CN114873629B - Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier - Google Patents
Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier Download PDFInfo
- Publication number
- CN114873629B CN114873629B CN202210695944.XA CN202210695944A CN114873629B CN 114873629 B CN114873629 B CN 114873629B CN 202210695944 A CN202210695944 A CN 202210695944A CN 114873629 B CN114873629 B CN 114873629B
- Authority
- CN
- China
- Prior art keywords
- nano
- solution
- product
- drug
- peptide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G3/00—Compounds of copper
- C01G3/12—Sulfides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/84—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by UV- or VIS- data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/16—Pore diameter
- C01P2006/17—Pore diameter distribution
Abstract
The invention relates to a preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier, which comprises the following steps: firstly, near-infrared light response nano-material hollow mesoporous copper sulfide nano-particles (HMCuS NPs) are synthesized, a chemotherapeutic drug Doxorubicin (DOX) is encapsulated by utilizing a unique cage-shaped structure of the HMCuS NPs, the drug loading capacity is greatly improved, then the outer surface of the HMCuS NPs is modified by a liver cancer targeting peptide 9R-P201 peptide to obtain the hollow mesoporous copper sulfide nano-drug HMCD9P with liver cancer targeting, and finally the combined treatment effect of nano-drug chemotherapy, photo-thermal treatment and photodynamic treatment is realized. In tumor-bearing mice experiments, the tumor-bearing mice treated by the HMCD9P + L group under near infrared light irradiation showed a tumor inhibition rate of about 88.2%. The HMCD9P can be used as a nano therapeutic agent for efficiently and accurately inducing chemotherapy, photo-thermal treatment and photodynamic treatment, and has excellent anti-tumor effect and small side effect.
Description
Technical Field
The invention belongs to the technical field of biological medicine and health, and particularly relates to a preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier.
Background
Copper sulfide is used as a novel near-infrared light nano response material, and has good photo-thermal stability and biocompatibility. On the one hand, copper sulfide as a p-type semiconductor has a strong Local Surface Plasmon Resonance (LSPR) effect on NIR light, and the photothermal conversion efficiency is higher than that of other photothermal conversion materials. In addition, the copper sulfide absorbs NIR to generate heat to cause the expansion of biological tissues, can generate photoacoustic signals, can be used as an excellent photoacoustic imaging contrast agent, and can accurately position tumor parts/sizes/forms. On the other hand, under the irradiation of near infrared light, copper ions leaked from the copper sulfide can generate oxidation reduction reaction with a buffer solution matrix in the surrounding environment of the tumor to generate hydroxyl radicals (\8729OH) for photodynamic therapy. Copper sulfide, unlike other NIR-responsive materials, can only produce a single heat or reactive oxygen species for anti-tumor therapy. It can be used for photothermal therapy (PTT), photodynamic therapy (PDT) and photoacoustic imaging (PAT) at the same time, and has great advantages in tumor diagnosis and treatment.
Although copper sulfide is a photo-thermal nano-carrier material with great potential, the application of copper sulfide in preparing tumor treatment drugs still faces many challenges, such as: poor water dispersibility, low tumor cell targeting property and the like, and is difficult to realize the targeted transfer of the medicine and the high-efficiency and low-toxicity photo-thermal combined chemotherapy. Therefore, how to prepare the hollow mesoporous copper sulfide nano-drug carrier modified by the liver cancer targeting peptide to realize the application in preparing the drugs for treating tumors is a technical problem to be solved seriously.
Disclosure of Invention
The invention mainly aims to overcome the defects of the prior art and provides a preparation method of a hollow mesoporous copper sulfide nano-drug carrier.
The invention also aims to provide the application of the hollow mesoporous copper sulfide nano-drug carrier in drug loading.
The invention also provides a method for preparing the nano-medicament by using the nano-medicament carrier.
In order to achieve the above object, the present invention provides the following technical solutions:
a preparation method of a hollow mesoporous copper sulfide nano-drug carrier comprises the following steps:
Specifically, in the step 1, the molecular weight of the polyvinylpyrrolidone (PVP-K30) is 50000-60000 Da.
The invention provides the hollow mesoporous copper sulfide nano-drug carrier prepared by the method.
The invention also provides the application of the nano-drug carrier in drug loading, for example, the nano-drug carrier is used for preparing drugs, in particular preparing anti-tumor drugs and the like.
The invention also provides a method for preparing the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using the nano-drug carrier, which comprises the following steps:
a, performing ultrasonic treatment on the product E for 20-30 min by using an ultrasonic cell crusher at room temperature, adding 100-300 mg of sulfydryl-containing coating, stirring for 2-48 h, centrifuging, washing, performing freeze drying for 20-30 h under the conditions of low temperature and high vacuum, and re-dissolving by using ultrapure water to obtain a product F; wherein the mass ratio of the black brown solid in the sulfydryl-containing coating and the product E is 1-3: 1;
b, performing ultrasonic treatment on the product F for 20-30 min by using an ultrasonic cell crusher at room temperature, adding adriamycin (DOX) medicine, stirring for 2-48 h in a dark place, centrifuging, washing, performing freeze drying for 20-30 h under the low-temperature high-vacuum condition, and redissolving by using a phosphate buffer solution to obtain a product G; wherein the mass ratio of the black brown solid in the adriamycin medicine and the product E is 1-3: 1;
step c, placing the 9R-P201 peptide into a phosphate buffer solution with the pH value of 7-9 at room temperature, adding carbodiimide hydrochloride and N-hydroxysuccinimide to activate carboxyl on the 9R-P201 peptide, and stirring for 20-40 min to obtain an activated 9R-P201 peptide solution H; wherein the mass ratio of the 9R-P201 peptide to the carbodiimide hydrochloride to the N-hydroxysuccinimide is 1: 0.3-0.7:0.3-0.7;
d, mixing the product G with the activated 9R-P201 peptide solution H at room temperature, stirring for 12-48H in the dark, centrifuging, washing, and freeze-drying for 20-30H under the low-temperature high-vacuum condition (preferably, the product can be re-dissolved with ultrapure water again, then centrifuging, washing, and freeze-drying for 20-30H under the low-temperature high-vacuum condition), thus obtaining the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug I (HMCuS @ DOX-9R-P201, abbreviated as HMCD 9P); wherein the mass ratio of the 9R-P201 peptide to the adriamycin is 1: 1-3.
Specifically, in the step a, the mercapto group-containing coating comprises beta-mercaptoethylamine, mercaptopropionic acid or thioglycolic acid and the like, and is mainly used as a bridge to connect HMCuS and 9R-P201 peptide.
Specifically, the liver cancer targeting peptide includes (such as 9R-P201 peptide, A54 peptide, SP94 peptide, AM-2 peptide, T7 peptide, BP9 peptide, X1 peptide, L5 peptide, etc.), such as 9R-P201 peptide. In step c, the 9R-P201 peptide is one of liver cancer targeting peptides, and the peptide sequence is as follows: AAAAAAAGSGSTHLATPSMTLA.
The invention also provides the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug prepared by the method, and the nano-drug can be applied to the aspects of chemotherapy, thermotherapy, photodynamic combination therapy and the like. Namely, the invention provides a drug with chemotherapy-thermotherapy-photodynamic combined treatment function, which comprises the hollow mesoporous copper sulfide nano-drug carrier. The invention introduces the adriamycin medicine into the hollow mesoporous copper sulfide nano-medicine carrier, and can be applied to the combined treatment of chemotherapy, photodynamic treatment, photothermal treatment and the like of cancers.
The invention introduces the liver cancer targeting peptide 9R-P201 peptide into the surface of the hollow mesoporous copper sulfide nano-drug carrier, and can be applied to the specific targeting of liver cancer.
Compared with the prior art, the hollow mesoporous copper sulfide nano-drug carrier has the following advantages:
1) Taking copper chloride dihydrate, polyvinylpyrrolidone (PVP-K30), sodium hydroxide, hydrazine hydrate and sodium sulfide nonahydrate as raw materials, and taking the prepared dark brown solid as hollow mesoporous copper sulfide nano particles; then taking the adriamycin medicine, beta-mercaptoethylamine, 9R-P201 peptide and hollow mesoporous copper sulfide nano particles as raw materials to obtain the liver cancer targeted peptide modified hollow mesoporous copper sulfide nano medicine. The raw materials adopted by the invention have low toxicity and high safety.
2) The hollow mesoporous copper sulfide nano-particles are synthesized in a low-temperature aqueous solution by adopting nontoxic and easily obtained polyvinylpyrrolidone (PVP-K30) as an active agent and a stabilizing agent, and the preparation method is simple to operate, mild and controllable in reaction conditions and low in cost; the surface of the hollow mesoporous copper sulfide nano drug carrier is modified with the 9R-P201 peptide with the liver cancer target, so that the hydrophilicity of the prepared hollow mesoporous copper sulfide nano drug carrier with the liver cancer target modification in an aqueous solution and the effect of specifically targeting the liver cancer are further improved.
3) The surface potential of the hollow mesoporous copper sulfide nano-drug carrier is negative, the negative potential is beneficial to the dispersion of the nano-drug carrier, the size is 100-150 nm, the size distribution is uniform and the dispersion is uniform, and the circulation in organisms is facilitated.
4) The invention can effectively combine the photodynamic and photothermal treatment effects of the hollow mesoporous copper sulfide material with the chemotherapy of the adriamycin medicine, thereby enhancing the photodynamic; the prepared liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-medicament has little toxicity to normal liver cells and strong toxicity to liver cancer tumor cells, and can realize the photo-thermal/photodynamic/chemotherapy combined treatment of tumors.
5) The preparation method has the characteristics of simple operation, high safety, mild reaction conditions, controllable reaction process and low cost, and the prepared hollow mesoporous copper sulfide nano-drug carrier has good hydrophilicity, small size, specific targeting and low reagent toxicity, and is beneficial to in vivo circulation.
Drawings
FIG. 1 shows the products E (HMCuS) (a) and G (HMCuS-NH) of example 1 2 Transmission Electron Microscopy (TEM) images of @ DOX) (b) and product I (HMCD 9P) (c);
FIG. 2 shows the results of example 1, product E (HMCuS), product F (HMCuS-NH) 2 ) Product G (HMCuS-NH) 2 @ DOX) and product I (HMCD 9P);
FIG. 3 shows the products E (HMCuS) and F (HMCuS-NH) of example 1 2 ) Product G (HMCuS-NH) 2 The Zeta potential maps of @ DOX), the 9R-P201 peptide and product I (HMCD 9P);
FIG. 4 shows the product E (HMCuS) and the product F (HMCuS-NH) of example 1 2 ) An infrared spectrum of (1);
FIG. 5 is the EDS diagram of product E (HMCuS) from example 1;
FIG. 6 is a graph of the in vitro release of product I (HMCD 9P) from example 1 at various pHs and with or without laser irradiation;
FIG. 7 is a graph showing the experimental hemolysis rate of product I (HMCD 9P) in example 1;
FIG. 8 shows the laser intensity of 808 nm (1W/cm) of product I (HMCD 9P) of example 1 2 ) Irradiating for 8 min at different concentrations for temperature change graph (a) and irradiating for product I (HMCD 9P) at 100 μ g/mL for 8 min at 808 nm for temperature change graph (b) at different powers;
FIG. 9 shows the laser intensity at 808 nm (1W/cm) of product I (HMCD 9P) of example 1 2 ) Irradiating for 5 min to obtain infrared thermal imaging images with different concentrations;
FIG. 10 shows the product I (H) from example 1MCD 9P) at 808 nm (1W/cm) 2 ) Temperature profile over 5 laser on/off cycles with 100 μ g/mL of down-irradiation;
FIG. 11 is a graph showing the survival rate of HePG2 cells of product E (HMCuS) before and after the presence or absence of laser irradiation in example 1 (a), product G (HMCuS-NH) 2 Graph of survival of HePG2 cells with and without laser irradiation for product I (HMCD 9P), and doxorubicin (b);
FIG. 12 is an imaging plot of product I (HMCD 9P) from example 1 ex vivo on the major organs of H22 tumor-bearing mice;
FIG. 13 shows the results of example 1, wherein the product I (HMCD 9P) was applied to H22 tumor-bearing mice on a 808 nm laser (1W/cm) 2 ) Irradiating for 5 min, and imaging in vivo with infrared heat;
FIG. 14 shows the results of example 1, product E (HMCuS), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and doxorubicin at the end of treatment of H22 tumor-bearing mice with or without laser irradiation (a) representative photographic images of the different groups, (b) digital images of the tumor tissue, (c) a graph of the change in mouse body weight, (d) a graph of tumor growth, and (e) a graph of the change in tumor weight;
FIG. 15 shows the products E (HMCuS) and G (HMCuS-NH) of example 1 2 @ DOX), product I (HMCD 9P) and doxorubicin are dissected for staining patterns of hind Heart Heart, liver Live, spleen Spleen, lung Lung, kidney Kidney tissue sections HE when treatment of H22 tumor-bearing mice is finished before and after laser irradiation;
FIG. 16 shows the results of example 1, product E (HMCuS), product G (HMCuS-NH) 2 @ DOX), product I (HMCD 9P) and doxorubicin the HE staining and TUNEL staining profile of the dissected tumor tissue sections at the end of treatment of H22 tumor-bearing mice with or without laser irradiation.
Detailed Description
For a further understanding of the invention, reference should be made to the following detailed description taken in conjunction with the accompanying drawings, which are included to further illustrate the features and advantages of the invention, and are not intended to limit the scope of the invention.
Name and model of the experimental instrument:
U.S. Perkin-Elmer Lambda-850 UV Spectrophotometer;
japanese JEOL JEM-200CX transmission electron microscope;
a BioTek multifunctional microplate reader;
LEICA TCS SP8+ STED laser confocal microscopy, germany;
BD facverse flow cytometer in usa;
laboconco-FreeZone 6L freeze-drying system, usa;
an ultrasensitive multifunctional imager of American Cytiva and AI800 flours;
unless otherwise specified, room temperature refers to 25 ± 5 ℃.
Example 1
A preparation method and application of a hollow mesoporous copper sulfide nano-drug carrier. The preparation method of the embodiment comprises the following steps:
And 2, adding 26 mu L of 50% hydrazine hydrate solution into the product A, and stirring for 5 min to obtain a product B.
And 3, adding 50mL of a sodium hydroxide solution with the pH =9 into the product B, and stirring for 5 min to obtain a product C.
And 4, adding 400 mu L of 320 mg/mL sodium sulfide nonahydrate solution into the product C, stirring for 5 min, and carrying out oil bath reaction for 2 h at the temperature of 60 ℃ to obtain a product D.
The invention also provides a method for preparing the liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using the nano-drug carrier, which comprises the following steps:
step a, under the condition of room temperature, performing ultrasonic treatment on 200 mL of the product E by using an ultrasonic cell crusher for 25 min, then adding 100 mg of beta-mercaptoethylamine, stirring for 24h under the condition of 1000 rpm, centrifuging for 10 min at 12000 rpm, washing for three times by using ultrapure water, performing freeze drying for 24h under low temperature (-80 ℃) and high vacuum (1 Pa), and re-dissolving by using 200 mL of ultrapure water to obtain a product F (HMCuS-NH) 2 ）。
B, ultrasonically treating 200 mL of the product F with an ultrasonic cell crusher for 25 min at room temperature, placing the product F into a glass round-bottom flask, adding 50 mg of adriamycin (DOX) medicine into the glass round-bottom flask, stirring the product F in the dark at 1000 rpm for 24h, centrifuging the product F at 12000 rpm for 10 min, washing the product F with ultrapure water for three times, freeze-drying the product F at low temperature (-80 ℃) under high vacuum (1 Pa) for 24h, and re-dissolving the product F with 200 mL of phosphate buffer solution with pH =7.4 to obtain a product G (HMCuS-NH) 2 @DOX）。
And c, under the condition of room temperature, putting 50 mg of 9R-P201 peptide (manufacturer: shanghai Qiangyao Biotechnology Co., ltd., number: 04010020031) into phosphate buffer solution with pH =7.4, adding 30 mg of carbodiimide hydrochloride and 23 mg of N-hydroxysuccinimide for activation, and stirring for 30 min to obtain activated 9R-P201 peptide solution H. The 9R-P201 peptide sequence is: AAAAAAAGSGSTHLATPSMTLA.
Step d, placing 200 mL of the product G in a glass round-bottom flask at room temperature, adding the activated 9R-P201 peptide solution H into the glass round-bottom flask, stirring for 24H in the dark at 1000 rpm, centrifuging for 10 min at 12000 rpm, washing for three times with ultrapure water, and freeze-drying for 24H under a high vacuum (1 Pa) at low temperature (-80 ℃). Redissolving with 200 mL of ultrapure water, centrifuging at 12000 rpm for 15 min, washing with ultrapure water for 3 times, and freeze-drying at low temperature under high vacuum for 24h to obtain the hollow mesoporous copper sulfide nano-drug I (HMCuS @ DOX-9R-P201, abbreviated as HMCD 9P) modified by the liver cancer targeting peptide.
Size of TEM image of hollow mesoporous copper sulfide and composite by Transmission Electron Microscopy (TEM)The degree of dispersion was characterized and the results are shown in FIG. 1. From fig. 1 it can be observed that: the prepared hollow mesoporous copper sulfide nano-drug carrier HMCuS is of a hollow mesoporous structure, and the hollow mesoporous structure is clear, small in size, uniform in appearance and 100-150 nm in size (see a in figure 1). In figure 1, b is the product HMCuS-NH after the completion of the doxorubicin loading 2 @ DOX, it can be seen that there are black substances inside the wells, and the success of doxorubicin loading is concluded. In FIG. 1, c is the product HMCD9P after attachment of the 9R-P201 peptide, and a layer of transparent material is seen to wrap around, thus proving the successful modification of the 9R-P201 peptide.
The nanoparticles were scanned at full wavelength using uv absorption spectroscopy and the results are shown in figure 2. As can be seen in fig. 2: HMCuS and HMCuS-NH 2 The ultraviolet absorption is strong in the near infrared region, and the ultraviolet absorption is weak after DOX is loaded and 9R-P201 peptide is connected, probably because DOX is loaded in HMCuS and the modification of the 9R-P201 peptide influences the ultraviolet absorption.
The Zeta potential of the HMCuS nanoparticles and the components of the nanoparticles was studied using a Zeta potential meter, and the results are shown in FIG. 3. As can be seen in fig. 3: the potential value of HMCuS is-13.6 mV; modified amino HMCuS-NH 2 The potential value of (d) was changed to-2.5 mV; after loading DOX, the potential value is changed to 29.7 mV; the potential value was changed to 40.6 mV after the 9R-P201 peptide was attached.
Infrared spectroscopy on HMCuS-NH 2 The characterization results are shown in FIG. 4. The results in FIG. 4 show that: mercaptoethylamine at 2558 cm -1 A characteristic peak of S-H stretching vibration appears; in the presence of HMCuS-NH 2 The characteristic peak of the medium S-H stretching vibration disappears, and the characteristic peak of C-N stretching vibration of the amino at 1210 cm < -1 > appears, thereby proving that the mercaptoethylamine is modified on the HMCuS.
The energy elements of the HMCuS were analyzed by transmission electron microscopy and the results are shown in FIG. 5. Fig. 5 shows: the method detects that Cu and S elements are mainly contained in the sample, and provides a basis for synthesizing the HMCuS.
The in-vitro drug release of the HMCD9P is studied, as shown in fig. 6, after a drug release experiment is carried out for 36 hours, the drug release rate of the HMCD9P in a phosphate buffer solution with pH 5.4 is only 6.1% and 25.5% higher than that of a phosphate buffer solution with pH 6.8 and a phosphate buffer solution with pH 7.4 when no laser irradiation with 808 nm is carried out; and when 808 nm laser is irradiated, the medicine release rate of the corresponding laser group is increased compared with that of a non-laser group. It is worth noting that the release rate of the phosphate buffer solution with pH 5.4+ L is up to 51.3% and 70.7% compared with the phosphate buffer solution with pH 6.8 and the phosphate buffer solution with pH 7.4. The result shows that the amide bond of the HMCD9P nano-drug is broken under the slightly acidic environment, and then the hole of the hollow mesoporous material is opened to release the drug, thereby achieving the purpose of dual-stimulation response type drug release. Wherein, the pH sensitive drug release characteristic of the DOX is that the acidic environment causes the protonation of the amino group in the DOX structure to cause the breakage of hydrogen bonds, thereby promoting the drug release; in addition, under the irradiation of near-infrared laser, the HMCuS generates heat, so that the viscosity of a surrounding medium is reduced, and the diffusion of the medicine is promoted. Therefore, after the nano-drug specifically targets liver cancer tumor cells, the release of DOX is promoted in an acidic environment and by external near-infrared laser irradiation. The dual stimulus response type drug release characteristic can enhance the anti-tumor effect of the drug at the tumor part.
Fig. 7 is a safety experiment of the hollow mesoporous copper sulfide nano-drug product I, and fig. 7 can see that: the hemolysis rate of HMCD9P NPs (NPs refer to nanoparticles, the same applies below) at 800 μ g/mL is still less than 5%, which indicates that the safety of the whole system is higher.
Preparing the obtained hollow mesoporous copper sulfide nano-drug product I into solutions with different concentrations by using water, and then using the solution with the particle size of 808 nm and the particle size of 1W/cm 2 The variation of the solution temperature is recorded by an FLIR thermal imaging instrument to obtain the temperature variation curve chart of the hollow copper sulfide nano-drug product I in the aqueous solution. As can be observed from FIG. 8, the graph of the concentration change of (a) shows that the hollow mesoporous copper sulfide nano-drug carrier is subjected to 808 nm laser (1W/cm) when the concentration change is 100 mug/mL 2 ) Irradiating for 8 min to raise the temperature to about 52 deg.C; (b) Shows the power change pattern of (D) at 808 nm laser (1W/cm) when 100. Mu.g/mL 2 ) The temperature can be raised to about 52 ℃ after the lower irradiation for 8 min; tumor cells can be killed, corresponding to the concentration change chart. Therefore, the photothermal conversion property of the hollow mesoporous copper sulfide nano drug carrier proves that the hollow mesoporous copper sulfide nano drug carrier can be used as an excellent photothermal material for tumor photothermal treatment.
FIG. 9 shows the concentrations (0, 10,25. 50, 100 and 200. Mu.g/mL) of HMCD9P NPs solution received 1W/cm 2 After 5 min of laser irradiation, the temperature rose rapidly. The results show that the HMCD9P NPs have excellent photothermal performance and can be used for anti-tumor treatment through photothermal therapy.
Fig. 10 is a graph for evaluating photo-thermal stability of nano-drugs through a plurality of laser on/off processes. In each cycle, the nano-drug solution is irradiated by laser for 5 min, and is naturally cooled to room temperature after the laser is turned off. The on/off cycles were repeated 5 times and the temperature profile was recorded during these cycles by plotting the temperature versus irradiation time. The results demonstrate that the photo-thermal stability of HMCD9P NPs is good.
In vitro cell inhibition
And (3) detecting the toxicity of the hollow mesoporous copper sulfide nano-drug carrier on tumor cells by using an MTT (methyl thiazolyl tetrazolium) experiment.
Using MTT method to treat DOX, HMCuS and HMCuS-NH 2 And @ DOX and HMCD9P NPs are used for in vitro tumor activity detection. HePG2 in a good culture state is paved on cells at the bottom of a culture dish, the cells are firstly digested by pancreatin, centrifuged by a centrifugal machine, supernatant liquid is sucked out, 1 mL of culture medium (DMEM culture medium containing 1% of streptomycin, 10% of fetal calf serum and the same below) is added for uniformly blowing the cells, a proper amount of cell suspension is taken for dilution, the number of the cells in each hole is about 4500, and the cells are inoculated into a 96-well plate and cultured for 24 hours. Adding DOX, HMCuS and HMCuS-NH 2 The @ DOX and HMCD9P NPs are diluted to different concentrations by culture medium, placed in test tubes for standby, each concentration contains 4 side wells, and a blank control group without inoculated cells and a negative control group without medicine are set for 24 hours of action. The laser control group experiments are divided into 8 groups, namely DOX group, DOX + L group, HMCuS + L group and HMCuS-NH group 2 @ DOX group, HMCuS-NH 2 @ DOX + L group, HMCD9P NPs + L group, the laser group used 808 nm laser (1W/cm) 4h after administration 2 5 min), and continuing to culture for 24 h; the non-laser group was incubated for 24h after dosing. Adding 50 muL 1 mg/mL MTT solution into each hole for acting for 4h, throwing a plate, adding 100 muL DMSO into each hole, shaking the table for 10 min, and measuring the light absorption value A at 570 nm by using a multifunctional microplate reader; by the formula: cytostatic rate × 100% = (average OD value in negative group)-average OD value of experimental group)/(average OD value of negative group-average OD value of blank group), calculating the inhibition rate of each concentration of sample on cells, calculating the corresponding IC with software 50 The value is obtained.
As can be seen from FIG. 11, the results of the proliferation rate of HePG2 cells indicate that the cell survival rate of the HMCuS NPs group is as high as about 50% at a concentration of 500. Mu.g/mL, indicating that the vector has little toxicity to HePG2 cells. Therefore, the HMCuS NPs are nano materials with high biological safety. Next, it was examined whether or not the product G (HMCuS-NH) was irradiated with laser light 2 @ DOX), product I (HMCD 9P) and DOX, toxicity to HePG2 cells, cell proliferation rate of each group is reduced under laser irradiation, and the phototherapy (thermal therapy and photodynamic therapy) effect is remarkable. Wherein HMCuS-NH 2 The @ DOX + L has higher cell proliferation rate than HMCD9P NPs + L, and is presumed to be caused by that the 9R-P201 peptide modified nanoparticle promotes the uptake of cells. In addition, both phototherapy and chemotherapy reduce the rate of cell proliferation, but do not achieve the desired therapeutic effect. While the HMCD9P NPs + L group greatly reduces the cell proliferation rate to 12.35 percent, and shows higher cytotoxicity. The reason is mainly that the HMCD9P NPs group carries out phototherapy (thermal therapy and photodynamic therapy) through near-infrared laser irradiation, and the phototherapy and the DOX chemotherapy effect are cooperated to inhibit tumors, so that the liver cancer is treated by the combination therapy.
In vivo tumor treatment
To evaluate the in vivo biodistribution of the hollow mesoporous copper sulfide nano-drug product I (HMCD 9P), HMCD9P NPs were injected into H22 mice via tail vein (administration dose: 5mg/kg mouse body weight), and after 1, 2, 4, 6, 8, 12, 24H injection, the mice were dissected for hearting Heart, liver Live, spleen spenen, lung, kidney and Tumor for fluorescence imaging, and the results are shown in fig. 12. As shown in fig. 12, the imaging result shows: after HMCD9P NPs are injected, the fluorescence signal of the tumor part is gradually enhanced, the fluorescence signal reaches the maximum value after 6 hours of injection, and the fluorescence begins to be weakened at 8 hours. The time-dependent enhancement of the fluorescence signal at the tumor site may be attributed to HMCD9P NPs through EPR effect and active specific targeting of the liver cancer. Liver and kidney also have fluorescence due to metabolism, but organs such as heart, spleen, lung and the like have no obvious fluorescence signals, which shows that the multifunctional nano-drug carrier can specifically deliver nano-drugs and has low toxicity of the whole body.
In order to further study the in vivo anti-tumor effect of the hollow mesoporous copper sulfide nano-drug product I (HMCD 9P), a BALB/c mouse subcutaneous transplantation tumor model is constructed by selecting H22 cells, and the anti-tumor effect of the nano-drug is studied by tail vein injection and laser control. 2 mice were selected for intravenous injection of different formulations (Saline group normal Saline, HMCD9P NPs). Using 808 nm laser (1W/cm) 24h after intravenous injection 2 5 min), performing in vivo thermal imaging by using an infrared thermal imaging instrument, and detecting the temperature change in real time, wherein the result is shown in figure 13. As shown in fig. 13, the temperature rapidly increased to 57.8 ℃ at the tumor of HMCD9P NPs injected mice during 5 min of laser irradiation. The rapid temperature rise may be due to the specific targeting of the nanoparticles and the high photothermal effect of HMCuS. The thermal imaging result shows that the HMCD9P NPs have good photothermal performance and can be used for tumor thermotherapy.
In addition, the mice were randomly divided into 7 groups of 5 mice each. A BALB/c mouse subcutaneous transplantation tumor model is constructed by using H22 cells, and the anti-tumor effect of the nano-drug is researched by tail vein injection (5 mg/kg mouse body weight) in combination with laser control. The tumor size of the mice was observed every day until the tumor volume was about 100 mm 3 In this case, 7 groups of mice were administered separately. Respectively, the control group (normal saline), (2) HMCuS group, (3) HMCuS + L group, (4) positive drug DOX, (5) positive drug DOX + L group, (6) HMCD9P NPs group, (7) HMCD9P NPs + L group. The preparation is administered every other day for seven times, and the body weight and tumor volume of mice are measured while the preparation is administered, and 808 nm laser (1W/cm) is used every other day 2 5 min) irradiated the tumor area. The tumor volume of the mice was calculated as V = W2 × L/2 (V represents tumor volume, W represents tumor minor diameter, and L represents tumor major diameter), and the results are shown in fig. 14.
After 7 administrations, as shown in fig. 14, the weight gains of the mice in the HMCuS group, HMCuS + L group, HMCD9P NPs + L group and the control group were similar, while the weight of the mice decreased significantly due to the positive drug DOX and the positive drug DOX + L group, which probably prevented the normal growth of the mice due to the side effect of the positive drug toxicity.Compared with a control group, the HMCD9P NPs group and the HMCD9P NPs + L group have obvious inhibition effects on tumor growth, wherein the HMCD9P NPs + L group has the best inhibition effect, the tumor weight of the HMCD9P NPs + L group is only 0.098 g, the tumor volume of the mouse is far lower than that of the control group 0.832 g, the DOX group 0.351 g and the HMCD9P NPs + L group is only 131.28 mm 3 398.83 mm far lower than that of the control group 3 And DOX group 207.13 mm 3 And the tumor inhibition rate reaches 88.2 percent, which shows that the nano-drug HMCD9P can better inhibit the growth of tumors under the laser irradiation condition.
Hematoxylin-eosin (HE) staining was performed on tumor tissue and heart, liver, spleen, lung, kidney tissue sections, and tissue damage was observed using a fluorescence microscope. The hematoxylin dye is alkaline, and mainly makes chromatin in cell nucleus and ribosome in cytoplasm be violet blue; eosin is an acid dye that primarily causes components in the cytoplasm and extracellular matrix to appear red. The experimental results of fig. 15 show: compared with organs of a control group, the organs treated by the nano-drug HMCD9P, the nano-drug HMCD9P + L, the nano-carrier material HMCuS and the nano-carrier material HMCuS + L have no obvious change, which shows the biological safety of the nano-drug and the nano-material. However, liver, spleen and kidney tissues of free DOX and DOX + L were slightly damaged, indicating that DOX is toxic to mice. The results further confirm that the multifunctional nano-drug carrier synthesized by the application has good biocompatibility in organisms.
FIG. 16 is a H & E stained paraffin section of a tumor control group, which shows dense arrangement of tumor cells and a large amount of stroma inside. Compared with the control group, the tumor tissue section of the free DOX group can see partial tumor cell vacuole formation, but the tumor cell density is similar to that of the control group. However, in the tumor tissue sections of the nano-drug HMCD9P NPs + L treatment group, a large amount of vacuolation can be observed, and typical cell apoptosis morphological characteristics such as cytoplasm loss, nuclear chromatin contraction or fragmentation can be observed. TUNEL detects apoptosis in tumor tissues and can see: the HMCD9P NPs + L positive fluorescence signal is strongest. These morphological changes indicate that the anticancer effect of the nano-drug HMCD9P NPs + L is more significant, so that a large number of tumor cells in tumor tissues are killed.
In conclusion, the hollow mesoporous copper sulfide nano-drug carrier prepared by the invention has good hydrophilicity, high safety, small size and specific targeting effect on liver cancer. According to the application, the near-infrared light response nano-material hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) are firstly synthesized, and the chemotherapeutic drug Doxorubicin (DOX) is encapsulated by utilizing the unique cage-shaped structure of the hollow mesoporous copper sulfide nanoparticles, so that the drug loading capacity is greatly improved. Then, the outer surface of the HMCuS NPs is modified by liver cancer targeting peptide 9R-P201 peptide to obtain the hollow mesoporous copper sulfide nano-drug HMCuS @ DOX-9R-P201 (HMCD 9P) with liver cancer targeting, and finally the combined treatment effect of nano-drug chemotherapy, photo-thermal and photodynamic treatment is realized. In vitro and in vivo studies, the nano-drug HMCD9P actively targets into HepG2 cells via liver cancer cell surface-specific receptor-mediated endocytosis, and subsequently triggers release of the drug in the Tumor Microenvironment (TME). Under irradiation with Near Infrared (NIR) light, HMCD9P is not only effective in converting near infrared light into heat for photothermal therapy, but also produces high levels of Reactive Oxygen Species (ROS) for photodynamic therapy. In tumor-bearing mouse experiments, in near infrared light (808 nm, 1W/cm) 2 5 min) the HMCD9P NPs + L group treated tumor-bearing mice showed a tumor inhibition rate of about 88.2%. Therefore, the HMCD9P developed by the invention has great potential, can be used as a nano therapeutic agent for efficiently and accurately inducing chemotherapy, photo-thermal and photodynamic therapy, and has excellent anti-tumor effect and smaller side effect.
Claims (3)
1. A method for preparing a liver cancer targeting peptide modified hollow mesoporous copper sulfide nano-drug by using a nano-drug carrier is characterized by comprising the following steps:
step a, performing ultrasonic treatment on the product E at room temperature, adding a mercapto-containing coating, stirring for 2-48 h, centrifuging, washing, freeze-drying, and re-dissolving with ultrapure water to obtain a product F; wherein the mass ratio of the mercapto group-containing coating to the blackish brown solid in the product E is 1-3: 1;
b, performing ultrasonic treatment on the product F at room temperature, adding an adriamycin medicament, stirring for 2-48 h in the dark, centrifuging, washing, freeze-drying, and redissolving by using a phosphate buffer solution to obtain a product G; wherein the mass ratio of the black brown solid in the adriamycin medicine and the product E is 1-3: 1;
step c, placing the 9R-P201 peptide into a phosphate buffer solution with the pH value of 7-9 at room temperature, adding carbodiimide hydrochloride and N-hydroxysuccinimide, and stirring for 20-40 min to obtain an activated 9R-P201 peptide solution H; wherein the mass ratio of the 9R-P201 peptide to the carbodiimide hydrochloride to the N-hydroxysuccinimide is 1: 0.3-0.7:0.3-0.7;
d, mixing the product G with the activated 9R-P201 peptide solution H at room temperature, stirring for 12-48H in a dark place, centrifuging, washing, and freeze-drying to obtain the compound; wherein the mass ratio of the 9R-P201 peptide to the adriamycin is 1: 1-3;
in the step c, the sequence of the 9R-P201 peptide as the liver cancer targeting peptide is as follows: AAAAAAAAAGSGSTHLATPSMTTLA;
the nano-drug carrier is prepared by the following steps:
step 1, dispersing a copper chloride dihydrate solution with the concentration of 0.4-0.6mol/L and polyvinylpyrrolidone in water at room temperature to obtain a mixed solution A; in the mixed solution A, the concentration of polyvinylpyrrolidone is 5-15 mg/mL, and the concentration of copper chloride dihydrate is 0.1-0.3 mg/mL;
step 2, adding a 50% hydrazine hydrate solution into the mixed solution A, and stirring to obtain a mixed solution B; wherein the volume ratio of the copper chloride dihydrate solution to the hydrazine hydrate solution is 1: 0.1-0.3;
step 3, adding a sodium hydroxide solution with the pH =9 into the mixed solution B, and stirring to obtain a mixed solution C; wherein the volume ratio of the copper chloride dihydrate solution to the sodium hydroxide solution is 1: 400-600;
step 4, adding 310-330 mg/mL sodium sulfide nonahydrate solution into the mixed solution C, stirring, and performing oil bath reaction for 1-4 h at the temperature of 30-90 ℃ to obtain a mixed solution D; wherein the volume ratio of the copper chloride dihydrate solution to the sodium sulfide nonahydrate solution is 1: 3-5;
step 5, centrifuging and washing the mixed solution D at room temperature, and freeze-drying to obtain a dark brown solid; dispersing the dark brown solid in water to obtain a product E, namely the nano-drug carrier; the solid-liquid ratio of the product E is 1: 3000-5000.
2. The method for preparing the hollow mesoporous copper sulfide nano-drug modified by the liver cancer targeting peptide by using the nano-drug carrier according to claim 1, wherein in the step a, the mercapto group-containing coating comprises beta-mercaptoethylamine, mercaptopropionic acid or thioglycolic acid.
3. The method for preparing the hollow mesoporous copper sulfide nano-drug modified by the liver cancer targeting peptide by using the nano-drug carrier as claimed in claim 1, wherein in the step 1, the molecular weight of the polyvinylpyrrolidone is 50000-60000 Da.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210695944.XA CN114873629B (en) | 2022-06-20 | 2022-06-20 | Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210695944.XA CN114873629B (en) | 2022-06-20 | 2022-06-20 | Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114873629A CN114873629A (en) | 2022-08-09 |
| CN114873629B true CN114873629B (en) | 2022-12-27 |
Family
ID=82682090
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210695944.XA Active CN114873629B (en) | 2022-06-20 | 2022-06-20 | Preparation method and application of hollow mesoporous copper sulfide nano-drug carrier |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114873629B (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6283177B2 (en) * | 2012-09-06 | 2018-02-21 | 松本油脂製薬株式会社 | Hollow particles and adhesive composition containing the same |
| CN105056243B (en) * | 2015-07-22 | 2017-11-14 | 郑州大学 | A kind of pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow and preparation method and application |
| CN105126113B (en) * | 2015-08-31 | 2018-10-23 | 郑州大学 | A kind of preparation method and applications of hollow mesoporous copper sulfide/Artesunate nanoparticle of Surface-modified by Transferrin |
| CN108324955B (en) * | 2018-01-26 | 2021-03-19 | 东华大学 | Preparation method of ultra-small copper sulfide loaded hollow mesoporous silicon targeted nano drug-loaded compound |
| CN110384799A (en) * | 2019-08-26 | 2019-10-29 | 同济大学 | PH responsiveness composite nano materials, preparation based on hollow copper sulfide and ruthenium complex and its application in treating cancer drug |
| CN113082213A (en) * | 2021-03-10 | 2021-07-09 | 武汉科技大学 | Hollow copper sulfide nano-drug carrier, preparation method and application |
| CN112850779A (en) * | 2021-03-12 | 2021-05-28 | 南京师范大学 | Hollow Cu7S4Nano cubic structure and preparation method and application thereof |
| CN113376132A (en) * | 2021-06-07 | 2021-09-10 | 青岛科技大学 | Mesoporous-based copper sulfide composite material, preparation method and detection method |
-
2022
- 2022-06-20 CN CN202210695944.XA patent/CN114873629B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114873629A (en) | 2022-08-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tang et al. | An aza-BODIPY photosensitizer for photoacoustic and photothermal imaging guided dual modal cancer phototherapy | |
| Liu et al. | Functionalized poly (pyrrole-3-carboxylic acid) nanoneedles for dual-imaging guided PDT/PTT combination therapy | |
| Gulzar et al. | Nano-graphene oxide-UCNP-Ce6 covalently constructed nanocomposites for NIR-mediated bioimaging and PTT/PDT combinatorial therapy | |
| Chen et al. | A theranostic nrGO@ MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor | |
| Yang et al. | Indocyanine green-modified hollow mesoporous Prussian blue nanoparticles loading doxorubicin for fluorescence-guided tri-modal combination therapy of cancer | |
| Rong et al. | Protein-based photothermal theranostics for imaging-guided cancer therapy | |
| Dong et al. | A self-assembled carrier-free nanosonosensitizer for photoacoustic imaging-guided synergistic chemo–sonodynamic cancer therapy | |
| Liu et al. | A near infrared-modulated thermosensitive hydrogel for stabilization of indocyanine green and combinatorial anticancer phototherapy | |
| Liu et al. | In vivo 808 nm image-guided photodynamic therapy based on an upconversion theranostic nanoplatform | |
| CN108888767B (en) | Nano composite material, preparation method and application thereof | |
| Liu et al. | IR780-based light-responsive nanocomplexes combining phase transition for enhancing multimodal imaging-guided photothermal therapy | |
| Ji et al. | Activatable photodynamic therapy for prostate cancer by NIR dye/photosensitizer loaded albumin nanoparticles | |
| CN110215438B (en) | Preparation method and application of mesoporous silicon nanoparticles carrying anthracyclines and photosensitizers | |
| Liu et al. | Carbon nanocage-based nanozyme as an endogenous H 2 O 2-activated oxygenerator for real-time bimodal imaging and enhanced phototherapy of esophageal cancer | |
| Sun et al. | MnO 2 nanoflowers as a multifunctional nano-platform for enhanced photothermal/photodynamic therapy and MR imaging | |
| Li et al. | Dual-modal imaging-guided highly efficient photothermal therapy using heptamethine cyanine-conjugated hyaluronic acid micelles | |
| Lv et al. | Degradable magnetic-response photoacoustic/up-conversion luminescence imaging-guided photodynamic/photothermal antitumor therapy | |
| Wang et al. | Tumor-targeting multi-shelled hollow nanospheres as drug loading platforms for imaging-guided combinational cancer therapy | |
| Liu et al. | Combined photothermal–photodynamic therapy by indocyanine green loaded polydopamine nanoparticles enhances anti-mammary gland tumor efficacy | |
| Peng et al. | Polymer-directed supramolecular assembly of photosensitizers: Evocation of photothermal effect and highly efficient loading of disulfiram for chemo-phototherapy of cancer | |
| Gao et al. | Shifting the absorption to the near-infrared region and inducing a strong photothermal effect by encapsulating zinc (II) phthalocyanine in poly (lactic-co-glycolic acid)-hyaluronic acid nanoparticles | |
| CN113559064A (en) | Novel self-oxygen-supply liposome nanoparticle and preparation method and application thereof | |
| Zou et al. | Novel NIR-II semiconducting molecule incorporating sorafenib for imaging guided synergetic cancer phototherapy and anti-angiogenic therapy | |
| Zeng et al. | Highly efficient Chemo/Photothermal therapy alleviating tumor hypoxia against cancer and attenuate liver metastasis in vivo | |
| Shen et al. | A biodegradable nano-photosensitizer with photoactivatable singlet oxygen generation for synergistic phototherapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |