CN115583990B - Responsive small molecular peptide, nano drug carrier and application - Google Patents
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Abstract
The invention discloses a responsive small molecular peptide, a nano drug carrier and application thereof, and belongs to the technical field of design and preparation of small molecular peptide drug delivery platforms. The responsive small molecule peptide has glutathione responsiveness and can be used as a nano drug carrier. The responsive small molecule peptide can specifically respond to the glutathione with up-regulated expression in tumor cells; from the aspect of raw material selection, the responsive small molecular peptide is self-assembled to form spherical nano-particles after drug loading in Hepes buffer solution at room temperature, wherein the spherical nano-particles contain responsive sensitive groups and can be converted into nano-fibers under the induction of glutathione, and meanwhile, self-supporting hydrogel is formed to release model drugs loaded in core and pericardium; can prolong the residence time of the medicine, reduce the toxic and side effects of the medicine and improve the utilization rate of the medicine.
Description
Technical Field
Belongs to the technical field of design and preparation of small molecular peptide drug delivery platforms, and in particular relates to a responsive small molecular peptide, a nano drug carrier and application.
Background
Drug carriers based on Enhanced Permeability and Retention (EPR) effects have passive targeting effects. In addition, RGD peptides specifically bind integrin αvβ6, and can be used as an active targeted drug delivery strategy for tumors. The targeting design can help the drug target tumor cells. However, multi-drug resistant proteins such as P-glycoprotein (P-gp) can pump drugs out of cells through reverse concentration gradients, reducing intratumoral accumulation of chemotherapeutic drugs. Common drugs for P-gp substrates include DOX. Because the metabolism of the tumor cells is abnormal, the concentration of Glutathione (GSH) in the intracellular microenvironment of the tumor cells is 2-10mmol/L, which is at least 4 times of that of normal cells, so that disulfide bonds are introduced into the drug carrier and the high expression of GSH in the tumor cells is utilized, the transformation of the morphology of the peptide nano carrier is expected to be induced, and the retention time of the drug in the tumor cells is improved.
Disclosure of Invention
The invention provides a responsive small molecular peptide, a nano drug carrier and application thereof.
The invention aims at realizing the following technical scheme:
the small molecular peptide has glutathione responsiveness, can be used as a nano drug carrier, and has the structural formula as follows:
the invention can also be realized by the following technical scheme:
the application of the responsive small molecular peptide as a nano drug carrier is characterized in that the responsive small molecular peptide is glutathione responsive small molecular peptide which can be used as the nano drug carrier, and the responsive small molecular peptide is self-assembled in Hepes buffer solution to form spherical nanoparticles after drug loading, so as to encapsulate the antitumor drug.
The invention can also be realized by the following technical scheme:
a nano medicine carrier contains glutathione responsive small molecular peptide as nano medicine carrier.
Preferably, the nano medicine carrying carrier responds to glutathione in tumor cells, the self-assembled morphology is converted into nano fibers, self-supporting hydrogel is formed, and the residence time of medicine in the tumor cells is prolonged; the concentration of the glutathione is 2-10mmol/L.
The invention can also be realized by the following technical scheme:
a method for preparing a nano drug carrier, which comprises the following steps: adding glutathione-responsive small molecular peptides and anti-tumor drugs into Hepes buffer solution together, and self-assembling the glutathione-responsive small molecular peptides to form drug-loaded spherical nanoparticles.
Preferably, the pH of the Hepes buffer is 7.4, and the concentration of the glutathione-responsive small molecule peptide is 4-20mg/mL.
Preferably, the concentration of the glutathione-responsive small molecule peptide is 10mg/mL.
Preferably, the preparation method of the nano drug carrier comprises the following steps: adding 1/5 of anti-tumor drug DOX into a glutathione responsive small molecular peptide solution with the concentration of 4-20mg/mL according to the mass ratio, vibrating and mixing uniformly, and standing at room temperature for 24 hours to obtain the nano drug carrier.
In this work we constructed an RGD modified peptide drug delivery vehicle for drug nanocarriers targeting tumor cells, helping to release encapsulated anti-tumor drugs into tumor cells. In the presence of GSH highly expressed in tumor cells, the nano-drug delivery system is converted from a responsive small molecular peptide solution state to a responsive small molecular peptide hydrogel, so that the intracellular residence time of the encapsulated drug is prolonged, the drug outflow is reduced, the treatment effect of the chemotherapeutic drug is enhanced, and the toxic and side effects of the drug on normal cells are reduced.
Advantageous effects
First: the glutathione responsive small molecular peptide adopts a solid phase synthesis technology, and the technology has the advantages of high yield, few intermediate products, simplicity in operation and the like; second,: the glutathione responsive small molecular peptide can self-assemble to form spherical nano particles at room temperature after drug loading, and the spherical nano particles have stable properties and can be stored for a long time; third,: the drug targeted delivery platform contains GSH sensitive groups, and the selective targeting effect of RGD peptide is utilized to enhance the drug intake of tumor tissues by utilizing the EPR effect of the nano particles; fourth,: the responsive small molecular peptide nano drug carrier is converted into nano fiber under the induction of GSH with up-regulated tumor cell expression, and the responsive small molecular peptide solution is converted into responsive small molecular peptide hydrogel, so that the intratumoral residence time of the drug entrapped can be prolonged.
The drug targeted delivery carrier of the invention has the greatest difference from the prior art that: GSH that can be specifically responsive to up-regulated expression in tumor tissue; the raw materials are convenient to select, and the responsive small molecular peptide is self-assembled in Hepes buffer solution at room temperature after drug loading to form spherical nano particles with stable properties; the preparation method comprises the steps that a GSH sensitive group with specific response is contained, under the induction of GSH with up-regulated expression of tumor cells, spherical nano particles can be converted into nano fibers, a small molecule peptide solution with release response is converted into self-supporting hydrogel, and a model drug carried by core package is formed and released; can prolong the residence time of the medicine, reduce the toxic and side effects of the medicine and improve the utilization rate of the medicine.
Drawings
FIG. 1 is a structural formula of a responsive small molecule peptide;
FIG. 2 is an RP-HPLC chromatogram of a responsive small molecule peptide;
FIG. 3 is an optical photograph of a responsive small molecule peptide (4 mg/mL) entrapped in Hepes solution (pH 7.4) with anti-tumor model drug DOX;
FIG. 4 is an optical photograph of a responsive small molecule peptide (10 mg/mL) entrapped in Hepes solution (pH 7.4) with anti-tumor model drug DOX;
FIG. 5 is an optical photograph of a responsive small molecule peptide (20 mg/mL) entrapped in Hepes solution (pH 7.4) with anti-tumor model drug DOX;
FIG. 6 is a graph of self-assembled morphology of a responsive small molecule peptide (4 mg/mL) after entrapment of anti-tumor model drug DOX in Hepes solution (pH 7.4) with a scale of 100nm observed by transmission electron microscopy;
FIG. 7 is a graph of self-assembled morphology of a responsive small molecule peptide (10 mg/mL) after entrapment of anti-tumor model drug DOX in Hepes solution (pH 7.4) with a scale of 100nm observed by transmission electron microscopy;
FIG. 8 is a graph of self-assembled morphology of a responsive small molecule peptide (20 mg/mL) after entrapment of anti-tumor model drug DOX in Hepes solution (pH 7.4) with a scale of 100nm observed by transmission electron microscopy;
FIG. 9 is an optical photograph of drug-loaded (DOX) responsive small molecule peptide (4 mg/mL) after addition of GSH (2 mmol/L);
FIG. 10 is an optical photograph of drug-loaded (DOX) responsive small molecule peptide (10 mg/mL) after addition of GSH (5 mmol/L);
FIG. 11 is an optical photograph of drug-loaded (DOX) responsive small molecule peptide (20 mg/mL) after addition of GSH (10 mmol/L);
FIG. 12 is a self-assembled morphology of drug-loaded (DOX) responsive small molecule peptide (4 mg/mL) after GSH (2 mmol/L) addition, scale bar 100nm;
FIG. 13 is a self-assembled morphology of drug-loaded (DOX) responsive small molecule peptide (10 mg/mL) after GSH (5 mmol/L) addition, scale bar 100nm;
FIG. 14 is a self-assembled morphology of drug-loaded (DOX) responsive small molecule peptide (20 mg/mL) after addition of GSH (10 mmol/L), scale bar 100nm;
FIG. 15 is a graph showing particle size of drug-loaded (DOX) responsive small molecule peptide (10 mg/mL) prior to addition of GSH (5 mmol/L);
FIG. 16 is particle size of drug-loaded (DOX) responsive small molecule peptide (10 mg/mL) after addition of GSH (5 mmol/L);
FIG. 17 is a rheological analysis of drug-loaded (DOX) responsive small molecule peptides (10 mg/mL) forming hydrogels upon addition of GSH (5 mmol/L);
FIG. 18 is drug release behavior of drug-loaded (DOX) responsive small molecule peptide (10 mg/mL) after addition of GSH (5 mmol/L);
FIG. 19 is a flow cytometer used to detect DOX, DOX/peptide uptake in tumor cells;
FIG. 20 is a graph showing the detection of DOX and DOX/peptide retention in tumor cells using a confocal laser microscope.
Detailed Description
The invention is described in further detail below in connection with specific examples, but is not intended to limit the scope of the invention as claimed.
Firstly, the specification and model of main experimental instruments selected by the invention are briefly described, and the following experimental instruments can be purchased through commercial channels:
reduced GSH (98%)
Microwave auxiliary polypeptide synthesizer (Liberty Blue type)
Reverse high performance liquid chromatograph (UltiMate 3000 type)
High-speed refrigerated centrifuge (CF 16RXII type)
Ultrasonic cleaning machine (KQ-200 KDE type)
Clean bench (SR-DJ-2F type)
PH meter (HI 8424 and HI1330 type)
Freeze dryer (GSHha 1-2LD plus type)
Electronic balance (AL 204 type)
Pipettor (Reserch plus type)
Cell incubator (HERACELL 150i type)
Enzyme label instrument (Spectra Max M2 e)
Transmission electron microscope (HT 7700 type)
Zetasizer Nano (ZS 90 type)
Desk type refrigerated centrifuge (5810R type)
Ultra-clean bench (Airtech type)
Disposable cell culture flask (25 cm, costar type)
Disposable cell culture plate (goods No. 3599, costar type)
Disposable cell culture plate (goods No. 3548, costar type)
Liquid nitrogen container (YDS-30-125 type).
Example 1: preparation and self-assembly morphology of drug-loaded responsive small molecule peptide
The responsive small molecule peptide is synthesized by a solid phase synthesis method by using a microwave polypeptide synthesizer, and the structural formula is shown in figure 1. The synthetic purity was above 95% (see FIG. 2). At room temperature, adding the responsive small molecular peptide into Hepes buffer with pH of 7.4, preparing responsive small molecular peptide solutions with the concentration of 4mg/mL, 10mg/mL and 20mg/mL, respectively adding 1/5 of anti-tumor drug DOX into the responsive small molecular peptide solutions according to the mass ratio, fully vibrating and uniformly mixing, standing for 24 hours, photographing, and observing the morphology by using a Transmission Electron Microscope (TEM).
The results show that: after DOX is added into the responsive small molecular peptide solution, the responsive small molecular peptide of the entrapped drug is in a solution state, and the results are shown in fig. 3, 4 and 5; the self-assembled morphology is spherical nano-particles, and a part of the self-assembled morphology is accompanied by a small amount of nano-fibers, and the results are shown in fig. 6, 7 and 8.
Example 2: the self-assembled morphology of the drug-loaded responsive small molecular peptide is changed after GSH is added, and the responsive small molecular peptide hydrogel is formed
Preparing GSH solution with 0.2mol/L for standby. 1mL of drug-loaded responsive small molecule peptide solution with the concentration of 4mg/mL is prepared as a sample 1, 10 mu L of GSH solution is added, and the final concentration of GSH is 2mmol/L; 1mL drug-loaded responsive small molecule peptide solution with the concentration of 10mg/mL is prepared as a sample 2, 25 mu L of GSH solution is added, and the final concentration of GSH is 5mmol/L; 1mL drug-loaded responsive small molecule peptide solution with the concentration of 20mg/mL is prepared as a sample 3, 50 mu L of GSH solution is added, and the final concentration of GSH is 10mmol/L; after subsequent thorough mixing, incubation at 37 ℃ for 3 days, photographs were taken and observed using a transmission electron microscope.
The results showed that sample 1, sample 2, and sample 3 formed self-supporting hydrogels under GSH induction, as shown in fig. 9, 10, and 11. Meanwhile, the self-assembled morphology is changed, and the self-assembled morphology is changed from spherical nanoparticles and the like to a nanofiber structure, as shown in fig. 12, 13 and 14.
Example 3: particle size change of drug-loaded responsive small molecule peptide before and after GSH response
Preparing 1mL of a response small molecule peptide solution with the concentration of 10mg/mL, adding DOX with the mass of 1/5 of the response small molecule peptide, fully vibrating and uniformly mixing to obtain a sample 1, and standing for 3 days to be detected. Preparing 1mL of drug-loaded (DOX with the mass of 1/5 of that of the responsive small molecule peptide) responsive small molecule peptide solution with the concentration of 10mg/mL, adding 25 mu L of GSH with the concentration of 0.2mol/L as a sample 2, and standing at 37 ℃ for 3 days; particle sizes were measured after the treatment was completed.
The results show that: the particle size of sample 1 was about 80 nm; sample 2, in which GSH was added, had a larger particle size, about 2000nm, and was consistent with the electron microscopy results, and a nanofiber structure was formed at this time, as shown in fig. 15 and 16.
Example 4: rheological measurements
1mL of drug-loaded (DOX with 1/5 of the mass of the responsive small molecule peptide) responsive small molecule peptide solution with the concentration of 10mg/mL is prepared, 25 mu L of GSH with the concentration of 0.2mol/L is added, and after 3 days of standing at 37 ℃, the rheological property of the drug-loaded (DOX) responsive small molecule peptide solution is measured by a DHR rotary rheometer. Dynamic frequency scanning (0.1-100 Hz,1% stress) was performed using a lamina (taper angle, 2.0 °; diameter, 20 mm).
The results show that: after GSH is added into the drug-loaded responsive small molecule peptide solution, peptide hydrogel is formed, the storage modulus G 'is about 2000Pa, and the energy consumption modulus G' is about 220Pa, as shown in figure 17.
Example 5: drug release profile of drug-loaded responsive small molecule peptide entrapped DOX
The in vitro drug release of DOX entrapped in the nano drug delivery vehicle was measured by dialysis. Preparing 3mL of a response small molecule peptide solution with the concentration of 10mg/mL at room temperature, adding DOX with the mass of 1/5 of that of the response small molecule peptide, performing ultrasonic treatment for 30min, and standing for 24h. The treated solution was equally divided into two groups, 25. Mu.L of GSH at a concentration of 0.2mol/L was added to one of the groups, and transferred to dialysis bags (MWCO 1000 Da), respectively. And monitoring the drug release behavior of the drug-loaded responsive small molecular peptide in GSH-free and GSH-free environments by an ultraviolet-visible spectrophotometer. The dialysis bag was immersed in Hepes solution. At the set time, the dialysate was changed and after each sampling the same volume of fresh Hepes solution was added, the Hepes solution having a pH of 7.4. The absorbance of the sample at 480nm was measured by an ultraviolet-visible spectrophotometer, and the amount of the accumulated released DOX was calculated. The results are shown in fig. 18, where the drug-loaded responsive small molecule peptides have GSH response properties.
Example 6: cellular uptake
Uptake of DOX (2 mg/mL) and DOX/peptide (DOX: 2 mg/mL), responsive small molecule peptide: 10 mg/mL) by tumor cells was studied by flow cytometry. HepG2 cells were subjected to adherent culture in cell culture plates. The free DOX and drug-loaded responsive small molecule peptide solutions corresponding to one-tenth of the cell culture medium area were added to HepG2 cells, respectively, and co-cultured for 30 minutes, and analyzed by flow cytometry. The results indicate that DOX/peptide contributes to better uptake of DOX by tumor cells, as shown in figure 19.
Example 7: detection of residence time of responsive small molecule peptides in tumor cells using confocal laser scanning microscopy
The retention of DOX (2 mg/mL) and DOX/peptide (DOX: 2 mg/mL), and the response small molecule peptide: 10 mg/mL) in tumor cells was investigated by confocal laser scanning microscopy.
Respectively inoculating HepG2 cells into cell culture holes, and after attaching the cells, adding a drug-loaded responsive small molecule peptide (DOX/peptide) solution with one plate with one tenth of the liquid volume in the holes; another plate was added to the free DOX solution of one-tenth of the liquid volume in the well. After 60h co-culture with HepG2 cells, respectively, hepG2 nuclei were labeled with DAPI, cytoplasm was stained with Calcein-AM stain, DOX autored fluorescence. The distribution of DOX in cells was observed using a confocal scanning microscope.
The results show that: as shown in FIG. 20, after 60 hours of culture, red fluorescence of free DOX group was hardly observed in HepG2 cells, indicating that free DOX was hardly retained in the cells; red fluorescence of the DOX/peptide group was observed in both cytoplasm and nucleus, and fluorescence intensity was higher than that of the DOX group, indicating that DOX/peptide was able to stay in tumor cells for a long period of time. The drug-loaded responsive small molecule peptide hydrogel designed by the invention can prolong the residence time of the drug in tumor cells.
Claims (8)
1. The responsive small molecule peptide is characterized by having glutathione responsiveness, can be used as a nano drug carrier, and has the structural formula:
2. the application of the responsive small molecular peptide as a nano drug carrier is characterized in that the responsive small molecular peptide is the glutathione responsive small molecular peptide which can be used as the nano drug carrier according to claim 1, and the responsive small molecular peptide is self-assembled in Hepes buffer solution to form spherical nano particles after drug loading, so as to encapsulate anti-tumor drugs.
3. A nano-drug carrier, characterized in that the nano-drug carrier comprises the glutathione-responsive small molecule peptide which can be used as the nano-drug carrier according to claim 1.
4. The nano-drug carrier of claim 3, wherein the nano-drug carrier is responsive to glutathione in tumor cells to convert self-assembled morphology into nanofibers to form self-supporting hydrogels, prolonging drug residence time in tumor cells; the concentration of the glutathione is 2-10mmol/L.
5. A method for preparing a nano-drug carrier, characterized in that the method is used for preparing the nano-drug carrier according to claim 3, and comprises the following steps: adding glutathione-responsive small molecular peptides and anti-tumor drugs into Hepes buffer solution together, and self-assembling the glutathione-responsive small molecular peptides to form drug-loaded spherical nanoparticles.
6. The method for preparing a nano-drug carrier according to claim 5, wherein the Hepes buffer has a pH of 7.4 and the concentration of glutathione-responsive small molecule peptide is 4-20mg/mL.
7. The method for preparing a nano drug carrier according to claim 6, wherein the concentration of the glutathione-responsive small molecule peptide is 10mg/mL.
8. The method for preparing the nano-drug carrier according to claim 5, comprising the steps of: adding 1/5 of anti-tumor drug DOX into a glutathione responsive small molecular peptide solution with the concentration of 4-20mg/mL according to the mass ratio, vibrating and mixing uniformly, and standing at room temperature for 24 hours to obtain the nano drug carrier.
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