) are nearly ignored, and remain elusive. Here we show that the role of NOSFE and NIWFE for ion gating can be distinguished by constructing DNA architectures using dual-current readout. The established molecular switches have continuously tunable and reversible ion-gating ability. We find that NOSFE exhibits negligible ion-gating behavior, but it can produce a synergistic effect in alliance with NIWFE. Moreover, the high-efficiency gating systems display more noticeable synergistic effect than the low-efficiency ones. We also reveal that the probe amount of NOSFE and NIWFE is almost equally distributed in our biomimetic nanochannels, which is potentially a premise for the synergistic ion-gating phenomena.
Assuntos
Materiais Biomiméticos , Ativação do Canal Iônico , Transporte de Íons , Nanoestruturas , Óxido de Alumínio , Técnicas de Patch-ClampRESUMO
Although extensively used in all fields of chemistry, molecular recognition still suffers from a significant limitation: host-guest binding displays a fixed, hyperbolic dose-response curve, which limits its usefulness in many applications. Here we take advantage of the high programmability of DNA chemistry and propose a universal strategy to engineer biorecognition-based sensors with dual programmable dynamic ranges. Using DNA aptamers as our model recognition element and electrochemistry as our readout signal, we first designed a dual signaling "signal-on" and "signal-off" adenosine triphosphate (ATP) sensor composed of a ferrocene-labeled ATP aptamer in complex to a complementary, electrode-bound, methylene-blue labeled DNA. Using this simple "dimeric" sensor, we show that we can easily (1) tune the dynamic range of this dual-signaling sensor through base mutations on the electrode-bound DNA, (2) extend the dynamic range of this sensor by 2 orders of magnitude by using a combination of electrode-bound strands with varying affinity for the aptamers, (3) create an ultrasensitive dual signaling sensor by employing a sequestration strategy in which a nonsignaling, high affinity "depletant" DNA aptamer is added to the sensor surface, and (4) engineer a sensor that simultaneously provides extended and ultrasensitive readouts. These strategies, applicable to a wide range of biosensors and chemical systems, should broaden the application of molecular recognition in various fields of chemistry.
Assuntos
Trifosfato de Adenosina/química , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais , DNA/análise , Técnicas Eletroquímicas , Aptâmeros de Nucleotídeos/síntese química , Propriedades de SuperfícieRESUMO
Scattered Au 3D nanoparticles form distinct functional regions with an uncovered internal surface in confined channels, named the "Janus" annulus. Electrochemical impedance spectroscopy responses to the variations in DNA self-assembly and hybridization in the channels decorated by the "Janus" annulus are presented. Single nucleotide mutations are further detected in a linear DNA chain, including terminal base polymorphisms.