Tumor exocytosis bodies / AIEgen hybrid nanovesicle, promote tumor infiltration and photodynamic therapy
Photodynamic therapy (PDT) is a clinical strategy, which is the use of a photosensitizer (PS) exposure to a particular wavelength of the compound in an oxygen (O 2 ) the presence of light, and then generates free radicals and cytotoxicity reactive oxygen species (of ROS), such as singlet oxygen, thereby treating or localized superficial tumors and other diseases. PS development of drug-induced aggregation has a characteristic emission (AIE) of the new strategy PDT can be achieved. When the AIE fluorophore groups present in the solution in the form of isolated molecules, the minimum emissivity which, when they are present in the form of aggregates, it will produce more intense emission. AIE luminescent agent (AIEgens) is ideal for bio-imaging applications, because they have a high degree of light stability, biocompatibility, and can achieve a high contrast imaging. Importantly, many AIEgens can easily generate ROS and based therapeutic intervention for PDT. Unfortunately, most of the AIE-PS compound is very hydrophobic, and therefore can not easily be used in vivo biological environment. Before drug loading based AIEgen system (DLC) is low, encapsulation efficiency (EE) is low, the limited ability of the particular tumor, tissue penetration ability, therefore, to develop new platforms based AIEgen as a more effective penetration It means the tumor is very necessary. In addition to these limitations, common solid tumors of hypoxic tumor microenvironment (TME) due to lack of O2 and affect the efficacy of PDT, while O2 is the key to the effectiveness of these treatment strategies. Tumor exocytosis bodies (exosomes, EXO) over a potential way to enhance penetration and AIE-PS tumor efficacy. EXO is a small particles (50-200 nm), secreted by cells, derived from multivesicular bodies. EXO has many features, including a lack of immunogenicity, good biocompatibility, and the ability due to the endogenous origin and circulation for long periods, making it a promising candidate methods of drug delivery. Also able to cross the blood brain barrier and deep into the structure or other dense tissue types. Is important, EXO may be internalized by the cell, and may be based on the specific EXO membrane protein profile and cell surface-specific manner attributable to a particular tissue or cell type. EXO can not only increase the solubility of water-insoluble compounds, but also very suitable for clinical drug delivery applications, therefore, EXO / AIEgen nanovesicle hybrid has great potential to achieveEffective PDT treatment of cancer. Recently, Tang Benzhong Fellow Hong Kong University of Science and Technology in \” Angewandte Chemie International Edition \” published a paper entitled \”Tumor-exocytosed exosome / AIEgen hybrid nano-vesicles facilitate efficient tumor penetration and\” article, the use of electricity Preparation of tumor perforation exocytosis bodies / (DES), the vesicles permeable to efficient tumor. Then dexamethasone function in blood vessels TME normalization, in order to reduce local hypoxia, thereby significantly enhancing the effect of PDT DES nanovesicles, it is possible to effectively inhibit tumor growth. They first time AIEgen tumor exocytosis and biological hybrid bodies, and the PDT method for normalizing blood vessels within the tumor in combination with, as a means of reducing local tissue hypoxia.
Photo Introduction [123 ]
1. preparation and characterization of DES
tumor exocytosis bodies / AIEgen hybrid nanovesicle (DES) was prepared by Method electroporation, wherein AIEgen employed DCPy (BZ Tang previous studies, [ 123] ACS Nano
2018, 12, 8145-8159). The film subjected to a fluorescent probe DiO dye can be observed under a confocal microscope to bright green and red fluorescence DCPy DiO fluorescence (FIG. 1C), confirmed the success of the coupling in these DCPy of DES. Further DES nanovesicle ultraviolet-visible absorption spectrum exhibits characteristic absorption peaks DCPy (FIG. 1D) at at 452nm. The efficiency value DCPy electroporation, DCPy with increasing initial concentration, coating efficiency increased slowly until a maximum value reached 88.2%, than the commonly used polymeric nanoparticles much higher. In the PB 4 ℃S stored for 3 days, DES nanovesicle size and no significant change in the zeta potential, indicating that these particles are highly stable (Fig. 1F and 1G). Photoluminescence (PL) spectra show, the nature of the AIE and PL properties DCPy DCPy blue shift occurs in the formation of DES, once again demonstrates the successful preparation of nano hybrid vesicles.
the DES target cancer cells in vitro tests. Since DES nanovesicle are prepared from tumor cells, so they are easy of target tumor cells. DCPy in the body of the living cells capable of specifically staining mitochondria, so this can easily be tracked internalization. They were incubated with 4T1 cells nanovesicle DES, and commercial mitochondria Mito-tracker Green FM dye probe (FIGS. 2A and 2E). After 30 minutes incubation period, DES nanovesicle visible adhered to the 4T1 cells, after 2 hours, DCPy staining seen in tumors DES nanovesicle mitochondria. These results demonstrated that DES is an ideal platform for targeting tumor cells and mitochondria.
O 2 for generating a PDT effect is important. Accordingly, they use ABDA assessed their ability to produce 1 O 2 , which may be 1 O 2 to generate the oxide peroxide, resulting in reducing the absorption of ABDA. In 0.5W / cm at 2 The dose, the presence of absorption ABDA DCPy DES and a sharp decline. Further, even at high concentrations DCPy, they also have satisfactory biocompatibility. Then assessed the efficacy of PDT DES nanovesicles (FIG. 2B) under normal and hypoxic conditions. Under normoxic conditions, DES or treatment DCPy significant phototoxic appropriate laser irradiation. However, under hypoxic conditions, this effect is significantly reduced. When the active oxygen of these cells using quantitative probe DCFH-DA is generated, fluorescence intensity significantly lower than the normal conditions under hypoxic conditions (Figure 2C). It confirmed that oxygen levels can profoundly affect the efficacy of anti-tumor PDT treatment regimen DES or DCPy mediated. To overcome this limitation, use of the (DEX) up TME as modifier, as a means of improving the supply of available oxygen of these tumors. To confirm the validity of the method, from 11-14 days after tumor implantation, with a daily DEX (3mg / kg) or PBS (n = 3 / group) were injected subcutaneously BALB / c mice with a primary tumor 4T1. The results showed that, compared to PBS treatment, of DEX treatment significantly reduced the hypoxia inducible factor HIF-1 staining intensity, it was confirmed that the therapeutic interventions sufficient to significantly alleviate the tumor hypoxia. 3. Test vivo in vivo pharmacokinetics of the drug DES, biodistribution and tumor tissue permeability evaluation. In addition to having a high degree of cytotoxicity and are easily within the tumor cells completely apart, over the internet antitumor further required to have good bio-distribution system. To highlight the DES in vivo biodistribution and pharmacokinetic characteristics of drugs, they polylactic acid – glycolic acid (PLGA) to embedded DCPy, and successfully PLGA / DCPy hybrid nanoparticles (the DPS), compared with DES prepared. (N = 3 / group) and in vivo DES DPS found by observing the distribution of 4T1 tumor-bearing mice, DES DPS accumulate in the liver and is relatively strong, and exhibit more effective than DES DPS tumor predisposition in an animal ( Figure 3D). It is noteworthy that, after treatment mediated DES (Fig. 3E and 3F), can be detected from the blood vessel of about 200μm DCPy fluorescence was nanovesicle DES can be easily leaking from the vessel, so that there is or depth of tumor tissue without DEX case.
, 20 minutes 4 irradiation spot, the irradiation point of 5 minutes each); 3) DEX; 4) DES; 5) DES + L; and 6) DES + DEX + L group (FIG. 4A). DES administration and laser irradiation mediates tumor growthThe partial inhibition, whereas when the animals treated with of DEX, this inhibition is more effective (FIGS. 4B, 4C). Hematoxylin and eosin (H & E) stained tissue sections confirmed, DES + DEX + L treatment significantly large tumor necrosis or apoptosis of tumor cell death (FIG. 4D) about the simultaneous loss. Treatment of these mice generate tumor reactive oxygen species (ROS) was measured using DCFH-DA, the display DES + DEX + L tumor staining combined treatment of mice significantly enhanced. This confirms the enhanced efficacy observed in these animals and to improve the related free radical generation. Summary