AU2019101195A4 - Methord on anti - inflammatory and anti - tumor effects of gelatin - based on pH - responsive drug - loaded nanoparticles - Google Patents
Methord on anti - inflammatory and anti - tumor effects of gelatin - based on pH - responsive drug - loaded nanoparticles Download PDFInfo
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Abstract
The invention lies in the field of nanomedicine. It is able to release anti-inflammatory drug and anti-tumor drug according two different environment: the inflammatory condition in early stage of cancers, and the acid condition which has specific pH value after appearing of tumour cells.Gelatin as one kind of nano-drug carrier is a polysaccharide which can be absorbed after releasing all nano-drugs. Poly(ethylene glycol) as a polymer material that can modify nano-drugs is able to extend circulatory time of doxorubicin and aspirin, enhance stability and reduce toxicity. At precancerous, aspirin will be released slowly to resist inflammation. When tumor cell appear at a more advance stage, doxorubicin release from Gel to achieve anti-tumor effect. After all those step, poly(ethylene glycol) could be expelled from body.
Description
TITLE
Methord on anti - inflammatory and anti - tumor effects of gelatin - based on pH - responsive drug - loaded nanoparticles
FIELD OF THE INVENTION
The present invention relates to treatment of tumor by nano-drug which holds significance in biology, medical engineering and pharmacy.
BACKGROUND OF THE INVENTION
Over the past decades, nanomedicines based on polymers have been intensively studied for cancer therapy, regarding their potential to increase drug solubility, enhance therapeutic effect and reduce side effects. Comparing to small molecular anticancer drugs, nanomedicines have shown many advantages including prolonged circulation time by evading glomerular filtration, improved pharmacokinetic properties, as well as enhanced tumor accumulation via the enhanced permeation and retention (EPR) effect. Among various nanomedicines such as polymeric nanoparticles, prodrugs, micelles, vesicles, nanogels and liposomes, prodrug-based nanoparticles have drawn much more attention due to the clear and simple structure and great potential in clinical translation.
Adriamycin, a new antineoplastic drug, has a good therapeutic effect on
2019101195 03 Oct 2019 many tumors and can inhibit the growth of tumors greatly, such as solid tumors and hematological malignancies. Although adriamycin has some side effects, its efficacy is better than that of similar drugs. Therefore, it can achieve good therapeutic effect in small doses. Adriamycin therapy results in dose-limiting hematologic and cardiac toxicity, as well as stomatitis, nausea, vomiting, and alopecia, but in general these toxicities are predictable and reversible.
Gelatin is a commonly used natural polymer which is derived from collagen. The isoelectric point of gelatin can be modified during the fabrication process to yield either a negatively charged acidic gelatin, or a positively charged basic gelatin at physiological pH. This theoretically allows electrostatic interactions to take place between a charged biomolecule and gelatin of the opposite charge, forming polyion complexes. Various forms of gelatin carrier matrices can be fabricated for controlledrelease studies, and characterization studies have been performed which show that gelatin carriers are able to sorb charged biomolecules such as proteins and plasmid DNA through polyion complexation. The crosslinking density of gelatin hydrogels has been shown to affect their degradation rate in vivo, and the rate of biomolecule release from gelatin carriers has been shown to have a similar profile, suggesting that complexed gelatin/biomolecule fragments are released by
2019101195 03 Oct 2019 enzymatic degradation of the carrier in vivo.
SUMMARY OF THE INVENTION
This research aims to solve the existing problems by combining synthesized drugs of low biotoxicity and high pH sensitivity with nano-drug carriers, which not only do little harm but also stay longer inside the body to release drug when available.
Preparation of nano drugs
In order to diminish the biotoxicity of aspirin and DOX and enhance the efficiency of the drug delivery system, we first synthesize 2 new drugs: PEG-ASP, which resists inflammatory, and PEC-DOX, which is characterized with high pH sensitivity and targets at the tumor cells. In order to synthesize PEG-ASP, we mix HO-PEG-OH, aspirin(pure drug), EDCI (as dehydrator), DMAP (as catalyst to activate the carboxyl group), and CH2CI2 (as solvent), leaving them to react for 24 hours. After all components readily react, we extract the solution for 3 times, using water, HC1, and NaCl solution. After extracting, DMAP, EDCI and extra PEG has been removed from the PEG-ASP solution. Considering PEG-DOX, we mix PEC-CHO, doxorubicin, and TEA (as solvent), leaving them react for 48 hours . After PEG-ASP and PEG-DOX are synthesized, we use rotary evaporator to distill and purify PEG-ASP and PEG-DOX. Then
2019101195 03 Oct 2019 we obtain PEG-ASP and PEG-DOX solid, which are later used to make a multi-functional and versatile drug. We first make highly purified PEG-ASP and PEG-DOX solution. Then we combine PEG-ASP and PEG-DOX solid in another solution, and thus forms a new drug, which is both anti-tumor and anti-inflammatory.
Preparation of three colloids
Furthermore, we also design gel drug carriers with high drug loading and entrapment efficiency, biocompatibility as well as biodegradability. We choose gelatin gel, where drugs are physically encapsulated, because it’s flexible to shift phases under different temperatures. Plus, the gelatin gel is sticky enough to attach to the cell membrane and take advantage of the EPR effect, thus prolonging the half-life of drug circulation in vivo. We make gelatin gels, combine them with both pure drugs and synthesized ones, and set up different test groups to examine their capability of drug release. We first make 2 sets of drugs with different solvents, each with PEG-DOX, PEG-aspirin and DOX-PEG-ASP. We then coated them with gelatin gel by adding gelatin powder into preheated drug solution, as gelatin powder solves better in solution with high temperature. After gelatin powder are readily solved and gels are formed, we store them inside the fridge to maintain their phase. Consequently, we obtain three different test groups with combinations of gel, drug and solvent as
2019101195 03 Oct 2019 follows: 1)PEG-ASP coated with 15% gelatin in ethanal-water(l:4) solution; 2) PEG-DOX coated with 15% gelatin in ethanal-water(l:4) solution; 3) DOX-PEG-ASP coated with 15% gelatin in ethanal-water(l :4) solution;Therefore, we obtain gelatin gels loaded with PEG-DOX, PEG-ASP, DOX-PEG-ASP, as well as aspirin and doxorubicin.
Detection of nanoscale drugs and gels
After the synthesis of gelatin gels loaded with drugs, we adopt machines to test the gels’ capability in 4 aspects: 1) we use UV spectrophotometer to supervise drug release of 5 gels within 48 hours after made to test the capability of gels, and that of gels after acid and base are added to test the drugs’ pH sensitivity; 2) we use SEM and TEM to observe the shape, topography and surface characterization of the gels we prepare; 3) we use NMR to examine structures of the gels; 4) we use the particle size analyzer to examine sizes of PEG-DOX and PEG-ASP nanoparticles we synthesize.
DESCRIPTION OF DRAWINGS
Figure 1 standard curve of aspirin
Figure 2 standard curve of doxorubicin
Figure 3 electron microscope image of drug carrier gel
Figure 4 electron microscope image of gel
Figure 5 aspirin release curve
2019101195 03 Oct 2019
Figure 6 doxorubicin release curve
Figure 7 schematic diagram of aspirin
Figure 8 schematic diagram of doxorubicin
Figure 9 Experimental flow chart.
DESCRIPTION OF PREFERRED EMBODIMENT
The experimental principle
Nanoparticles have been widely used in the treatment of cancer in the past decade because of their good effect and less side effects. In this experiment, adriamycin and aspirin were selected to construct nanoparticles to inhibit the production and elimination of cancer cells. Adriamycin is a new type of cancer drug which has good therapeutic effect on most tumors, but it can cause great side effects on human body when used in large quantities or in excess. Therefore, when using doxorubicin for cancer treatment, try to avoid heavy use and high frequency use to minimize the adverse effects of side effects. PEG-CHO was constructed by using polyethylene glycol (PEG), and then reacted with deionized doxorubicin. TEA was used as catalyst to construct Schiff base bond to form nanoparticles. Gelatin was used as carrier to encapsulate doxorubicin nanoparticles. The Schiff base bond will break under a specific environment (cancer environment), release doxorubicin to kill cancer cells, and because the gelatin carrier is coated with doxorubicin, doxorubicin does not immediately act on cancer cells. It is
2019101195 03 Oct 2019 in a state of sustained release, which allows the release of doxorubicin in the body for a prolonged period of time and maintains it at a relatively suitable concentration for a long time to achieve the effect of treating cancer.
Aspirin is a mature anti-inflammatory drug so far. Most cancers need to undergo an inflammatory environment before they develop. In this experiment, dihydroxy polyethylene glycol was used to react with aspirin to form ester bond to construct nanoparticles. EDCI was used as dehydrating agent, DMAP was used as catalyst, and dichloromethane was used as liquid environment. The constructed aspirin nanoparticles and adriamycin nanoparticles were loaded into gelatin carrier together. In most inflammatory environments, acidic substances will be produced, which will destroy the ester bond between polyethylene glycol and aspirin. Aspirin will be released to achieve anti-inflammatory effect, because in gelatin carrier, it will also have the effect of slow-release and achieve the purpose of long-term anti-inflammatory. Aspirin can be used to prevent cancer in early stage. If inflammation is eliminated in time, the human body will not suffer from cancer due to long-term deterioration of inflammation.
Preparation of nano drugs
1. 150 mg of HO-PEG-OH, 36 mg of aspirin, 4.88 mg of EDCI and 42.08 mg of DMAP were dissolved in 50 ml of dichloromethane for 24 h,
2019101195 03 Oct 2019 extracted three times with saturated brine, dehydrated with MgSO4, filtered, and evaporated to remove the solvent. The drug was a white solid and the white solid was recorded as the sample PEG-ASP.
2. Take 50mg PEG-CHO, 25mg deionized doxorubicin dissolved in 35ml TEA for 48h, remove the reaction solvent by rotary evaporation, the drug is red solid, record the red solid as sample PEG-DOX.
Measuring sample PEG-ASP and sample PEG-DOX particle size and nuclear magnetic
1. Take 10 mg of sample PEG-ASP, dissolve it in 10 ml of pure water, prepare a PEG-ASP solution at a concentration of 1 mg/ml, and measure the particle size and nuclear magnetic properties of the sample. The reaction was carried out for 12 hours by adding NaOH, and the particle diameter of the sample after the reaction was measured. It can be seen from the nuclear magnetic map that HO-PEG-OH reacts with aspirin to synthesize a new substance.
2. Take 10 mg of sample PEG-DOX, dissolve it in 10 ml of pure water, prepare a PEG-DOX solution at a concentration of 1 mg/ml, and measure the particle size and nuclear magnetic properties of the sample. The reaction was carried out for 30 min, and the particle size of the sample after the reaction was measured. It can be seen from the nuclear magnetic diagram that PEG-CHO and doxorubicin have produced new substances.
Production of aspirin standard curve
2019101195 03 Oct 2019
Take 10 mg of aspirin and dissolve it in 10 ml of aqueous solution to prepare aspirin mother liquor at a concentration of 1 mg/ml, and dilute some of the mother liquor to obtain solution concentrations of 0.5 mg/ml, 0.1 mg/ml, 0.01 mg/ml, 0.001 mg/ml. The absorbance values of five different concentrations of aspirin solution were determined separately. The absorbance is the abscissa and the corresponding concentration is the ordinate. A standard curve is produced, as shown in Figure 1.
Production of doxorubicin standard curve
Take 10 mg of doxorubicin and dissolve it in 10 ml of aqueous solution to prepare doxorubicin mother liquor at a concentration of 1 mg/ml, and dilute some of the mother liquor to obtain solution concentrations of 0.5 mg/ml, 0.1 mg/ml, 0.01 mg/ml, 0.001 mg/ml. The absorbance values of five different concentrations of doxorubicin solution were determined separately. The absorbance is the abscissa and the corresponding concentration is the ordinate. A standard curve is produced, as shown in Figure 2.
Preparation of PEG-ASP colloid and its release in ethanol
Take 0.5mg sample PEG-ASP dissolved in 1ml absolute ethanol, add 4ml pure water, the solution concentration is O.lmg/ml, add 750mg gelatin, heat to shake to dissolve, put it into the refrigerator to freeze and solidify, remove the solidified colloid, cut A small portion was observed under
2019101195 03 Oct 2019 electron microscope for the morphology of the drug-loaded colloid, as shown in Figure 3. The remaining colloids were immersed in pure ethanol, and the absorbance of the samples were measured at Ih, 2h, 4h, 8h, 12h, and 24h. The aspirin concentration in ethanol was calculated from the standard curve of aspirin for Ih, 2h, 4h, 8h, 12h, and 24h. The reaction was carried out by adding NaOH for 12 hours, and the absorbance was measured to obtain an aspirin concentration. As shown in Figure 5, it can be seen that as the concentration of aspirin increases, the amount of colloidal drug release increases. When the concentration of aspirin is less than 20 mg/ml, the release amount increases with the increase of aspirin concentration and increases rapidly. When the concentration of aspirin is greater than 20 mg/ml, the release amount increases with the increase of aspirin concentration, but the growth rate gradually decreases.
Preparation of PEG-DOX colloid and its release in ethanol
Take 0.5mg sample PEG-DOX dissolved in 1ml absolute ethanol, add 4ml pure water, the solution concentration is O.lmg/ml, add 750mg gelatin, heat to shake to dissolve, put it into the refrigerator to freeze and solidify, take out the solidified colloid, soak In pure ethanol, the absorbance of the samples was measured at Ih, 2h, 4h, 8h, 12h, and 24h, respectively. The doxorubicin concentration in ethanol was calculated from the standard curve of aspirin for Ih, 2h, 4h, 8h, 12h, and 24h. The io
2019101195 03 Oct 2019 reaction was carried out for 30 min by adding HC1, and the absorbance was measured to obtain the concentration of doxorubicin. As shown in Figure 6, it can be seen that the amount of doxorubicin released gradually increased with increasing doxorubicin concentration before the addition of HC1. After the addition of HC1, as the concentration of doxorubicin increased, the release amount increased rapidly.
Preparation of PEG-ASP and PEG-DOX mixed colloids and their release in ethanol
Take 0.5 mg sample PEG-ASP and 1.315 mg sample PEG-DOX dissolved in 1 ml absolute ethanol, add 4 ml pure water, the solution concentration is 0.1 mg/ml, add 750 mg gelatin, heat to shake to dissolve, put into the refrigerator to freeze and solidify, The solidified colloid was taken out and immersed in pure ethanol. The absorbance of the sample was measured at 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h, respectively. The drug concentration of PEG-DOX and PEG-ASP mixed colloid was obtained. After adding NaOH for 12 hours, HC1 was added for 30 min, and the colloidal absorbance was measured to obtain the concentration of the drug released by the colloid after the chemical reaction bond was broken.
EDITORIAL NOTE
2019101195 03 Oct 2019
There is one page of the claims only.
Claims (1)
1. Method on anti - inflammatory and anti - tumor effects of gelatin based on pH - responsive drug - loaded nanoparticles, wherein the nano-drug that have doxorubicin and aspirin is able to prevent the growth of tumor cells and kill them when they appear more precisely
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