CN117618583A - 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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CN117618583A
CN117618583A CN202410104354.4A CN202410104354A CN117618583A CN 117618583 A CN117618583 A CN 117618583A CN 202410104354 A CN202410104354 A CN 202410104354A CN 117618583 A CN117618583 A CN 117618583A
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mtdi
photosensitizer
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tumor
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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 wireless charging light-emitting diode (wLED), 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 combining MTDi and wLED, 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 for malignant tumors that has emerged over the last two decades, enabling accurate drug tracking and tumor visualization as a non-invasive treatment 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 Jiyou 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, a THF solution of 2- ((5- (4- (bis (4-methoxyphenyl) amino) phenyl) thiophen-2-yl) methyl) Malononitrile (MT), DSPE-PEG2000 (1, 2-distearoyl-sn-glycero-3-phosphate acetamide-N-amino (polyethylene glycol) -2000) and DSPE-PEG 2000-igd is added to ultrapure water, the mass volume ratio of DSPE-PEG 2000-igd to THF solution is 0.9-1.1mg/mL, the volume ratio of ultrapure water to THF solution 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 (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 wireless charging light emitting diode (wLED).
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 to the surface of MTDi 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 wireless power supply wLED which can be implanted and safely remained in the body for a long time is obtained by wrapping the LED in PDMS with good biocompatibility and nondegradability, and the MTDi accumulated in the tumor is triggered to generate I-type ROS by the wireless charging wLED, so that the purpose of inhibiting the growth of the tumor is achieved. Unlike classical strategies to develop PSs of long excitation wavelength in the near infrared window, integrated implantable optoelectronic devices (wleds) can skillfully bypass the optical attenuation of biological tissue and the photosensitivity of skin, thereby increasing 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 using the combination system of the type I AIEgen photosensitizer MTDi and the wLED, and results of in-vivo experiments and in-vitro experiments prove that the combination system can overcome the limitations 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 a wLED;
FIG. 2 is an actual photograph of an illuminated wLED;
FIG. 3 is a graph showing the optical power results for a wLED at a different relative position to a charging coil;
FIG. 4 shows the results of temperature rise at 25℃and 37℃for the wLED emission;
fig. 5 is an absorption spectrum and an emission spectrum of MTDi;
fig. 6 is the photodynamic performance results of MTDi for different color wleds;
FIG. 7 is a test of the tightness of PDMS encapsulated wLED;
FIG. 8 is a Transmission Electron Microscope (TEM) (upper left plot) and Dynamic Light Scattering (DLS) detection results;
FIG. 9 shows MTDi at H 2 O, PBS and DMEM, and structural stability;
FIG. 10 is a measurement setup diagram;
FIG. 11 is an ESR spectrum;
FIG. 12 is the total ROS production of MTDi, bengalhong (RB) and trichloroethane (Ce 6) with DCFH as fluorescent indicator;
FIG. 13 shows hydroxyl radical yields of MTDi, bengalhon (RB) and trichloroethane (Ce 6) with HPF as fluorescent indicator;
FIG. 14 shows the superoxide radical production of MTDi, bengalhondral (RB) and trichloroethane (Ce 6) with fluorescent indicator DR 123;
FIG. 15 shows singlet oxygen production for MTDi, bengalhondral (RB) and trichloroethane (Ce 6) with fluorescent indicator ABDA;
FIG. 16 is a confocal fluorescence imaging of cells incubated with different concentrations of MTDi for 12 hours;
FIG. 17 is a flow chart of cells after 12 hours incubation with MTDi at different concentrations;
fig. 18 is cytotoxicity data after incubation of different cells with different concentrations of 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 under normoxic and hypoxic conditions;
FIG. 22 shows the efficacy of wireless PDT under normoxic and hypoxic conditions for different concentrations of MTDi;
fig. 23 is a fluorescence image of the major organs at various time points after intravenous MTDi injection in the tail of the mice;
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. 31 a 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 preparation of wLED
A cylindrical die with a bottom diameter of 1.2cm 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 mold, and then soaking the wLED into the mold. Finally, incubating for 6 hours at 65 ℃ to obtain the packaged wLED.
Example 2 characterization of wLED
The emission spectrum of the wLED was measured using a fluorescence spectrophotometer, and as shown in fig. 1, it is seen from fig. 1 that the emission spectrum of the wLED under wireless charging covers the entire visible light range.
An actual photograph of the illuminated wLED is shown in fig. 2.
It is well known that the electromagnetic field distribution around a wireless charger is not uniform. Therefore, it is important to determine the output power of the wler at a position different from the charging coil, and therefore, the optical power of the wler at a position different from the charging coil is measured by an optical power meter, 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 the wLED is measured to be 250 mW/cm by an optical power meter 2 。
Secondly, considering the potential side effects of heat generation, the temperature rise when the wLED emits light at 25 ℃ and 37 ℃ was measured with a thermal infrared imager, and the results are shown in fig. 4, and it is seen from fig. 4 that the temperature rises by 5 ℃ from 25 ℃ and by 2.5 ℃ from 37 ℃ after continuous wireless charging for 2 minutes, and these results indicate that the wLED has no significant thermal effect.
Further, the reliability (sealing property) of the wLED in the physiological environment was also studied, and as a result, as shown in fig. 7, it is seen from fig. 7 that the wLED was immersed in H 2 O, PBS and DMEM medium, even inThe LED lamp can be lightened by wireless charging after 21 days, and a solid foundation is laid for the long-term use of the wLED lamp.
EXAMPLE 3 preparation of MTDi
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), i.e., MT@DSPE-PEG2000@iRGD NPs (MTDi for short) were obtained.
Example 4 characterization of MTDi
The ultraviolet-visible spectrophotometer (UV-vis-NIR) and the fluorescence spectrophotometer detect the absorption spectrum and the emission spectrum of MTDi, as shown in fig. 5, with a distinct absorption peak observed at 513 nm and an emission maximum observed at 719 nm. The absorption spectrum of MTDi partially overlaps with the blue-green light wLED (as opposed to fig. 1), and long wavelength emissions help track the biodistribution of MTDi in vivo.
The absorption spectrum of MTDi partially overlaps with the wleds of different colors. Thus, it is necessary to test and compare the photodynamic properties of MTDi of different color wleds. As shown in fig. 6, the blue wLED produces the strongest ROS compared to the green, orange and red wleds.
The structure of MTDi was observed using a Transmission Electron Microscope (TEM). Dynamic Light Scattering (DLS) detects the hydrodynamic properties of MTDi and the diameter of MTDi is detected with dynamic light scattering and transmission electron microscopy. As shown in FIG. 8, dynamic light scattering measures the hydrodynamic size of MTDi to 113-nm, while transmission electron microscopy measures the dehydrated size of MTDi to 100-nm. All MTDi are nearly spherical, indicating that MTDi has a very high monodispersity, which is most suitable for biomedical applications.
Further study of MTDi at H 2 O, PBS and structural stability in DMEM (fig. 9). As shown in fig. 9, there was no significant change in hydrodynamic size of MTDi over the extended 15 days, indicating MTDi at H 2 O, PBS and DMEM have good structural stability.
The measurement setup is shown in FIG. 10, using a plastic cuvette (1X 1 cm), with a wLED 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 photo-activated MTDi. As shown in FIG. 11, the different ESR signals indicate the presence of superoxide radicals (O 2 - ) And hydrogen peroxide radicalsIndicating the type I nature of ROS. In contrast, 2, 6-Tetramethylpiperidine (TEMP) was used as spin-scavenger with almost no detectable singlet oxygen 1 O 2 ) Is a constant value (ESR) signal.
Further using the general ROS fluorescence indicator Dichlorofluorescein (DCFH), the total ROS yields of MTDi and standard PSs (bengal (RB) and trichloroethane (Ce 6)) were further compared. As shown in fig. 12, the fluorescence intensity of DCFH rapidly increased 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 ROS type produced by MTDi under wireless charging was 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, the fluorescence intensity of DHR123 and HPF increased significantly in the presence of MTDi, 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 containing 10% (v/v) fetal bovine serum (Hyclone), 100 UI mL-1 penicillin and 100 UI mL-1 streptomycin at 37℃in a humidified chamber containing 5% carbon dioxide.
(2) Cellular uptake
Pre-cultured 4T1 cells were obtained. Pre-cultured 4T1 cells were plated at 3×10 4 The density of individual cells/wells was seeded onto confocal dishes and after incubation for 24h, attached. MTDi was added to each of the above prepared confocal dishes at different concentrations, and as an experimental group, a control group (Blank) was incubated for 12 hours without MTDi, 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 (480 nm excitation, emission collected with a 640/50nm bandpass filter). The uptake efficiency of each group was also assessed using a flow cytometer (CytoFLEX, beckman) (excitation at 488nm, emission collected with 690/50nm bandpass filter).
As shown in fig. 16, as the concentration of MTDi increases, the orange moiety appearing in the fluorescence imaging map increases, indicating that the uptake of MTDi by cultured 4T1 cells increases; as shown in fig. 17, the results shifted right (increased) in order with increasing concentration of MTDi, indicating that the uptake of MTDi by cultured 4T1 cells increased.
(3) Cytotoxicity test
To measure cytotoxicity of MTDi, 5×10 per well 3 Individual cells 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 of 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 30 minutes incubation with CCK-8, 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 of MTDi was not significantly different from that of the control group incubated without MTDi, indicating that MTDi was almost non-cytotoxic to Hs578T, MCF, heLa and 4T1 cells.
(4) Cellular reactive oxygen species detection
Experimental setup as shown in fig. 19, a wLED was attached to the inner surface of a 24-well plate cover plate, with a charging coil placed over the cover plate. 1X 10 per well 4 Individual cells were seeded in 24 well plates (500 μl) and attached overnight. After 4T1 cells grew to about 80%, they studied in normoxic (21% O 2 ) And hypoxia (2%O) 2 ) The conditions under which different concentrations of MTDi produced active oxygen in 4T1 cells were divided into control (PBS), material (MTDi) and experimental (wled+mtdi). Both material and experimental groups were incubated with the same concentration of MTDi (10 uM) for 12h, then 2',7' -dichlorofluorescein diacetate (DCFH-DA) was added for 30 min, followed by washing 4T1 cells 3 times with PBS (pH 7.4). The experimental group was illuminated with a wLED light for 1 minute and then photographed using an EVOS M5000 microscope (invitrogen by Thermo Fisher Scientific). In addition, flow cytometry was also used to study the reaction of the reaction mixture in normoxic (21% O 2 ) And hypoxia (2% O) 2 ) Under conditions where different concentrations of MTDi produce reactive oxygen species within 4T1 cells. AnairPackTM-AbNAero anaerobic gas generator was used to create hypoxic conditions in a sealed chamber.
As shown in fig. 20, after 1 minute of wLED irradiation 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, different concentrations of MTDi observed stronger average fluorescence intensity under hypoxic conditions, probably because hypoxia could alter the activity of mitochondrial oxidative phosphorylated cytochrome chains, reduce the activity of cellular antioxidant systems, and thereby increase ROS production, leading to increased oxidative stress.
(5) Killing effect of wireless photodynamic on cancer cells
To demonstrate that MTDi produces type I ROS under wLED illumination, which can lead to apoptosis and even death, in vitro normoxicity was first constructedCell model and in vitro hypoxia cell model, and comparing and analyzing MTDi in normoxic (21% O) by CCK-8 experiment, living/dead cell staining experiment and apoptosis experiment 2 ) And hypoxia (2% O) 2 ) Killing effect on 4T1 cells under the environment.
CCK-8 experiment:
4T1 cells were incubated in 24-well plates as described previously. In the presence of normal oxygen (21% O) 2 ) And hypoxia (2% O) 2 ) Under the environment, replace the waste liquid with 300 mu L DMEM culture medium that contains different concentration MTDi, as the treatment group, then directly replace the waste liquid with 300 mu L DMEM culture medium with control group (Blank), after incubating for 12 hours, replace the waste liquid with 300 mu L DMEM culture medium. The wLED was then illuminated for 20 minutes and incubation was 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 30 minutes incubation with CCK-8, 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. In the presence of normal oxygen (21% O) 2 ) And hypoxia (2%O) 2 ) Under the environment, replacing the waste liquid with 300 mu L of DMEM medium containing MTDi with different concentrations, taking the DMEM medium as a treatment group, directly replacing the waste liquid with 300 mu L of DMEM medium in a control group (Blank), and replacing the waste liquid with the MTDi 300 mu L of DMEM medium after 12 hours of incubation. The wLED was then illuminated for 20 minutes and incubation was continued for 8 hours. The waste solution was then aspirated off and staining solution (300 μl containing 2 μΜ Calcein AM and 8 μΜ PI) was mixed with each well. After 15 minutes, fluorescence imaging was collected with EVOS M5000 (invitrogen).
4T1 cells were incubated in 24-well plates as described previously. In the presence of normal oxygen (21% O) 2 ) And hypoxia (2%O) 2 ) Under the environment, an MTDi 300 mu L DMEM culture medium containing different concentrations is used for replacing waste liquid, and a control group (Blank) is used as a treatment group, so that 300 mu L DM is directly usedAnd (3) replacing the waste liquid with the EM culture medium, and replacing the waste liquid with the MTDi 300 [ mu ] L DMEM culture medium after incubation for 12 hours. The wLED was then 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 any concentration of MTDi, wireless PDT twice (under hypoxic conditions and under normoxic conditions) significantly expands the efficacy.
EXAMPLE 6 in vivo Wireless charging photodynamic therapy
(1) In vivo fluorescence imaging distribution studies of MTDi
It is important to analyze the accumulation of MTDi in major organs (heart, liver, spleen, lung, kidney) and tumors in mice. 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 equal volume of PBS. Tumors and major organs were dissected and harvested after 6h, 12h, 24h, 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 showed the strongest fluorescence at the tumor after injection of 12h, indicating that the maximum retention time and most appropriate treatment time of MTDi at the tumor was 12h after injection. In addition, after 6h MTDi accumulates in liver and kidney tissues and gradually subsides, which indicates that both liver and urine are the main clearance pathways for MTDi. Accumulation of MTDi in the lung may be related to the size effects of MTDi and the abundant vasculature in the lung. 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, one mouse was on day 7The wound on the abdomen 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 wounds and grow tumors (fig. 21). Female Balb/C mice were randomly divided into 4 groups of 5 animals each. Subcutaneous injection of 4T1 cells (1X 10) 6 And/or) establishing a tumor-bearing mouse model. The wLED was then implanted into mice. When the wound on the abdomen heals, the tumor volume reaches about 80-100mm 3 At this point, the mice are ready to receive different treatments: blank groups were not treated at all; the MTDi group was injected with 200. Mu.L of MTDi (3 mmol/mL) on days 0, 3, 6, and 9, respectively; the wLED group mice are implanted with the wLEDs without further treatment; the wLED+MTDi group was implanted with wLED and tail vein injected with MTDi and PDT treatment was performed under wireless charging. At each treatment, the wLED group and the wled+mtdi group placed mice in a charging coil, the wLED for PDT was triggered and irradiated by wireless charging for 1 h. 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×W 2 . The mice body weight was recorded at the same time and analyzed. As shown in fig. 26, 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. As shown in fig. 27, significant tumor growth was observed in the blank, MTDi, and wLED groups, indicating that no effective treatment was taken yet. In sharp contrast, the bioluminescence area and intensity of the wled+mtdi group is greatly reduced due to the generation of type I ROS in the wled+mtdi group.
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 the combined application of the wLED and the MTDi has better treatment effect on the 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 a 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 inhibition rate of 76.4% (fig. 30).
Hematoxylin-eosin (HE) staining of each group of tumor sections. As shown in a of fig. 31, a large number of nuclear deletions and significant nuclear contractions were observed only on the wled+mtdi treated tumor sections, indicating that PDT successfully destroyed the tumor tissue.
In addition, terminal 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, the wled+mtdi group 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 MTDi-activated PDT type I under wireless charging 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 4000-4800rpm, 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 structural formula of the MT is as follows:
。
2. the method for preparing a photosensitizer according to claim 1, wherein in step S2, the rotational speed of the dialysis is 4400rpm and the rotational time is 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. 6.5h 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 1.2cm and a height of 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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