RESUMO
Owing to the complementary high spatial resolution and signal-to-noise ratio, the dual-modality imaging technique of photoacoustic imaging (PAI)/the second near-infrared window fluorescence imaging (NIR-II FI) holds great promise for the detection of tumor tissues and sentinel lymph nodes (SLNs). Herein, by developing two aggregation-induced emission luminogens (AIEgens) (C-NTBD and O-NTBD) with benzodithiadiazole as the electron acceptor, PAI/NIR-II FI was applied to the diagnosis and treatment of neuroendocrine neoplasms (NENs) and their SLNs for the first time. Both AIEgens exhibited good PAI properties as well as intense NIR-II fluorescence emission. Among them, C-NTBD nanoparticles (NPs) have better PAI and NIR-II FI performance with maximum absorption at 732 nm and emission peak at 1042 nm. In NENs-bearing nude mice model, after successful preoperative localization of NENs by PAI, NIR-II FI was then used to detect SLNs. Under the NIR-II FI guidance of C-NTBD NPs, an SLN with a diameter of 1 mm located in the chest wall and far away from the primary tumor site was even detected and precisely removed. This dual-modality imaging technology could improve the detection of NENs and the accuracy of intraoperative SLNs dissection, improve patient prognosis, and provide a new strategy for the precise treatment of NENs.
Assuntos
Nanopartículas , Neoplasias , Linfonodo Sentinela , Animais , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Camundongos , Camundongos Nus , Nanopartículas/química , Neoplasias/patologia , Imagem Óptica/métodos , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgiaRESUMO
Herein, we report an activatable near-infrared (NIR) afterglow theranostic prodrug that circumvents high background noise interference caused by external light excitation. The prodrug can release hydroxycamptothecin (HCPT) in response to the high intratumoral peroxynitrite level associated with immunogenic cell death (ICD), and synchronously activate afterglow signal to monitor the drug release process and cold-to-hot tumor transformation. The prodrug itself is an ICD inducer achieved by photodynamic therapy (PDT). PDT initiates ICD and recruits first-arrived neutrophils to secrete peroxynitrite to trigger HCPT release. Intriguingly, we demonstrate that HCPT can significantly amplify PDT-mediated ICD process. The prodrug thus shows a self-sustainable ICD magnification effect by establishing an "ICD-HCPT release-amplified ICD" cycling loop. In vivo studies demonstrate that the prodrug can eradicate existing tumors and prevent further tumor recurrence through antitumor immune response.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Pró-Fármacos , Linhagem Celular Tumoral , Humanos , Morte Celular Imunogênica , Neoplasias/tratamento farmacológico , Ácido Peroxinitroso/uso terapêutico , Medicina de Precisão , Pró-Fármacos/metabolismoRESUMO
Fluorescence imaging has been widely used in the biomedical field owing to its merits of high sensitivity, excellent accuracy, high biosafety, etc. However, despite the good performance of fluorescent materials in the diagnosis of subcutaneous tumors or some orthotopic tumors in mice, their potential clinical application for most orthotopic tumors in humans is still limited due to their weak tissue penetration ability and the high thickness of human tissues. Given that the human tongue can extend out of the mouth and is approximately 1 cm thick, the diagnosis of tongue squamous cell carcinoma (TSCC) by fluorescence has great potential for clinical applications. However, to the best of our knowledge, a few studies have been performed to detect tongue tumors using fluorescence imaging, and most of them are administered in a subcutaneous tumor-bearing mouse model and are based on fluorescent materials with aggregation-caused quenching effects. Herein, by developing DPA-TPE-DCM with intense near-infrared fluorescence emission in the aggregation state, aggregation-induced emission materials were used for the first time in the early diagnosis of orthotopic TSCC and sentinel lymph node (SLN) mapping in an immunocompetent mouse model of orthotopic TSCC with a high signal-to-background ratio of 10.2. Moreover, with the guidance of the fluorescence of DPA-TPE-DCM NPs, SLNs smaller than 2 mm in diameter were successfully excised. This study provides new insight and a method for the early diagnosis of TSCC in clinical practice and provides more possibilities to broaden the potential clinical applications of fluorescent materials.
Assuntos
Carcinoma de Células Escamosas , Linfonodo Sentinela , Neoplasias da Língua , Animais , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Corantes , Diagnóstico Precoce , Verde de Indocianina , Camundongos , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/métodos , Língua/patologia , Neoplasias da Língua/diagnóstico por imagemRESUMO
Understanding the mechanism and progression of neutrophil-involved diseases (e.g., acute inflammation) is of great importance. However, current available analytical methods neither achieve the real-time monitoring nor provide dynamic information during the pathological processes. Herein, a peroxynitrite (ONOO-) and environmental pH dual-responsive afterglow luminescent nanoprobe is designed and synthesized. In the presence of ONOO- at physiological pH, the nanoprobes show activated near-infrared afterglow luminescence, whose intensity and lasting time can be highly enhanced by introducing the aggregation-induced emission (AIE) effect with a twisted molecular geometry into the system. In vivo studies using three diseased animal models demonstrate that the nanoprobes can sensitively reveal the development process of acute skin inflammation including infiltration of first arrived neutrophils and acidification initiating time, make a fast and accurate discrimination between allergy and inflammation, and rapidly screen the antitumor drugs capable of inducing immunogenic cell death. This work provides an alternative approach and advanced probes permitting precise disease monitoring in real time.
Assuntos
Luminescência , Neutrófilos , Animais , Inflamação , Ácido PeroxinitrosoRESUMO
Persistent luminescence without excitation light and tissue autofluorescence interference holds great promise for biological applications, but is limited by available materials with long-wavelength emission and excellent clinical potential. Here, we report that porphyrin derivatives can emit near-infrared persistent luminescence over 60â min after cessation of excitation light or on interaction with peroxynitrite. A plausible mechanism of the successive oxidation of vinylene bonds was demonstrated. A supramolecular probe with a ß-sheet structure was constructed to enhance the tumor targeting ability and the photoacoustic and persistent luminescence signals. Such probes featuring light-triggered function transformation from photoacoustic imaging to persistent luminescence imaging permit advanced image-guided cancer surgery. Furthermore, peroxynitrite-activated persistent luminescence of the supramolecular probe also enables rapid and precise screening of immunogenic cell death drugs.
Assuntos
Nanopartículas , Neoplasias , Porfirinas , Humanos , Luminescência , Nanopartículas/química , Ácido PeroxinitrosoRESUMO
Photoacoustic (PA) imaging emerges as a promising technique for biomedical applications. The development of new strategies to boost PA conversion without depressing other properties (e.g., fluorescence) is highly desirable for multifunctional imaging but difficult to realize. Here, we report a new phenomenon that active intramolecular motions could promote PA signal by specifically increasing thermal-to-acoustic conversion efficiency. The compound with intense intramolecular motion exhibits amplified PA signal by elevating thermal-to-acoustic conversion, and the fluorescence also increases due to aggregation-induced emission signature. The simultaneously high PA and fluorescence brightness of TPA-TQ3 NPs enable precise image-guided surgery. The preoperative fluorescence and PA imaging are capable of locating orthotopic breast tumor in a high-contrast manner, and the intraoperative fluorescence imaging delineates tiny residual tumors. This study highlights a new design guideline of intramolecular motion amplifying PA effect.
Assuntos
Corantes Fluorescentes/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Técnicas Fotoacústicas , Fármacos Fotossensibilizantes/uso terapêutico , Acústica , Humanos , Neoplasias/cirurgia , Cirurgia Assistida por Computador , TemperaturaRESUMO
Herein, we report a new bioprobe with aggregation-induced emission (AIE) characteristics by conjugation of a far-red/near-infrared emissive AIE luminogen and two polymyxinB peptides. Due to the strong binding effect between polymyxin B and the lipopolysaccharide in the cell wall of Gram-negative bacteria, the bioprobe can selectively visualize Gram-negative bacteria and effectively kill them via photodynamic treatment.
Assuntos
Técnicas Biossensoriais , Bactérias Gram-Negativas , PeptídeosRESUMO
The shortened Abstract is as follows: Therapeutic gas nitric oxide (NO) has demonstrated the unique advances in biomedical applications due to its prominent role in regulating physiological/pathophysiological activities in terms of vasodilation, angiogenesis, chemosensitizing effect, and bactericidal effect. However, it is challenging to deliver NO, due to its short half-life (<5 s) and short diffusion distances (20-160 µm). To address these, various polymeric NO delivery nanoplatforms (PNODNPs) have been developed for cancer therapy, antimicrobial and cardiovascular therapeutics, because of the important advantages of polymeric delivery nanoplatforms in terms of controlled release of therapeutics and the extremely versatile nature. This reviews highlights the recent significant advances made in PNODNPs for NO storing and targeting delivery. The ideal and unique criteria that are required for PNODNPs for treating cancer, cardiovascular diseases and infection, respectively, are summarized. Hopefully, effective storage and targeted delivery of NO in a controlled manner using PNODNPs could pave the way for NO-sensitized synergistic therapy in clinical practice for treating the leading death-causing diseases.
Assuntos
Doenças Cardiovasculares , Neoplasias , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Óxido Nítrico , Doadores de Óxido Nítrico , PolímerosRESUMO
As a common method for postoperative adjuvant treatments of bladder tumor, chemotherapy encounters low tumor targeting, short tumor retention time and bad bioavailability in clinical applications, which result in unsatisfactory high chemotherapeutical doses, frequent administration and subsequent severe side effects. Herein, we innovatively introduced the enzyme-assisted assembly to construct a bladder tumor-specific transformable peptide prodrug (i.e. HCPT-FF-GFLG-EEYSA). The prodrug targeted bladder tumor through the specific binding capacity of YSA to EphA2 and underwent on-demand structural transformation intracellularly from micelles to fibrils catalyzed by cathepsin B (CtsB), of which EphA2 and CtsB are overexpressed on the outer membrane and in cytoplasm of bladder tumor cells, respectively. Comparing with hydroxycamptothecin (HCPT), the prodrug can prolong the drug retention time and release the active drug in a sustained manner, which in turn decrease the administration frequencies of chemotherapeutics and reduce the side toxicities, etc. This strategy provides an alternative for bladder tumor chemotherapeutics and shows great potential to inhibit the relapse of postoperative tumors.
Assuntos
Antineoplásicos Fitogênicos , Pró-Fármacos , Neoplasias da Bexiga Urinária , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Portadores de Fármacos , Humanos , Peptídeos , Microambiente Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Semiconducting polymer nanoparticles (SPNs) emitting in the second near-infrared window (NIR-II, 1000-1700 nm) are promising materials for deep-tissue optical imaging in mammals, but the brightness is far from satisfactory. Herein, we developed a molecular design strategy to boost the brightness of NIR-II SPNs: structure planarization and twisting. By integration of the strong absorption coefficient inherited from planar π-conjugated units and high solid-state quantum yield (ΦPL) from twisted motifs into one polymer, a rise in brightness was obtained. The resulting pNIR-4 with both twisted and planar structure displayed improved ΦPL and absorption when compared to the planar polymer pNIR-1 and the twisted polymer pNIR-2. Given the emission tail extending into the NIR-IIa region (1300-1400 nm) of the pNIR-4 nanoparticles, NIR-IIa fluorescence imaging of blood vessels with enhanced clarity was observed. Moreover, a pH-responsive poly(ß-amino ester) made pNIR-4 specifically accumulate at tumor sites, allowing NIR-IIa fluorescence image-guided cancer precision resection. This study provides a molecular design strategy for developing highly bright fluorophores.
RESUMO
On the basis of the Jablonski diagram, the photophysical properties of optical agents are highly associated with biomedical function and efficacy. Herein, the focus is on organic/polymer optical agents and the recent progress in the main strategies for regulating their photophysical properties to achieve superior cancer diagnosis/phototheranostics applications are highlighted. Both the approaches of nanoengineering and molecular design, which can lead to optimized effectiveness of required biomedical function, are discussed.
Assuntos
Neoplasias/diagnóstico , Compostos Orgânicos/química , Polímeros/química , Nanomedicina Teranóstica , Animais , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Imagem Óptica/métodos , Teoria Quântica , Espécies Reativas de Oxigênio/metabolismoRESUMO
Aggregation-induced emission (AIE) nanoparticles (NPs) are widely used for image-guided tumor resection because of their high signal-to-noise ratios and long systemic circulation time. These NPs are derived by encapsulating small-molecule fluorescent dyes with AIE property inside the cores of NPs assembled by amphiphilic polymers. Although the systemic circulation of AIE NPs is prolonged, hydrophilic polymer coatings simultaneously decrease the binding and uptake of AIE NPs by tumor cells. To overcome this problem, surface-adaptive AIE dye-encapsulated mixed-shell micelles (MSMs) with polyethylene glycol/poly (ß-amino ester) (PEG/PAE) surfaces were prepared. Due to the charge conversion ability of PAE, MSMs demonstrated enhanced cellular uptake by tumor cells in acidic conditions. In addition, compared with single-PEG-shelled micelles (PEGSMs), MSMs exhibited prolonged systemic circulation due to the presence of micro-phase separated surfaces. Moreover, due to the co-ordination effect of enhanced cancer cell uptake and prolonged systemic circulation time, MSMs were more enriched than PEGSMs in the tumor cells and exhibited excellent performance during image-guided tumor resection.
Assuntos
Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/diagnóstico por imagem , Polietilenoglicóis/química , Polímeros/química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Raios Infravermelhos , Camundongos , Micelas , Imagem Óptica , Ratos , Propriedades de Superfície , Distribuição Tecidual , Microambiente TumoralRESUMO
Planar donor and acceptor (D-A) conjugated structures are generally believed to be the standard for architecting highly efficient photothermal theranostic agents, in order to restrict intramolecular motions in aggregates (nanoparticles). However, other channels of extra nonradiative decay may be blocked. Now this challenge is addressed by proposing an "abnormal" strategy based on molecular motion in aggregates. Molecular rotors and bulky alkyl chains are grafted to the central D-A core to lower intermolecular interaction. The enhanced molecular motion favors the formation of a dark twisted intramolecular charge transfer state, whose nonradiative decay enhances the photothermal properties. Result shows that small-molecule NIRb14 with long alkyl chains branched at the second carbon exhibits enhanced photothermal properties compared with NIRb6, with short branched chains, and much higher than NIR6, with short linear chains, and the commercial gold nanorods. Both in vitro and in vivo experiments demonstrate that NIRb14 nanoparticles can be used as nanoagents for photoacoustic imaging-guided photothermal therapy. Moreover, charge reversal poly(ß-amino ester) makes NIRb14 specifically accumulate at tumor sites. This study thus provides an excited molecular motion approach toward efficient phototheranostic agents.
RESUMO
Targeted drug delivery of nanomedicines offered a promising strategy to improve the tumor accumulation and reduce the side effects of chemotherapeutics. However, undesired recognition of the targeting ligands on the surface of nanocarriers by immune systems or normal tissues decreased the circulation time and reduced the targeting efficiency. Here, we developed a ligand-switchable micellar nanocarrier that can hide the targeting ligands when circulating in the bloodstream and expose them on the surface when entering the tumor microenvironments. With the ligand-switching capability, the nanocarrier achieved a 66% longer blood circulation half-life and a 23% higher tumor accumulation than the nanocarrier with targeting ligands on the surface. This targeting strategy could serve as a universal approach to improve the targeting efficiency for nanomedicines.
Assuntos
Nanoestruturas , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Ligantes , Micelas , Nanomedicina , NanopartículasRESUMO
Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems. STATEMENT OF SIGNIFICANCE: Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.
Assuntos
Tempo de Circulação Sanguínea , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas , Animais , Antineoplásicos/administração & dosagem , Células HEK293 , Células Hep G2 , Humanos , Íons , Metacrilatos/química , Micelas , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Polímeros/química , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição Tecidual , Microambiente TumoralRESUMO
Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Catequina/administração & dosagem , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Micelas , Nanoestruturas/administração & dosagem , Chá/química , Antibióticos Antineoplásicos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Catequina/análogos & derivados , Catequina/isolamento & purificação , Catequina/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos , Humanos , Nanoestruturas/químicaRESUMO
Based on the protonation/deprotonation of poly(ß-amino ester) (PAE), mixed-shell micelles (MSMs) with adaptive surfaces could rapidly and reversibly change surface properties to prolong circulation time in blood (pH 7.4) and enhance cellular uptake at tumor sites (pH 6.5).