CN117618583B - Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof - Google Patents

Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof Download PDF

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CN117618583B
CN117618583B CN202410104354.4A CN202410104354A CN117618583B CN 117618583 B CN117618583 B CN 117618583B CN 202410104354 A CN202410104354 A CN 202410104354A CN 117618583 B CN117618583 B CN 117618583B
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徐周睿
唐世棋
杨成彬
许改霞
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Shenzhen University
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Abstract

The invention discloses a photosensitizer for tumor photodynamic therapy based on wireless charging and a combination system thereof, which comprises a photosensitizer (MTDi) and an implantable light-emitting diode (wLED) which is wireless charged, wherein the preparation method of the photosensitizer comprises the following steps: s1, the mass ratio of the components is (1.8-2.2): (8-10): 1, DSPE-PEG2000 and DSPE-PEG 2000-igd in THF is added to ultrapure water, the mass volume ratio of the DSPE-PEG 2000-igd to the THF is 0.9-1.1mg/mL, the volume ratio of the ultrapure water to the THF is (9-11): 1, a step of; s2, carrying out dialysis after vigorously stirring for 1.8-2.2 minutes, wherein the molecular weight cut-off value of an ultrafiltration membrane used in the dialysis is 100kDa, the rotating speed is 4000-4800rpm, and the rotating time is 15-25 minutes; s3, dispersing the nano particles obtained by dialysis in PBS buffer solution to obtain the photosensitizer. The invention treats tumors by using the MTDi and wLED combined system, can overcome the limitation of insufficient light penetrability and high oxygen dependence, and has obvious potential for treating solid tumors.

Description

Photosensitizer for tumor photodynamic therapy based on wireless charging and combination system thereof
Technical Field
The invention relates to the technical field of biomedicine, in particular to a photosensitizer for tumor photodynamic therapy based on wireless charging and a combination system thereof.
Background
In recent years, the incidence and mortality of cancers (malignant tumors) have been on the rise. Chemotherapy/radiotherapy and surgical treatment are traditional treatment means, but the traditional treatment means cause great wounds to human bodies, and have the problems of incomplete treatment, serious side effects and the like. Photodynamic therapy (Photodynamic Therapy, PDT) is a new therapy emerging over the last two decades for the treatment of malignant tumors, enabling accurate drug tracking and tumor visualization as compared to traditional therapies, which is a minimally invasive, effective treatment. Three elements of PDT are Photosensitizers (PSs), light and oxygen molecules. The photosensitizer is a key part of PDT, is injected into a human body through vein, can gather at a tumor part through blood circulation (blood vessel is rich), absorbs energy to become an activated photosensitizer under light irradiation, and then the activated photosensitizer transfers energy to surrounding oxygen molecules through electron transfer or a photochemical mechanism of energy transfer to generate active oxygen clusters (ROS) with strong oxidability and cytotoxicity, and can destroy biological macromolecules such as lipid, protein, DNA and the like, thereby achieving the purpose of killing tumor cells.
Because of the limited depth of penetration of light into the human body and the light scattering effect of biological tissue, PDT is currently only approved clinically for the treatment of several early cancers or residual tumors located in shallow organs, such as skin, oral cavity, esophagus, lung, bladder, etc. In order to enhance the efficacy of PDT, making it applicable for the treatment of deeper tumors, researchers have adopted different approaches: (1) design and development of photosensitizers for long wavelength excitation; (2) Treatment of deep lesions sites with laparoscopically mediated PDT (Kim Jiyoung et al) effectively kills cancer cells under laser irradiation, but suffers from different problems: with the improvement means (1), since the energy required for conversion from triplet oxygen to singlet oxygen is large, it is difficult to push the absorption wavelength of the photosensitizer into the near infrared window (NIR) with a high penetration depth; with the improved approach (2), PDT efficacy is unreliable due to laser unpredictable and irregular, and invasive procedures may be required each time. And because PDT requires consumption of oxygen molecules, it has a high oxygen dependence, and because solid tumors tend to be severely hypoxic, the anticancer effects of PDT are also reduced.
Disclosure of Invention
The invention provides a photosensitizer for tumor photodynamic therapy based on wireless charging and a combination system thereof, and aims to solve the technical problems.
The invention provides a preparation method of a photosensitizer for tumor photodynamic therapy based on wireless charging, which comprises the following steps:
S1, the mass ratio of the components is (1.8-2.2): (8-10): 1 and DSPE-PEG 2000-igd, said DSPE-PEG 2000-igd to said THF solution having a mass to volume ratio of 0.9-1.1mg/mL, said ultrapure water to said THF solution having a volume ratio of (9-11): 1, a step of;
S2, carrying out dialysis after vigorously stirring for 1.8-2.2 minutes, wherein the molecular weight cut-off value of an ultrafiltration membrane used in the dialysis is 100kDa, the rotating speed is 4000-4800rpm, and the rotating time is 5-15 minutes;
s3, dispersing nano particles obtained through dialysis in PBS buffer solution to obtain the photosensitizer (MTDi);
the structural formula of the MT is as follows:
。
further, in the step S2, the rotational speed of the dialysis is 4400rpm, and the rotational time is 20 minutes.
The invention provides a photosensitizer for tumor photodynamic therapy based on wireless charging, which is prepared by the preparation method.
The invention provides a combination system for tumor photodynamic therapy based on wireless charging, which comprises an implantable light emitting diode (wLED) with wireless charging.
Further, the preparation method of the light emitting diode comprises the following steps:
a. manufacturing a mould;
b. the volume ratio is (9-11): 1, uniformly mixing a polydimethylsiloxane solution and a curing agent to obtain a mixed solution, pouring the mixed solution into the mold, and then soaking an LED into the mixed solution;
c. Incubating at 60-70deg.C for 5.5-6.5h to obtain the light emitting diode.
Further, the mold was made of tin foil, and the mold was a cylindrical mold having a bottom diameter of 1.2cm and a height of 1 cm.
Further, the volume ratio of the Polydimethylsiloxane (PDMS) solution to the curing agent is 10:1.
Further, the temperature of the incubation in the step c is 65 ℃ and the incubation time is 6h.
Further, the photosensitive agent is also included.
The invention also provides application of the photosensitizer in tumor treatment.
The invention also provides the use of a combination system as described above comprising a photosensitizer as described above and an implantable wirelessly charged light emitting diode in the treatment of a tumor.
Further, the tumor is a hypoxic solid tumor.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention uses DSPE-PEG2000 to modify MT to obtain nano particles (MTD) with good dispersibility and stable optical behaviors, and the invention also attaches DSPE-PEG2000-iRGD polypeptide on MTDi surfaces to obtain MTDi with good targeting to 4T1 tumor (mouse breast cancer cell strain). The obtained nano particles (MTDi) have the advantages of high stability, small particle size, good dispersibility, good biocompatibility and the like, and are expected to be widely applied to the field of photodynamic therapy;
2. According to the invention, the LED is wrapped in PDMS which is good in biocompatibility and non-degradable, so that wLED which is capable of being implanted and safely reserved in a human body for a long time is obtained, and the wireless charging wLED triggers MTDi accumulated in tumors to generate I-type ROS, so that the purpose of inhibiting tumor growth is achieved. Unlike classical strategies to develop PSs of long excitation wavelength in the near infrared window, the integrated implantable optoelectronic device (wLED) can skillfully bypass the optical attenuation of biological tissue and the photosensitivity of skin, thereby increasing the optical accessibility to solid tumors. The implanted device can be kept in the body for a long time and can be remotely controlled on a free-behaving mouse at any time, so that the method has good controllability;
3. the invention treats tumors by combining the I-type AIEgen photosensitizers MTDi and wLED, and results of in-vivo experiments and in-vitro experiments prove that the combined system can overcome the limitation of insufficient light penetrability and high oxygen dependence, and has obvious potential for treating solid tumors (especially hypoxic solid tumors).
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments of the present invention will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is an emission spectrum of wLED;
FIG. 2 is an actual photograph of wLED illuminated;
FIG. 3 is a graph showing the optical power results for wLED at different relative positions to the charging coil;
FIG. 4 shows the temperature rise results at 25℃and at 37℃for wLED luminescence;
FIG. 5 is an absorption spectrum and an emission spectrum of MTDi;
FIG. 6 is a graph showing the results of the photodynamic properties of MTDi of wLED for different colors;
FIG. 7 is a diagram showing the sealing of the PDMS package wLED;
FIG. 8 is a Transmission Electron Microscope (TEM) (upper left plot) and Dynamic Light Scattering (DLS) detection results;
FIG. 9 shows the results of the detection of MTDi for optical and structural stability in H 2 O, PBS and DMEM;
FIG. 10 is a measurement setup diagram;
FIG. 11 is an ESR spectrum;
FIG. 12 is a graph showing total ROS production of MTDi, bengalhong (RB) and trichloroethane (Ce 6) for DCFH as fluorescent indicators;
FIG. 13 shows hydroxyl radical yields of MTDi, bengalhon (RB) and trichloroethane (Ce 6) for HPF as fluorescent indicators;
FIG. 14 shows the superoxide radical production of MTDi, bengalhondral (RB) and trichloroethane (Ce 6) for the fluorescent indicator DR 123;
FIG. 15 shows singlet oxygen production for ABDA at MTDi, bengalhong (RB), and trichloroethane (Ce 6) as fluorescent indicators;
FIG. 16 is a confocal fluorescence imaging of cells incubated with MTDi at different concentrations for 12 hours;
FIG. 17 is a flow chart of cells after incubation with MTDi at different concentrations for 12 hours;
FIG. 18 is cytotoxicity data after incubation of different cells with different concentrations MTDi for 24 hours;
FIG. 19 is a conceptual diagram of cell photodynamic therapy using a wireless charging system;
FIG. 20 is a fluorescence image of ROS production by 4T1 cells under hypoxic conditions (scale: 100 μm);
FIG. 21 is a flow cytometer used to detect the production of ROS in cells at various concentrations MTDi under normoxic and hypoxic conditions;
FIG. 22 shows wireless PDT efficacy under normoxic and hypoxic conditions at various concentrations MTDi;
FIG. 23 is a fluorescence image of the major organs at various time points following intravenous injection MTDi into the tail of a mouse;
FIG. 24 is a therapeutic strategy for wireless PDT;
FIG. 25 is a schematic diagram of PDT under wireless charging;
FIG. 26 is a photograph of a mouse wirelessly charged in daylight and dark conditions;
FIG. 27 is bioluminescence before and after PDT treatment in different groups of mice;
FIG. 28 is a photograph of an dissected tumor from different groups of mice sacrificed on day 14 after wireless PDT treatment;
FIG. 29 is a graph of tumor growth in different groups of mice over the course of 14 days of wireless PDT treatment;
FIG. 30 is tumor weights of tumors of different groups of mice over the course of 14 days of wireless PDT treatment;
FIG. 31 is a graph showing the results of HE, TUNEL and Ki67 staining (scale: 100 μm) of tumor tissue, wherein FIG. 31a is a graph showing the results of HE staining of tumor tissue; FIG. 31 b is a graph showing TUNEL staining results of tumor tissue; FIG. 31 c is a graph showing the results of Ki67 staining of tumor tissue.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved more clear, the invention is further described in detail below with reference to the embodiments and the accompanying drawings. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. The present invention will be specifically described with reference to the following specific examples.
The embodiment of the invention provides a preparation method of a photosensitizer for tumor photodynamic therapy based on wireless charging, which comprises the following steps:
S1, the mass ratio of the components is (1.8-2.2): (8-10): 1, DSPE-PEG2000 and DSPE-PEG 2000-igd in THF is added to ultrapure water, the mass volume ratio of the DSPE-PEG 2000-igd to the THF is 0.9-1.1mg/mL, the volume ratio of the ultrapure water to the THF is (9-11): 1, a step of;
S2, carrying out dialysis after vigorously stirring for 1.8-2.2 minutes, wherein the molecular weight cut-off value of an ultrafiltration membrane used in the dialysis is 100kDa, the rotating speed is 4000-4800rpm, and the rotating time is 5-15 minutes;
S3, dispersing the nano particles obtained by dialysis in PBS buffer solution to obtain the photosensitizer;
the structural formula of the MT is as follows:
。
preferably, in the step S2, the rotational speed of the dialysis is 4400rpm, and the rotational time is 10 minutes.
The embodiment of the invention provides a photosensitizer for tumor photodynamic therapy based on wireless charging, which is prepared by using the preparation method.
The embodiment of the invention provides a combined system for tumor photodynamic therapy based on wireless charging, which comprises an implantable light-emitting diode with wireless charging.
Specifically, the preparation method of the light emitting diode comprises the following steps:
a. manufacturing a mould;
b. the volume ratio is (9-11): 1, uniformly mixing a polydimethylsiloxane solution and a curing agent to obtain a mixed solution, pouring the mixed solution into the mold, and then soaking an LED into the mixed solution;
c. Incubating at 60-70deg.C for 5.5-6.5h to obtain the light emitting diode.
Specifically, the die is made of tin foil, and is a cylindrical die with the bottom diameter of 1.2cm and the height of 1 cm.
Specifically, the volume ratio of the polydimethylsiloxane solution to the curing agent is 10:1.
Specifically, the temperature of the incubation in the step c is 65 ℃, and the incubation time is 6h.
Specifically, the photosensitive agent is also included.
The embodiment of the invention also provides application of the photosensitizer in tumor treatment.
Embodiments of the present invention also provide for the use of a combination system as described above, comprising a photosensitizer as described above and an implantable wirelessly charged light emitting diode, in the treatment of a tumor.
Specifically, the tumor is a hypoxic solid tumor.
The following description is made in connection with specific embodiments:
The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available and, unless otherwise indicated, the techniques not described in detail are carried out according to standard methods well known to those skilled in the art.
Example 1 wLED preparation
A cylindrical mold with a bottom diameter of 1.2 cm and a height of 1. 1 cm was made of tin foil. Then, a Polydimethylsiloxane (PDMS) solution was mixed with a curing agent at 10:1, and then pouring the mixture into a mould, and soaking wLED into the mould. Finally, incubating for 6 hours at 65 ℃ to obtain the packaged wLED.
Characterization of example 2 wLED
The emission spectrum of wLED was measured using a fluorescence spectrophotometer, and as shown in fig. 1, it is seen from fig. 1 that the emission spectrum of wLED under wireless charging covers the entire visible light range.
An actual photograph of the illuminated wLED is shown in figure 2.
It is well known that the electromagnetic field distribution around a wireless charger is not uniform. Therefore, it is important to determine wLED the output power at a different relative position from the charging coil, and therefore the optical power at a different relative position from the charging coil is measured using an optical power meter wLED, and as a result, as shown in fig. 3, it is seen from fig. 3 that the closer to the coil, the greater the electromagnetic induction intensity of the coil, and the greater the output power. The maximum power density of wLED is measured by an optical power meter to be 250 mW/cm 2.
Secondly, considering the potential side effects of heat generation, the temperature rise at the time of wLED luminescence at 25 ℃ and 37 ℃ was measured with a thermal infrared imager, and the results are shown in fig. 4, and as seen from fig. 4, the temperature rise from 25 ℃ was 5 ℃ and the temperature rise from 37 ℃ was 2.5 ℃ after continuous wireless charging for 2 minutes, and these results showed that wLED had no significant thermal effect.
In addition, the reliability (sealing performance) of wLED in physiological environment was also studied, and as shown in fig. 7, wLED was soaked in H 2 O, PBS and DMEM media respectively, and can be lightened by wireless charging even after 21 days, thus laying a solid foundation for wLED long-term use.
Example 3 MTDi preparation
A THF solution (0.5 mL) containing MT (1 mg), DSPE-PEG2000 (4.5 mg) and DSPE-PEG2000-iRGD (0.5 mg) was injected into 5mL of ultrapure water, and then, after vigorously stirring for 2 minutes, the mixture was dialyzed against ultrapure water (molecular weight cut-off: 100 kDa) at 4400rpm for 20 minutes. After dialysis, the nanoparticles were dispersed in PBS buffer (1X) to obtain MT@DSPE-PEG2000@iRGD NPs (MTDi for short).
Characterization of example 4 MTDi
The ultraviolet-visible spectrophotometer (UV-vis-NIR) and the fluorescence spectrophotometer detect MTDi absorption spectra and emission spectra, as shown in fig. 5, with a distinct absorption peak observed at 513 nm and an emission maximum observed at 719 nm. MTDi overlap in part with the blue-green light wLED (in contrast to fig. 1), long wavelength emissions help track the biodistribution of MTDi in vivo.
The absorption spectrum of MTDi partially overlaps wLED of a different color. Therefore, it is necessary to test and compare the photodynamic properties of MTDi of wLED of different colors. As shown in fig. 6, blue light wLED produces the strongest ROS compared to green, orange and red light wLED.
The structure of MTDi was observed using a Transmission Electron Microscope (TEM). Dynamic Light Scattering (DLS) was examined MTDi for fluid dynamics and MTDi for diameter with dynamic light scattering and transmission electron microscopy. As shown in FIG. 8, dynamic light scattering measurement MTDi measures hydrodynamic dimensions of-113: 113 nm, while transmission electron microscopy measures the dehydrated dimensions of MTDi to 100: 100 nm. All MTDi were near spherical, indicating that MTDi had very high monodispersity, which is most suitable for biomedical applications.
The structural stability of MTDi in H 2 O, PBS and DMEM was further studied (fig. 9). As shown in fig. 9, there was no significant change in the hydrodynamic dimensions of MTDi over the extended 15 days, indicating that MTDi had good structural stability in H 2 O, PBS and DMEM.
The measurement setup is shown in FIG. 10, using a plastic cuvette (1X 1 cm), wLED was attached to the bottom of the cuvette. Electron Spin Resonance (ESR) measurements were performed using 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin scavenger to confirm the ROS properties generated by photoactivation MTDi. As shown in FIG. 11, the different ESR signals indicate the presence of superoxide radical (O 2 -) and hydrogen peroxide radicalIndicating the type I nature of ROS. In contrast, with 2, 6-Tetramethylpiperidine (TEMP) as a spin-scavenger, almost no ESR signal of singlet oxygen (1O2) was detected.
The total ROS production of MTDi and standard PSs (bengal (RB) and trichloroethane (Ce 6)) was further compared using the general ROS fluorescence indicator Dichlorofluorescein (DCFH). As shown in FIG. 12, the fluorescence intensity of DCFH increased rapidly in the presence of MTDi, faster than RB and Ce6, whereas the increase in fluorescence intensity was negligible when DCFH was used alone. This result shows well the great potential of MTDi as a photosensitizer.
The types of ROS generated by MTDi under wireless charging were further determined using hydroxyphenyl fluorescein (HPF), dihydrorhodamine 123 (DHR 123) and 9, 10-diphenyldiylbis (methylene) bis malonic acid (ABDA) as ROS fluorescence indicators, respectively. As shown in fig. 13 to 15, in the presence of MTDi, the fluorescence intensities of DHR123 and HPF increased significantly, and the decomposition of ABDA was negligible, which is well matched to the ESR results.
Example 5 in vitro Wireless charging photodynamic therapy
(1) Cell and cell culture
Cervical cancer cell line (Hela cells), mouse breast cancer cell line (4T 1 cells), human breast cancer cell line (MCF 7), human breast cancer cell line (Hs 578T) were all purchased from American Type Culture Collection (ATCC). Cells were cultured in DMEM medium supplemented with 10% (v/v) fetal bovine serum (Hyclone), 100 UI mL-1 penicillin and 100 UI mL-1 streptomycin, in a humidified chamber containing 5% carbon dioxide at 37 ℃.
(2) Cellular uptake
Pre-cultured 4T1 cells were obtained. Pre-cultured 4T1 cells were seeded onto confocal dishes at a density of 3X 10 4 cells/well and attached after 24h of incubation. MTDi with different concentrations was added to the prepared confocal dishes, and as an experimental group, no MTDi was added to the control group (Blank), incubated for 12 hours, and then 4T1 cells were washed 3 times with PBS (pH 7.4), and the washed 4T1 cells were fixed with 4% formaldehyde for 15 minutes. Formaldehyde-fixed 4T1 cells were then stained with 4', 6-diamino-2-phenylindole (DAPI) for 20 minutes. The filters of the confocal fluorescence microscope were set to DAPI (405 nm excitation, emission collected with a 450/50nm bandpass filter) and MTDi (excitation at 480nm, emission collected with a 640/50nm bandpass filter). The uptake efficiency of each group was also assessed by flow cytometry (CytoFLEX, beckman) (excitation at 488nm, emission collected with 690/50nm bandpass filter).
As shown in fig. 16, as the MTDi concentration increased, the orange moiety appeared in the fluorescence imaging plot increased, indicating that MTDi uptake by cultured 4T1 cells increased; as shown in FIG. 17, the results shifted right (increased) in order with increasing MTDi concentration, indicating that uptake of MTDi by cultured 4T1 cells increased.
(3) Cytotoxicity test
To measure the cytotoxicity of MTDi, 10, 3 cells per well were seeded in 96-well plates (100 μl) and allowed to attach overnight. After 24 hours, the medium was replaced with 100 μl DMEM medium containing different concentrations MTDi, and then incubated for 24 hours. The OD value was determined by adding 10. Mu.L of CCK-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt) solution to each well, indirectly reflecting the number of living cells. After incubation with CCK-8 for 30 min, absorbance at 450nm per well was measured on Microplate Reader (BioTek). Cell viability was calculated using the following formula: cell viability (%) = (mean absolute value of treatment group/mean absolute value of control group) ×100%.
As shown in fig. 18, the cell viability of the various cells incubated at different concentrations MTDi was not significantly different from that of the control group incubated without addition of MTDi, indicating that MTDi had little cytotoxicity to Hs578T, MCF, heLa and 4T1 cells.
(4) Cellular reactive oxygen species detection
Experimental setup as shown in fig. 19, wLED was attached to the inner surface of the 24-well plate cover plate, on which the charging coil was placed. 1X 10 4 cells per well were seeded in 24 well plates (500. Mu.L) and allowed to attach overnight. When 4T1 cells grew to about 80%, the generation of active oxygen in 4T1 cells at different MTDi concentrations under normoxic (21% O 2) and hypoxic (2%O 2) conditions was studied and divided into control (PBS), material (MTDi) and experimental (wLED + MTDi) groups. Both material and experimental groups were incubated at the same concentration MTDi (10 uM) for 12 h, then 2',7' -dichlorofluorescein diacetate (DCFH-DA) was added for 30 minutes, followed by 3 washes of 4T1 cells with PBS (pH 7.4). The experimental group was lit wLED for 1 minute and then photographed using a EVOS M5000 microscope (invitrogen by Thermo FISHER SCIENTIFIC). In addition, flow cytometry was used to investigate the generation of reactive oxygen species in 4T1 cells at different MTDi concentrations under normoxic (21% O 2) and hypoxic (2% O 2) conditions. The use of ANAIRPACKTM-AbnAero anaerobic gas generator creates hypoxic conditions in a sealed chamber.
As shown in fig. 20, after wLED irradiation for 1 min under hypoxic conditions (i.e., experimental group), a clear green fluorescent signal was observed in 4T1 cells, indicating that MTDi effectively produced ROS under wLED irradiation. In contrast, no green fluorescent signal was observed in the control and material (no light) groups. As shown in fig. 21, the higher average fluorescence intensity was observed under hypoxic conditions at different concentrations MTDi, probably because hypoxia could alter the activity of the mitochondrial oxidative phosphorylated cytochrome chain, reduce the activity of the cellular antioxidant system, and thereby increase ROS production, leading to increased oxidative stress.
(5) Killing effect of wireless photodynamic on cancer cells
In order to prove that MTDi can cause apoptosis and even death of cells when I-type ROS are generated under wLED illumination, an in-vitro normoxic cell model and an in-vitro hypoxic cell model are firstly constructed, and then the killing effect of MTDi on 4T1 cells under normoxic (21% O 2) and hypoxic (2% O 2) environments is compared and analyzed through a CCK-8 experiment, a living/dead cell staining experiment and an apoptosis experiment.
CCK-8 experiment:
4T1 cells were incubated in 24-well plates as described previously. Under the environments of normoxic (21% O 2) and hypoxic (2% O 2), 300 mu L of DMEM culture medium containing MTDi with different concentrations is used for replacing waste liquid, the treatment group is used, the control group (Blank) directly replaces the waste liquid with 300 mu L of DMEM culture medium, and after 12 hours of incubation, the waste liquid is replaced with 300 mu L of DMEM culture medium. Next, wLED was lit, illuminated for 20 minutes and incubation continued for 8 hours. Then 30 μl CCK-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt) solution was added to each well to determine OD values, indirectly reflecting the number of living cells. After incubation with CCK-8 for 30 min, absorbance at 450nm per well was measured on Microplate Reader (BioTek). Cell viability was calculated using the following formula: cell viability (%) = (mean absolute value of treatment group/mean absolute value of control group) ×100%.
Live/dead cell staining experiments and apoptosis experiments:
4T1 cells were incubated in 24-well plates as described previously. Under the environments of normoxic (21% O 2) and hypoxia (2%O 2), 300 [ mu ] L of DMEM culture medium containing MTDi with different concentrations is used for replacing waste liquid, as a treatment group, a control group (Blank) directly replaces the waste liquid with 300 [ mu ] L of DMEM culture medium, and after 12 hours of incubation, MTDi [ mu ] L of DMEM culture medium is used for replacing the waste liquid. Next, wLED was lit, illuminated for 20 minutes and incubation continued for 8 hours. The waste solution was then aspirated off and staining solution (300 μl containing 2 μ M CALCEIN AM and 8 μΜ PI) was mixed with each well. After 15 minutes, fluorescence imaging was collected with EVOS M5000:5000 (invitrogen).
4T1 cells were incubated in 24-well plates as described previously. MTDi 300 mu L DMEM culture mediums containing different concentrations are used for replacing waste liquid in normal oxygen (21% O 2) and hypoxia (2%O 2) environments, 300 mu L DMEM culture mediums are used as treatment groups, the control group (Blank) is used for directly replacing the waste liquid with 300 mu L DMEM culture mediums, and MTDi mu L DMEM culture mediums are used for replacing the waste liquid after 12 hours of incubation. Next, wLED was lit, illuminated for 20 minutes and incubation continued for 12 hours. The waste liquid was then aspirated, the cells were digested with trypsin, centrifuged and gently washed with PBS (pH 7.4), and then resuspended by adding binding buffer (100 μl). Annexin V-FITC (2.5. Mu.L) and PI (2.5. Mu.L) staining solutions were added to the cells, followed by incubation for 15 min and then addition of binding buffer (400. Mu.L). Apoptosis and death were measured by flow cytometry.
As shown in FIG. 22, based on CCK-8 experimental results, the therapeutic effect of wireless PDT under hypoxic conditions is generally stronger than under normoxic conditions. Furthermore, in MTDi at any concentration, wireless PDT in two times (under hypoxic conditions and under normoxic conditions) significantly expands the efficacy.
EXAMPLE 6 in vivo Wireless charging photodynamic therapy
(1) MTDi in vivo fluorescence imaging distribution studies
Analysis MTDi accumulation of major organs (heart, liver, spleen, lung, kidney) and tumors in mice is important. Female mice were randomly divided into 5 groups and MTDi material (200 μl,3 mmol/mL) was injected via the tail vein, and the control group was replaced with an equal volume of PBS. Tumors and major organs were dissected and harvested after 6h, 12 h, 24 h, 48 h, respectively. The fluorescence distribution of MTDi in mice (520 nm excitation, 670nm emission) was then observed using a small animal fluorescence imaging system (IVIS Spectrum, PERKELMER, US).
As shown in fig. 23, MTDi exhibited the strongest fluorescence at the tumor after injection of 12h, indicating that MTDi was 12h after injection for the maximum retention time and most appropriate treatment time of the tumor. In addition, MTDi accumulated in liver and kidney tissues after 6 h and gradually resolved, which suggests that liver and urine are both the main clearance pathways of MTDi. The accumulation of MTDi in the lungs may be related to the size effects of MTDi and the abundant vasculature in the lungs. Based on the results of fluorescence imaging, a treatment regimen was designed (see fig. 24).
(2) In vivo treatment for wireless PDT
As shown in fig. 25, on day 7, the wound on the abdomen of one mouse was completely closed and a bright blue light appeared under wireless charging. Bioluminescence can be used to reflect the growth of 4T1 cells before and after the entire PDT treatment. Initially, mice were implanted with wLED and 4T1 cells, followed by continuous feeding for 7 days to heal the wound and grow the tumor (fig. 21). Female Balb/C mice were randomly divided into 4 groups of 5 animals each. A tumor-bearing mouse model was established by subcutaneously injecting 4T1 cells (1×10 6/mouse). Then wLED was implanted into mice. When the wound on the abdomen heals and the tumor volume reaches approximately 80-100mm 3, the mice are ready to receive different treatments: blank groups were not treated at all; group MTDi was injected with 200 μ L MTDi (3 mmol/mL) on days 0, 3,6, 9, respectively; group wLED mice were implanted wLED without further treatment; the wLED + MTDi group was implanted wLED and injected MTDi into the tail vein for PDT treatment under wireless charging. At each treatment, mice were placed in a charging coil, trigger wLED for PDT, and irradiation was performed for 1h by wireless charging, for wLED groups and wLED + MTDi groups. The length (L: mm) and width (W: mm) of the tumor were measured every 3 days, and the formula for calculating the tumor volume (V) was: v (mm 3)=0.5×L×W2. Mice body weight was recorded simultaneously and analyzed. As shown in FIG. 26, on day 7, a wound on one mouse's abdomen was completely closed and bright blue light appeared under wireless charging. Bioluminescence could be used to reflect the growth of 4T1 cells before and after the entire PDT treatment. As shown in FIG. 27, significant tumor growth was observed in the blank, MTDi and wLED groups, indicating that no effective treatment was yet undertaken. In sharp contrast, bioluminescence areas and intensities were greatly reduced in the wLED + MTDi groups due to the generation of type I ROS, wLED + MTDi groups.
By establishing a subcutaneous tumor mouse model, the effect of wireless charging photodynamic therapy is verified again. After the end of the treatment, the major organs and tumor tissues of the mice were collected. As shown in fig. 28. The result shows that wLED and MTDi combined application has better treatment effect on 4T1 tumor. Fig. 29 tumor growth curves show that the tumor volumes of the control group (blank, wLED, MTDi) increased sharply during the treatment period, with no significant difference between the three. Notably, MTDi showed significant inhibition of tumor growth following the introduction of wireless charging. In addition, tumor weight also indicated that MTDi-mediated PDT treatment had a strong therapeutic effect on tumors in tumor-bearing mice with a tumor suppression rate of 76.4% (fig. 30).
Hematoxylin-eosin (HE) staining of each group of tumor sections. As shown in a of fig. 31, a substantial core loss and significant core shrinkage were observed only on wLED + MTDi treated tumor sections, indicating that PDT successfully destroyed tumor tissue.
In addition, the end deoxynucleotidyl transferase mediated gap end labeling (TUNEL) of tumor tissue was performed to further verify MTDi-mediated PDT-induced apoptosis of tumor tissue. As shown in b in fig. 31, a large number of TUNEL positive green fluorescence signals were observed in PDT treated tumor tissue, whereas no green fluorescence signals were detected in the control group, indicating that PDT induced severe apoptosis. Tumor tissues were stained with anti-Ki 67 mab immunofluorescence (Ki 67 staining), and the mechanism of action was further investigated. As shown in c in fig. 31, group wLED + MTDi had no Ki67 positive proliferating cells. In sharp contrast, 4T1 cells densely arranged in the tumor tissue of the control group have stronger proliferation activity. These results strongly demonstrate that type I PDT activated under wireless charging MTDi can effectively inhibit tumor growth by inducing tumor cell apoptosis and inhibiting tumor cell proliferation.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the invention, but any modifications, equivalents, improvements, etc. within the principles of the present invention should be included in the scope of the present invention.

Claims (8)

1. The preparation method of the photosensitizer for tumor photodynamic therapy based on wireless charging is characterized by comprising the following steps of:
S1, the mass ratio of the components is (1.8-2.2): (8-10): 1, DSPE-PEG2000 and DSPE-PEG 2000-igd in THF is added to ultrapure water, the mass volume ratio of the DSPE-PEG 2000-igd to the THF is 0.9-1.1mg/mL, the volume ratio of the ultrapure water to the THF is (9-11): 1, a step of;
s2, carrying out dialysis after vigorously stirring for 1.8-2.2 minutes, wherein the molecular weight cut-off value of an ultrafiltration membrane used in the dialysis is 100kDa, the rotating speed is 4000-4800 rpm, and the rotating time is 15-25 minutes;
S3, dispersing the nano particles obtained by dialysis in PBS buffer solution to obtain the photosensitizer;
the structural formula of the MT is as follows:
。
2. the method of claim 1, wherein in the step S2, the dialysis is performed at a rotational speed of 4400 rpm for a rotational time of 10 minutes.
3. A photosensitizer for photodynamic tumour therapy based on wireless charging, characterized in that it is prepared using a preparation method according to any one of claims 1-2.
4. A combination system for photodynamic therapy of tumors based on wireless charging, comprising an implantable wirelessly charged light emitting diode and a photosensitizer according to claim 3.
5. The combination of claim 4, wherein the method of manufacturing the light emitting diode comprises the steps of:
a. manufacturing a mould;
b. the volume ratio is (9-11): 1, uniformly mixing a polydimethylsiloxane solution and a curing agent to obtain a mixed solution, pouring the mixed solution into the mold, and then soaking an LED into the mixed solution;
c. Incubating at 60-70deg.C for 5.5-6.5 h to obtain the light-emitting diode.
6. The combination of claim 5, wherein the mold is made of tin foil and is a cylindrical mold having a bottom diameter of 1.2 cm and a height of 1.1 cm.
7. The combination of claim 5, wherein the volume ratio of said polydimethylsiloxane solution to said curative is 10:1.
8. The combination according to claim 5, wherein the incubation in step c is carried out at a temperature of 65℃for a period of 6 hours.
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