RESUMO
Eye size is a key parameter of visual function, but the precise mechanisms of eye size control remain poorly understood. Here, we discovered that the lipogenic transcription factor sterol regulatory element-binding protein 2 (SREBP2) has an unanticipated function in the retinal pigment epithelium (RPE) to promote eye size in postnatal mice. SREBP2 transcriptionally represses low density lipoprotein receptor-related protein 2 (Lrp2), which has been shown to restrict eye overgrowth. Bone morphogenetic protein 2 (BMP2) is the downstream effector of Srebp2 and Lrp2, and Bmp2 is suppressed by SREBP2 transcriptionally but activated by Lrp2. During postnatal development, SREBP2 protein expression in the RPE decreases whereas that of Lrp2 and Bmp2 increases as the eye growth rate reduces. Bmp2 is the key determinant of eye size such that its level in mouse RPE inversely correlates with eye size. Notably, RPE-specific Bmp2 overexpression by adeno-associated virus effectively prevents the phenotypes caused by Lrp2 knock out. Together, our study shows that rapid postnatal eye size increase is governed by an RPE-derived signaling pathway, which consists of both positive and negative regulators of eye growth.
Assuntos
Proteína Morfogenética Óssea 2 , Proteína de Ligação a Elemento Regulador de Esterol 2 , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Regulação da Expressão Gênica , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Epitélio Pigmentado da Retina/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)-releasing moieties, namely ZnPc-2NO and ZnPc-4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia-inducible factor protein HIF-1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen-dependent nature of PDT. Interestingly, the photodynamic action of ZnPc-2NO elicits the release of damage-associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen-economized PDT has been demonstrated through a series of in vitro and in vivo experiments.
RESUMO
An advanced photodynamic molecular beacon (PMB) was designed and synthesized, in which a distyryl boron dipyrromethene (DSBDP)-based photosensitizer and a Black Hole Quencher 3 moiety were connected via two peptide segments containing the sequences PLGVR and GFLG, respectively, of a cyclic peptide. These two short peptide sequences are well-known substrates of matrix metalloproteinase-2 (MMP-2) and cathepsin B, respectively, both of which are overexpressed in a wide range of cancer cells either extracellularly (for MMP-2) or intracellularly (for cathepsin B). Owing to the efficient Förster resonance energy transfer between the two components, this PMB was fully quenched in the native form. Only upon interaction with both MMP-2 and cathepsin B, either in a buffer solution or in cancer cells, both of the segments were cleaved specifically, and the two components could be completely separated, thereby restoring the photodynamic activities of the DSBDP moiety. This PMB could also be activated in tumors, and it effectively suppressed the tumor growth in A549 tumor-bearing nude mice upon laser irradiation without causing notable side effects. In particular, it did not cause skin photosensitivity, which is a very common side effect of photodynamic therapy (PDT) using conventional "always-on" photosensitizers. The overall results showed that this "double-locked" PMB functioned as a biological AND logic gate that could only be unlocked by the coexistence of two tumor-associated enzymes, which could greatly enhance the tumor specificity in PDT.
Assuntos
Fotoquimioterapia , Camundongos , Animais , Metaloproteinase 2 da Matriz , Catepsina B , Camundongos Nus , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Peptídeos/químicaRESUMO
Surface biotinylation has been widely adapted in profiling the cellular proteome associated with the plasma membrane. However, the workflow is subject to interference from the cytoplasmic biotin-associated proteins that compete for streptavidin-binding during purification. Here we established a bioorthogonal conjugation-assisted purification (BCAP) workflow that utilizes the Staudinger chemoselective ligation to label and isolate surface-associated proteins while minimizing the binding of endogenous biotin-associated proteins. Label-free quantitative proteomics demonstrated that BCAP is efficient in isolating cell surface proteins with excellent reproducibility. Subsequently, we applied BCAP to compare the surface proteome of proliferating and senescent mouse embryonic fibroblasts (MEFs). Among the results, EHD2 was identified and validated as a novel protein that is enhanced at the cell surface of senescent MEFs. We expect that BCAP will have broad applications in profiling cell surface proteomes in the future.
Assuntos
Proteoma , Proteômica , Animais , Biotinilação , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Fibroblastos/metabolismo , Espectrometria de Massas , Camundongos , Proteoma/metabolismo , Proteômica/métodos , Reprodutibilidade dos TestesRESUMO
A multifunctional photodynamic molecular beacon (PMB) has been designed and synthesized which contains an epidermal growth factor receptor (EGFR)-targeting cyclic peptide and a trimeric phthalocyanine skeleton in which the three zinc(II) phthalocyanine units are each substituted with a glutathione (GSH)-responsive 2,4-dinitrobenzenesulfonate (DNBS) quencher and are linked via two cathepsin B-cleavable GFLG peptide chains. This tailor-made conjugate is fully quenched in the native form due to the photoinduced electron transfer effect of the DNBS moieties and the self-quenching of the phthalocyanine units. It can target the EGFR overexpressed in cancer cells, and after receptor-mediated endocytosis, it can be activated selectively by the co-existence of intracellular GSH and cathepsin B, both of which are also overproduced in cancer cells, in terms of fluorescence emission and singlet oxygen generation. The cell-selective behavior of this PMB has been demonstrated using a range of cancer cells with different expression levels of EGFR, while the stimuli-responsive properties have been studied both inâ vitro and in various aqueous media. The overall results show that this advanced PMB, which exhibits several levels of control of the tumor specificity, is a promising photosensitizer for precise antitumoral photodynamic therapy.
Assuntos
Neoplasias , Fotoquimioterapia , Catepsina B/uso terapêutico , Linhagem Celular Tumoral , Dinitrofluorbenzeno/análogos & derivados , Receptores ErbB , Glutationa/química , Humanos , Indóis/química , Neoplasias/patologia , Peptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/químicaRESUMO
Nanovaccines, a new generation of vaccines that use nanoparticles as carriers and/or adjuvants, have been widely used in the prevention and treatment of various diseases, including cancer. Nanovaccines have sparked considerable interest in cancer therapy due to a variety of advantages, including improved access to lymph nodes (LN), optimal packing and presentation of antigens, and induction of a persistent anti-tumor immune response. As a delivery system for cancer vaccines, various types of nanoparticles have been designed to facilitate the delivery of antigens and adjuvants to lymphoid organs and antigen-presenting cells (APCs). Particularly, some types of nanoparticles are able to confer an immune-enhancing capability and can themselves be utilized for adjuvant-like effect for vaccines, suggesting a direction for a better use of nanomaterials and the optimization of cancer vaccines. However, this role of nanoparticles in vaccines has not been well studied. To further elucidate the role of self-adjuvanting nanovaccines in cancer therapy, we review the mechanisms of antitumor vaccine adjuvants with respect to nanovaccines with self-adjuvanting properties, including enhancing cross-presentation, targeting signaling pathways, biomimicking of the natural invasion process of pathogens, and further unknown mechanisms. We surveyed self-adjuvanting cancer nanovaccines in clinical research and discussed their advantages and challenges. In this review, we classified self-adjuvanting cancer nanovaccines according to the underlying immunomodulatory mechanism, which may provide mechanistic insights into the design of nanovaccines in the future.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Adjuvantes Imunológicos , Células Apresentadoras de Antígenos , Humanos , Imunoterapia , Nanopartículas/química , Neoplasias/terapiaRESUMO
Extracellular vesicles (EVs), spherical biological vesicles, mainly contain nucleic acids, proteins, lipids and metabolites for biological information transfer between cells. Microparticles (MPs), a subtype of EVs, directly emerge from plasma membranes, and have gained interest in recent years. Specific cell stimulation conditions, such as ultraviolet and X-rays irradiation, can induce the release of MPs, which are endowed with unique antitumor functionalities, either for therapeutic vaccines or as direct antitumor agents. Moreover, the size of MPs (100-1000 nm) and their spherical structures surrounded by a lipid bilayer membrane allow MPs to function as delivery vectors for bioactive antitumor compounds, with favorable phamacokinetic behavior, immunostimulatory activity and biological function, without inherent carrier-specific toxic side effects. In this review, the mechanisms underlying MP biogenesis, factors that influence MP production, properties of MP membranes, size, composition and isolation methods of MPs are discussed. Additionally, the applications and mechanisms of action of MPs, as well as the main hurdles for their applications in cancer management, are introduced.
Assuntos
Antineoplásicos , Micropartículas Derivadas de Células , Vesículas Extracelulares , Neoplasias , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Micropartículas Derivadas de Células/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Phthalocyanines exhibit superior photoproperties that make them a surely attractive class of photosensitisers for photodynamic therapy of cancer. Several derivatives are at various phases of clinical trials, and efforts have been put continuously to improve their photodynamic efficacy. To this end, various strategies have been applied to develop advanced phthalocyanines with optimised photoproperties, dual therapeutic actions, tumour-targeting properties and/or specific activation at tumour sites. The advantageous properties and potential of phthalocyanines as advanced photosensitisers for photodynamic therapy of cancer are highlighted in this tutorial review.
Assuntos
Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/uso terapêutico , Humanos , Indóis/química , Isoindóis , Luz , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismoRESUMO
A facile approach to assemble catalase-like photosensitizing nanozymes with a self-oxygen-supplying ability was developed. The process involved Fe3+ -driven self-assembly of fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids. By adding a zinc(II) phthalocyanine-based photosensitizer (ZnPc) and the hypoxia-inducible factor 1 (HIF-1) inhibitor acriflavine (ACF) during the Fe3+ -promoted self-assembly of Fmoc-protected cysteine (Fmoc-Cys), the nanovesicles Fmoc-Cys/Fe@Pc and Fmoc-Cys/Fe@Pc/ACF were prepared, which could be disassembled intracellularly. The released Fe3+ could catalyze the transformation of H2 O2 enriched in cancer cells to oxygen efficiently, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the released ZnPc. With an additional therapeutic component, Fmoc-Cys/Fe@Pc/ACF exhibited higher inâ vitro and inâ vivo photodynamic activities than Fmoc-Cys/Fe@Pc, demonstrating the synergistic effect of ZnPc and ACF.
Assuntos
Antineoplásicos/farmacologia , Compostos Férricos/farmacologia , Indóis/farmacologia , Nanopartículas/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Acriflavina/química , Acriflavina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Compostos Férricos/síntese química , Compostos Férricos/química , Células HT29 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Indóis/síntese química , Indóis/química , Íons/síntese química , Íons/química , Íons/farmacologia , Isoindóis , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Camundongos , Camundongos Nus , Imagem Óptica , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Tamanho da Partícula , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Propriedades de Superfície , Compostos de ZincoRESUMO
A series of 2-alkenyl- and 2,6-dialkenylboron dipyrromethene (BODIPY) derivatives were synthesized through Pd(II)-catalyzed regioselective and stereoselective oxidative C-H olefination in one step. The 2-alkenyl BODIPY derivative further reacted with various amines regioselectively at the 5-position through direct oxidative nucleophilic substitution. The photophysical properties of the 2-alkenyl- and 2,6-dialkenyl-substituted BODIPYs were investigated, which showed great potential in fluorescent bioimaging.
Assuntos
Alcenos/química , Compostos de Boro/química , Compostos de Boro/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Imagem Óptica/métodos , Carbono/química , Catálise , Técnicas de Química Sintética , Células Hep G2 , Humanos , Hidrogênio/química , Modelos Moleculares , Conformação Molecular , Oxirredução , Estereoisomerismo , TemperaturaRESUMO
A series of disulfide-linked dendritic phthalocyanines were synthesized by using the CuI -catalyzed alkyne-azide cycloaddition reaction as the key step. Whereas these compounds were essentially nonaggregated in N,N-dimethylformamide, they were stacked in citrate solution (pHâ 7.4, with 1 % Cremophorâ EL), as shown by the broad appearance of their Q-band absorption. Having two-to-six zinc(II) phthalocyanine units in a molecule, these compounds were significantly self-quenched, particularly in citrate solution. Both the fluorescence intensity and singlet-oxygen generation efficiency were significantly lower than those of the monomeric counterparts, and the self-quenching efficiency increased as the number of phthalocyanine units increased. Upon interaction with 5â mm glutathione (GSH) in citrate solution, the fluorescence intensity of these compounds increased as a result of cleavage of the disulfide linkages and separation of the phthalocyanine units, which thereby reduced the self-quenching effect. The "on/off" ratios were found to be 7, 18, 23, and 21 for the dimeric (PC2), trimeric (PC3), tetrameric (PC4), and hexameric (PC6) systems, respectively. GSH also enhanced the fluorescence emission inside human colon adenocarcinoma HT29 cells and promoted the formation of singlet oxygen of these compounds. Upon irradiation, their half maximal inhibitory concentration (IC50 ) values were found to be in the range of 0.18 to 0.38â µm. Finally, the biodistribution and activation of PC2 and PC6 were also examined in HT29 tumor-bearing nude mice. For both compounds, the fluorescence intensity per unit area at the tumor was found to grow gradually during the first 24â h. Whereas the intensity then dropped for PC2, the intensity for PC6 remained steady over the following 6â d, which might have been a result of the enhanced permeability and retention effect arising from the larger molecular mass of the hexameric system.
Assuntos
Dissulfetos/química , Glutationa/química , Indóis/síntese química , Fármacos Fotossensibilizantes/síntese química , Animais , Reação de Cicloadição , Dimetilformamida/química , Fluorescência , Glutationa/metabolismo , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Isoindóis , Camundongos Nus , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete/química , Relação Estrutura-Atividade , Distribuição Tecidual , ZincoRESUMO
Doxorubicin (Dox) was conjugated to a zinc(II) phthalocyanine (ZnPc) through an acid-cleavable hydrazone linker. This azido-containing conjugate was then anchored to the nanochannels of an alkyne-modified mesoporous silica nanoparticle (MSN) system via copper(I)-catalyzed azide-alkyne cycloaddition. An analogous nanosystem was also prepared by immobilization of a hydrazine-substituted ZnPc to the MSN followed by coupling with Dox. The release of Dox under acidic conditions was studied in phosphate-buffered saline. After internalization into human hepatocellular carcinoma HepG2 cells, these nanoparticles showed fluorescence not only for ZnPc, but also for Dox, suggesting that release of Dox was triggered by the acidic intracellular environment. The chemocytotoxic Dox together with singlet oxygen generated upon irradiation on the encapsulated ZnPc in these MSNs could kill the cells effectively. A synergistic cytotoxicity was suggested by a less-than-unity combination index. These nanoparticles function as both nanophotosensitizers for photodynamic therapy and as nanoplatforms for pH-controlled drug release.
Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Indóis/química , Nanopartículas/química , Compostos Organometálicos/química , Dióxido de Silício/química , Alcinos/química , Reação de Cicloadição , Doxorrubicina/metabolismo , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Isoindóis , Luz , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Fotoquimioterapia , Porosidade , Oxigênio Singlete/metabolismo , Compostos de ZincoRESUMO
A diiodo distyryl boron dipyrromethene (BODIPY) core was conjugated to two ferrocenyl quenchers through acid-labile ketal and/or thiol-cleavable disulfide linkers, of which the fluorescence and photosensitizing properties were significantly quenched through a photoinduced electron-transfer process. The two symmetrical analogues that contained either the ketal or disulfide linkers could only be activated by a single stimulus, whereas the unsymmetrical analogue was responsive to dual stimuli. Upon interaction with acid and/or dithiothreitol (DTT), these linkers were cleaved selectively. The separation of the BODIPY core and the ferrocenyl moieties restored the photoactivities of the former in phosphate buffered saline and inside the MCF-7 breast cancer cells, rendering these compounds as potential activable photosensitizers for targeted photodynamic therapy. The dual activable analogue exhibited the greatest enhancement in intracellular fluorescence intensity in both an acidic environment (pHâ 5) and the presence of DTT (4â mm). Its photocytotoxicity against MCF-7 cells also increased by about twofold upon preincubation with 4â mm of DTT. The activation of this compound was also demonstrated in nude mice bearing a HT29 human colorectal carcinoma. A significant increase in fluorescence intensity in the tumor was observed over 9â h after intratumoral injection.
Assuntos
Compostos de Boro/química , Fármacos Fotossensibilizantes/química , Compostos de Sulfidrila/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ditiotreitol/química , Células HT29 , Humanos , Concentração de Íons de Hidrogênio , Luz , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Imagem Óptica , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/toxicidade , Espectrometria de Fluorescência , Transplante HeterólogoRESUMO
A zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate group has been prepared. Its fluorescence emission and reactive oxygen species generation can be greatly enhanced by glutathione in phosphate-buffered saline and inside MCF-7 cells. This compound thus functions as a highly efficient molecular-based activatable photosensitizer.
Assuntos
Glutationa/química , Indóis/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Humanos , Isoindóis , Células MCF-7RESUMO
Mixing a glutathione (GSH)-responsive carboxy zinc(II) phthalocyanine (ZnPc*) and CuSO4·5H2O in water with or without the presence of the anticancer drug SN38 resulted in the formation of self-assembled nanotherapeutics labeled as ZnPc*/Cu/SN38@NP and ZnPc*/Cu@NP, respectively. The Cu2+ ions not only promoted the self-assembly of the carboxy phthalocyanine through metal complexation, but also catalyzed the transformation of H2O2 to oxygen via a catalase-like reaction, rendering an oxygen-replenishing property to the nanosystems. Both nanosystems exhibited high stability in aqueous media, but the nanoparticles disassembled gradually in an acidic or GSH-enriched environment and inside human colorectal adenocarcinoma HT29 cells, releasing the encapsulated therapeutic components. The disassembly process together with the activation by the intracellular GSH led to relaxation of the intrinsic quenching of the nanophotosensitizers and restoration of the photoactivities of ZnPc*. Under a hypoxic condition, ZnPc*/Cu/SN38@NP could attenuate the intracellular hypoxia level and maintain the photodynamic activity due to its Cu2+-promoted oxygen-replenishing ability. The photodynamic effect of ZnPc* and the anticancer effect of SN38 worked cooperatively, causing substantial apoptotic cell death. The dual therapeutic actions could also effectively inhibit the tumor growth in HT29 tumor-bearing nude mice without initiating notable adverse effects to the mice. STATEMENT OF SIGNIFICANCE: The oxygen-dependent nature of photodynamic therapy generally reduces its efficacy against tumor hypoxia, which is a common characteristic of advanced solid tumors and usually leads to resistance toward various anticancer therapies. We report herein a facile approach to assemble a glutathione-responsive carboxy phthalocyanine-based photosensitizer and an anticancer drug in aqueous media, in which Cu(II) ions were used to promote the self-assembly through metal complexation and catalyze the conversion of H2O2 to oxygen through a catalase-like reaction, making the resulting nanoparticles possessing an oxygen-replenishing property that could promote the photodynamic effect against hypoxic cancer cells and tumors. The use of Cu(II) ions to achieve the aforementioned dual functions in the fabrication of advanced nano-photosensitizing systems has not been reported.
Assuntos
Antineoplásicos , Nanopartículas , Compostos Organometálicos , Fotoquimioterapia , Humanos , Animais , Camundongos , Catalase/metabolismo , Oxigênio , Camundongos Nus , Hipóxia Tumoral , Peróxido de Hidrogênio , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Glutationa/metabolismo , Linhagem Celular Tumoral , Compostos Organometálicos/farmacologia , Nanopartículas/uso terapêutico , Compostos de ZincoRESUMO
Guest Editors Pui-Chi Lo, Dennis Ng, Ravindra Pandey, and Petr Zimcik introduce the Special Collection on Photodynamic Therapy and give an overview of the developments and challenges in this exciting field.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/tratamento farmacológicoRESUMO
We report herein a versatile and efficient bioorthogonal strategy to actualise targeted delivery and site-specific activation of photosensitisers for precise antitumoural photodynamic therapy. The strategy involved the use of an isonitrile-caged distyryl boron dipyrromethene-based photosensitiser, labelled as NC-DSBDP, of which the photoactivities could be specifically activated upon conversion of the meso ester substituent to carboxylate initiated by the [4 + 1] cycloaddition with a tetrazine derivative. By using two tetrazines conjugated with a galactose moiety or the GE11 peptide, labelled as gal-Tz and GE11-Tz, we could selectively label the cancer cells overexpressed with the asialoglycoprotein receptor and the epidermal growth factor receptor respectively. Upon encountering the internalised NC-DSBDP, these tetrazines triggered the "ester-to-carboxylate" transformation of this compound, activating its fluorescence and reactive oxygen species generation inside the target cells. The bioorthogonal activation was also demonstrated in vivo, leading to effective photo-eradication of the tumour in nude mice.
Assuntos
Compostos Heterocíclicos , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Camundongos Nus , Compostos Heterocíclicos/química , Neoplasias/tratamento farmacológicoRESUMO
A water-soluble 1,2,4,5-tetrazine-substituted carbon-dipyrromethene (C-DIPY) was synthesized from the previously reported carbonyl pyrrole dimer through a two-step procedure. Owing to the presence of a tetrazine moiety, the fluorescence emission of this compound was largely quenched in phosphate-buffered saline at pHâ 7.4. Upon addition of a bicyclo[6.1.0]non-4-yne (BCN) derivative, the tetrazine-based quenching component of the compound was disrupted through the inverse electron-demand Diels-Alder reaction to restore the fluorescence in up to 6.6-fold. This bioorthogonal activation was also demonstrated using U-87 MG human glioblastoma cells, in which the fluorescence intensity of this C-DIPY could be enhanced by 8.7-fold upon post-incubation with the BCN derivative. The results showed that this tetrazine-caged C-DIPY can serve as a bioorthogonally activatable fluorescent probe for bioimaging. The compound, however, was found to reside preferentially in the lysosomes instead of the mitochondria of the cells as predicted based on its cationic character, which could be attributed to its energy-dependent endocytic cellular uptake pathway, for which lysosomes are the end station.
Assuntos
Corantes Fluorescentes , Compostos Heterocíclicos , Humanos , Corantes Fluorescentes/química , Reação de Cicloadição , PorfobilinogênioRESUMO
Magnetic particle imaging (MPI) is an emerging non-invasive tomographic technique based on the response of magnetic nanoparticles (MNPs) to oscillating drive fields at the center of a static magnetic gradient. In contrast to magnetic resonance imaging (MRI), which is driven by uniform magnetic fields and projects the anatomic information of the subjects, MPI directly tracks and quantifies MNPs in vivo without background signals. Moreover, it does not require radioactive tracers and has no limitations on imaging depth. This article first introduces the basic principles of MPI and important features of MNPs for imaging sensitivity, spatial resolution, and targeted biodistribution. The latest research aiming to optimize the performance of MPI tracers is reviewed based on their material composition, physical properties, and surface modifications. While the unique advantages of MPI have led to a series of promising biomedical applications, recent development of MPI in investigating vascular abnormalities in cardiovascular and cerebrovascular systems, and cancer are also discussed. Finally, recent progress and challenges in the clinical translation of MPI are discussed to provide possible directions for future research and development.
RESUMO
Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.