AU2019101139A4 - The preparation of pH-responsive drug-loaded nanoparticles based on polyethylene glycol gel - Google Patents
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Abstract
The present study will be carried out focusing on the preparation of pH responsive nanoparticles for drug delivery based on polyethylene glycol (PEG) gel. In the process, the PEG-Schiff-DOX will be prepared by bonding doxorubicin to PEG polymer chain via acid-sensitive group (Schiff base bond). Consequently, it can be self assembled in aqueous solution to obtain nanoparticles for drug delivery and can be further loaded in the gelatin network to obtain PEG gel-based pH-responsive nanoparticles for drug delivery. Concerning its advantages, the composite material is characterized by high drug loading, high encapsulation efficiency and acid-controlled release, which can realize the construction of a multi-stage release system to achieve gradient or stimulated response release of doxorubicin.
Description
TITLE
The preparation of pH-responsive drug-loaded nanoparticles based on polyethylene glycol gel
FIELD OF THE INVENTION
The present invention relates to a present study will be carried out focusing on the preparation of pH-responsive nanoparticles for drug delivery based on polyethylene glycol (PEG) gel, specifically, concerning its advantages, the composite material is characterized by high drug loading, high encapsulation efficiency and acid-controlled release, which can realize the construction of a multi-stage release system to achieve gradient or stimulated response release of doxorubicin.
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, nanome- dicines 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) effec. Among various nanomedicines such as polymeric i
2019101139 30 Sep 2019 nanoparticles, prodrugs, micelles, vesicles,nanogels and liposomes, prodrug-based nanoparticles havedrawn much more attention due to the clear and simple structure and great potential in clinical translation. And tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment.
Over the last two decades, doxorubicin (DOX) as an anticancer drug, has been widely used in cancer therapy. It is an antineoplastic agent of non-selective class I anthracycline antibiotics class that are regarded as the most effective anticancer drugs. It has been clinically employed alone or in combination fbr treating various carcinomas. Despite of its potential benefits, however, it also has certain adverse effects such as bone marrow suppression, heart/liver dysfunction, and gastrointestinal response.The side effect of congestive heart failure limits the dose of this formulation that can be given, thereby limiting potential substitutionall of which severely affect its clinical applications. Therefore, it is necessary to reduce DOX adverse effects by binding with drug carrier, and enhance treatment efficiency.
New methods and technologies for malignant tumor therapy are of great significance. Polymeric micelles have emerged as one of the most
2019101139 30 Sep 2019 promising platforms for anti- cancer drug delivery due to their good biocompatibility, easy drug loading, and readily available multiple functionalities.5 - 7 Nanosized polymeric micelles not only have the ability to enhance the water solubility and prolong the circulation time of hydrophobic drugs such as doxorubicin (DOX) and pacli- taxel (PTX) but also could passively accumulate in tumor sites via the enhanced permeability and retention (EPR) eff ect, thus improving the drug delivery outcome.
Non-pegylated liposomal doxorubicin has been shown to improve therapeutic efficacy by significantly reduc- ing the risk of cardiotoxicity compared with that of con- ventional doxorubicin.Pegylated liposomal doxorubicin (Peg-Dox) is a useful drug for the treatment of various malignancies, including AIDS-related Kaposi sarcoma, ovarian cancer, lymphoma, metastatic breast cancer and multiple myeloma. In hematological malignancies, good outcomes were achieved in lymphoma and multiple myeloma by using Peg-Dox, with reduced cardiotoxicity and improved pharmacoki- netic profiles when compared to those of doxorubicin . In a recent study, Peg-Dox was used to treat elderly patients with acute lymphoblastic leukemia . The outcome showed that Peg-Dox had reduced myelosup- pression, reduced infections and less cardiac events with similar outcomes compared to that of continuous-infu- sion
2019101139 30 Sep 2019 doxorubicin.This treatment is especially suitable for older patients and for patients with heart dysfunction because of the low cardiotoxicity and mild myelosuppression of Peg-Dox. Peg-Dox was mainly taken up by cells in the liver, spleen and bone marrow, with a higher con- centration and a more prolonged period spent in these tissues compared to those of conventional doxorubicin . The mice with lymphocytic leukemia that were treated with Peg-Dox had a longer survival time com- pared to that of mice that were treated with conventional doxorubicin .
However, the delivery of these chemotherapeutic agents might be associated with multifaceted challenges, such as a lack of specificity to retain the therapeutic agent in the cancer environment, low solubility in the aqueous media, rapid elimination, and non-specific distribution, demanding larger dose administration, which leads to dose-related toxicities.Recently, design and development of effective drug delivery systems (DDSs), with a special attention to new strategies to control drug release and tumor targeting have attracted considerable attention.
Drug delivery systems can be used to specifically target tumors and improve the therapeutic index and the pharmacokinetic profile of anticancer drugs. Nanomedicines are submicrometer-sized carrier materials which intend to improve the biodistribution of systemically administered chemotherapeutic drugs. Nanoformulation aims at
2019101139 30 Sep 2019 improving the balance between the efficacy and the toxicity of systemic chemotherapeutic agentinterventions . Among others, the main examples of nanomedicine formulations are liposomes , micelles , nanoparticles and polymer-drug conjugates .
It is highly expected that an ideal drug delivery system maintains the blood concentration of therapeutic agent at a desired level, avoids a sharp increase in blood level of the therapeutic agent while preventing fast drug clearance, carries the drug into the target tumor cells, and enhances the permeability and retention of the therapeutic agent in solid tumors.
It has been proved that harnessing the low pH of the cancer environment is a strong and effective strategy in nano DDSs.Extracellular pH in tumors (6.0-7.0 in average) is lower than intracellular pH (7.4). The low extracellular pH in tumors due to high glycolysis rate of cancer cells along with the hypoxic condition of tumors contribute to the progression of cancer from in situ tumors to metastatic cancer. In this regard, vehicles based on pH-responsive polymers could provide the required intelligence for preparation of smart DDSs.
Drug release kinetics associates with intracellular drug concentration and the time of drug action. To max- imum tumor growth inhibition, it is necessary to keep eff ective drug concentration for a time period as long as possible. It was reported that incorporating of
2019101139 30 Sep 2019 encapsulated DOX and conjugated DOXin one drug delivery system would achieve programmed drug release, which meant the rapid release of encapsulated DOX could enhance intracellular drug concentration within a short time, and the later released conjugated DOX could continue the treatment over a longer period, resulting in improved therapeutic eff ect.
In this study, we designed and synthesized an amphiphilic polymerdrug conjugate, the PEG-Schiff-DOX (Peg-Dox) will be prepared by bonding doxorubicin to PEG polymer chain via acid-sensitive group (Schiff base bond), which could self-assemble into acid-labile micellar nano- particles. The resulted nanoparticles could serve as drug carriers to encapsulate free DOX. Therefore, we prepared two kind of nanoparticles, which been named as Peg-Dox NPs, Peg-Dox + 20%DOX NPs, and DOX, respectively, according to the ratio of free DOX and Peg-Dox, taking the free doxorubicin as a reference group. In order to regulate the release behavior of doxorubicin, as well as promote cell proliferation and tissue repair. So we put the drug-loaded nanoparticles in the hydrogel.
These nanoparticles possessed excellent storage stability, as- cribing to the low critical aggregation concentration (CAC) of Peg-Dox and protection of the outer PEG corona. Benefitting from the combination of physical encapsulation and chemical conjugation, the nanoparticles not
2019101139 30 Sep 2019 only achieved very high DLC and DOX concentration, but also exhibited a programed drug release behavior.The nano- particles penetrated into tumor tissues via EPR eff ect, then they were internalized by tumor cells via endocytosis. Under the acidic environ- ment of intracellular endosomal/lysosomal compartments, pH-trig- gered cleavage of Schiff base bonds led to disassembly of nanoparticles, resulting in rapid release of encapsulated DOX, subsequently the pre- viously hidden Schiff base bonds were exposed to the acidic environment and finally the conjugated DOX released completely. Here, preparation of Peg-Dox prodrugs and DOX-loaded nanoparticles, pH-responsive drug release.In addition to the antibacterial and anti-inflammatory effects, hydrogels can also promote the repair of damaged tissues. And it can prolong the release time of DOX, in order to prolong the maintenance of DOX in the tumor cells, so as to improve the therapeutic effect.
SUMMARY OF THE INVENTION
Our research focuses on the fabrication of PEGylated DOX acid sensitive nanoparticles with gel shell and studying its function. There are 13 steps to manufacture those particles. We first mix PEG-CHO, DOX hydrochloride, TEA, and DMF. The purpose of TEA is to transfer DOX-hydrochloride into DOX while DMF is to ionize all the matters in order to allow the reaction happen. The second step is to stir the solution
2019101139 30 Sep 2019 under 60 degrees for 48 hours. After 48 hours of stirring,
PEG-Schiff-DOX has been formed. We then distill the solution to get DMF out. After that, we use CH2CL2 to dissolve the product in order to extract the impurities out. We use NACL solution as another liquid for the extraction process. By leaving the CH2CL2 part, we keep most of the PEG-Schiff-DOX in CH2CL2 and impurities such as PEG-CHO, TEA are separated into NACL solution. Our team repeat the extraction process for 3 times. After the extraction process, we add MGSO4 powder in the solution to remove the extra water in CH2CL2 solution. After the filtration of the solution, we removed the MGSO4 solid from DOX-Schiff-PEG CH2CL2 solution. By distilling the solution, we successfully got PEG-Schiff-DOX solid. PEG-Schiff-DOX are transferred into nanoparticles via self-assembling in the water for 2 hours. We then coated them with gel shell by mixing the water solution with gelatine powder in a container. We heat the container to melt gelatine and freeze it and we successfully fabricated gel loaded with DOX-Schiff-PEG nanoparticles. By lyophilize the gel, we got our final product which is gel powder loaded with DOX-Schiff-PEG nanoparticles.
DESCRIPTION OF THE DRAWINGS
The appended drawings are only for the purpose of description and explanation but not for limitation, wherein:
2019101139 30 Sep 2019
Fig.l is H-NMR spectra of PEG-DOX
Fig.2 is the Comparison of water absorption between gelatin and chitosan
Fig.3 is the Doxorubicin standard curve.
DESCRIPTION OF PREFERRED EMBODIMENT
Data acquisition
All the data we acquired in this study was completed in the Chinese Academy of Sciences, which includes experiments in laboratory and data processing with several instruments.
The part in the laboratory contains all the trials that used for the selection between gelatin and chitosan, and the preparation of the pH-responsive nanoparticles we need for later data processing.
The part in data processing includes all the test for the properties of the pH-responsive nanoparticles and the feasibility of PEG-Schiff-DOX, which lead to the proof that this new material can be applied to drug delivery.
The followed are the detailed steps of our process.
Data processing
After we collect all the data, some of them are input into the computer manually and using software to generate a graph. They include the graph
2019101139 30 Sep 2019 of water absorption of gelatin and chitosan, the DLS and standard curve that is tested using the spectrometer.
The rest data will include: NMR is one of the methods we used for figuring out the embedding ratio of the DOX in PEG; SEM and TEM are used to see the characterization of the nanomaterial such as its morphology, particle size, and distribution. All these data will be automatically transferred to software installed in the computer when putting the sample in the instruments and start it. Table 1 shows the Particle size of nanoparticles
Table 1 The Particle size of nanoparticles
DLS Result
| PEG-schiff-DOX-7.4 | 132 nm |
| PEG-schiff-DOX-5.0-2 h | 23 nm, 226 nm and 623 nm |
| PEG-schiff-DOX@DOX-7.4 | 192 nm |
Procedure
Preparing of gels
1) Weigh 0.4 grams of chitosan and 5 grams of deionized water, then mix them in a 10ml specimen bottle.
2) Weigh 0.4 grams of gelatin and 5 grams of deionized water, then mix them in a 10ml specimen bottle.
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2019101139 30 Sep 2019
3) Place specimen bottles in the 16 degree Celsius for two hours.
4) Take the chitosan and gelatin gel out and soak them in a test tube with saturated sodium citrate solution for an hour
5) Take the gels out and weigh them on the balance, the record the weight of chitosan and gelatin gel.
6) Put chitosan and gelatin gel in the deionized water, weight the gel after an hour.
7) Repeat the step 6) 6 times and record the weight.
We analyze two groups of data from the previous experiment and then obtain the appropriate gel for our study based on their stability and water absorption.
Preparing of nanomaterial
1) Weigh 50 milligrams PEG-CHO, 25 milligrams doxorubicin hydrochloride, 35 microliter TEA and 5 milliliter anhydrous DMF.
2) Mix them into a flask.
3) Use foil to cover the flask, heat it at 60 degree Celsius and use the magnet mixer to stir the solution sustaining for 48 hours.
4) Distill the solution using distilling apparatus
5) Add dichloromethane into the flask with impurity product.
6) Leach the solution by adding sodium chloride into the solution
7) Waiting for an hour and collect the bottom layer of solution.
2019101139 30 Sep 2019
8) Repeat step 6) and 7) for 3 times
9) Distill the solution using distilling apparatus
After this experiment, we will use the product to make the gel, which loaded with the nanomaterial.
Preparation of gel with the function of loading the nanomaterial
1) Weigh 0.4 grams of gelatin and 5 grams of deionized water, then mix them in a 10ml specimen bottle.
2) Place specimen bottles in the 16 degree Celsius for two hours.
3) Weigh 1.21447 milligram DOX-PEG and 5 grams deionized water, then mix them in a 10ml specimen bottle.
4) Place specimen bottles in the 16 degree Celsius for two hours.
5) Weigh 0.1 milligrams DOX, 0.97 milligrams DOX-PEG and deionized water , then mix them in a 10 ml specimen bottle
6) Place specimen bottles in the 16 degree Celsius for two hours.
7) Take all gels out from the specimen bottle
8) Put them into centrifuge tube
9) Put the tubes into lyophilizer
10) Lyophilize the loaded material gels for 10 hours
Claims (2)
1. A preparation of pH-responsive drug-loaded nanoparticles based on polyethylene glycol gel, this study will be carried out focusing on the preparation of pH-responsive nanoparticles for drug delivery based on polyethylene glycol (PEG) gel, wherein the PEG-Schiff-DOX will be prepared by bonding doxorubicin to PEG polymer chain via acidsensitive group (Schiff base bond); consequently, it can be self assembled in aqueous solution to obtain nanoparticles for drug delivery and can be further loaded in the gelatin network to obtain PEG gel-based pHresponsive nanoparticles for drug delivery; concerning its advantages, the composite material is characterized by high drug loading, high encapsulation efficiency and acid-controlled release, which can realize the construction of a multi-stage release system to achieve gradient or stimulated response release of doxorubicin.
2. The preparation of pH-responsive drug-loaded nanoparticles based on polyethylene glycol gel of claim 1, wherein these nanoparticles possessed excellent storage stability, as- cribing to the low critical aggregation concentration (CAC) of Peg-Dox and protection of the outer PEG corona; benefi tting from the combination of physical encapsulation and chemical conjugation, the nanoparticles not only achieved very high DLC and
2019101139 30 Sep 2019
DOX concentration, but also exhibited a programed drug release behavior; the nano- particles penetrated into tumor tissues via EPR effect, then they were internalized by tumor cells via endocytosis; under the acidic environ- ment of intracellular endosomal/lysosomal compartments, pH-trig- gered cleavage of Schiff base bonds led to disassembly of nanoparticles, resulting in rapid release of encapsulated DOX, subsequently the pre- viously hidden Schiff base bonds were exposed to the acidic environment and fi nally the conjugated DOX released completely; here, preparation of Peg-Dox prodrugs and DOX-loaded nanoparticles, pH-responsive drug release; in addition to the antibacterial and anti-inflammatory effects, hydrogels can also promote the repair of damaged tissues; and it can prolong the release time of DOX, in order to prolong the maintenance of DOX in the tumor cells, so as to improve the therapeutic.
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| CN113712939A (en) * | 2021-09-16 | 2021-11-30 | 浙江海洋大学 | Nanoparticle of adriamycin coupled chitosan oligosaccharide |
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| CN113712939A (en) * | 2021-09-16 | 2021-11-30 | 浙江海洋大学 | Nanoparticle of adriamycin coupled chitosan oligosaccharide |
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