AU2020102467A4 - A method of preparing of PH-sensitive drug delivery nanoparticles - Google Patents
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Abstract
Doxorubicin (DOX) is an important chemotherapy drug developed against a broad
range of solid tumors, but it has obvious disadvantages of short circulation time, poor
targeting, and high cardiotoxicity. By conjugating DOX with polyethylene glycol
(PEG) via a Schiff base bond, we designed a PH-sensitive nano delivery system
(DOX-Schiff-PEG). Modification of PEG can prevent DOX degradation in
circulation (PH=7.4), and the Schiff base bond helps to specifically release DOX in
the acid tumor microenvironment (PH=5.0), thereby the nanoparticles demonstrated
less toxicity and higher antitumor activity.
Description
TITLE A method of preparing of PH-sensitive drug delivery nanoparticles
FIELD OF THE INVENTION This invention is in the field of anti-tumor drug carrier, which is a pH responsive polymer based on Schiff base bond, and has a good application prospect in cancer treatment.
Cancer is one of the most rampant diseases, which affects one billion people in 2014, accounting for 14% of the global population. With the use of chemotherapy drugs, five-year survival rates for many cancers have improved since the 1950s, but cancer is still the world's second leading cause of death2. There were about 10 million deaths of cancer worldwide in 20182. Therefore, it is vital to find more effective ways to treat cancer. Doxorubicin (DOX) is a chemotherapeutic anthracycline drug. DOX has a wide anti-tumor spectrum, suitable for leukemia and solid tumors such as breast cancer, lung cancer, and liver cancer. Its outstanding anticancer property is achieved by intercalating between base pairs and inhibiting topoisomerase 113, 4. However, its blood circulation time is short (t1/2a of 4.8 minutes, t1/2b of 2.6 hours, and tl/2g of 48 hours5). Worse still, lacking targeting, it can cause severe dose-cumulative toxicity such as cardiovascular toxicity6, neurotoxicity7, and placental toxicity8. Pegylated nanoparticles are developed to deliver DOX, in order to prolong its blood circulation time and lessen toxicity9-11. Doxil@ or Caelyx@ are approved pegylated liposomal doxorubicin. Compared with free DOX, modification of polyethylene glycol (PEG) not only can increase bioavailability by at least 60 times via reducing the uptake by the reticuloendothelial system but also increase drug concentration in cancer tissue via enhanced permeation and retention (EPR) effect12. Nevertheless, both kinds of DOX are processed by the physical drug loading method, which will cause inevitable drug leakage. To reduce drug leakage and release the drug accurately in tumor tissue, the Schiff base bond acts as a linker between DOX and PEG. Schiff base bond presents many advantages. As a pH-sensitive covalent bond, it can be specifically hydrolyzed in acidic tumor tissues (pH 4.0-7.0) and release drugs13, 14. In addition, 7-7 conjugation of Schiff base amphiphiles can improve the stability of imine bonds in water15. In this patent, we designed and constructed an amphiphilic polymer-drug conjugate, which could carry DOX and self-assemble into acid-labile micellar nanoparticles. Compared with free DOX, it has good stability and the larger size of the nanoparticles to increase blood circulation time. The stable nanoparticles also improve the drug loading capacity. What's more, with the pH-sensitive Schiff base bond, it ensures accurate drug release and reduces the toxicity of DOX. The chemical structures of amphiphilic polymer-drug conjugate were analyzed by 1H NMR and Figure 1 shows the formation and delivery of DOX loaded micelles. As shown in Figure 1, nanoparticles enter tumor tissues by the EPR effect and are then endocytosed by tumor cells. In the acidic environment of the intracellular endosomal /lysosomal compartment, Schiff base bond cleavage led to the decomposition of nanoparticles, the rapid release of encapsulated DOX, and the expose of previously hidden Schiff base bond.
In order to improve the safety of DOX(doxorubicin) in the treatment of cancer, improve the targeting of drugs to increase the utilization rate, and solve the shortcomings and deficiencies in the existing technology, this patent designed a pegylated nanoparticle as the drug carrier of DOX, and constructed a amphiphilic polymer-drug conjugate through the Schiff base bond. This method can prolong the circulation time of DOX in the blood, improve the bioavailability of the drug, and reduce the toxicity of DOX.
The process of building the conjugate mainly includes the synthesis of amphiphilic polymers, the load of DOX, and performance evaluation
In the process of design of amphiphilic polymers, we used the polyethylene glycol(PEG) which has good water solubility, non-toxic, and good biocompatibility as the main body, object of 4-carboxybenzaldehyde molecule. PEG-CHO amphiphilic polymer was obtained by the recognition of host and guest. The successful synthesis of PEG-CHO can be inferred by analyzing the Nuclear magnetic resonance spectrum (1H NMR) of PEG- CHO hydrogen of benzene ring and the end of the PEG in the methyl peak ratio. The polymer can be self-assembled to obtain micellar morphologic nanoparticles, which have good biocompatibility and pH responsiveness and can be loaded with anticancer drug DOX and achieve responsive release.
We designed and synthesized the amphiphilic prodrug of PEG-Cho and DOX connected by a ph-responsive Schiff base bond, and It can self-assemble and pack DOX to be a nano drug carrier. The successful synthesis of PEG-Schiff-DOX can be inferred by analyzing the corresponding situation of methyl peak of PEG terminal and main chain peak area in Nuclear magnetic resonance spectrum (1H NMR) of PEG-Schiff-DOX. This method greatly increases the solubility of DOX in water, and the prepared nano drug carrier can remain stable for a long time under neutral conditions, while releasing DOX active drug under acidic conditions to achieve pH responsive release of DOX in tumor sites.
We determined the stability of nano-drugs by measuring the dissolution of nano-drugs in PBS buffer solution with pH=7.4 and measuring their particle size distribution by dynamic light scattering, and tested them again two weeks after placement. And the nano drug was dissolved in PBS buffer solution with pH=5.0, and its particle size distribution was measured by dynamic light scattering after being placed in a 37 °C constant temperature water bath for 2 h to determine the pH responsiveness of the drug.
Figure 1 shows the PEG-Schiff-DOX synthesis scheme Figure 2 shows flow chart of the experimental
Figure 3 shows principle of drug action
Materials and methods
Materials
p-Hydroxybenzaldehyde , 4-dimethylaminopyridine , doxorubicin hydrochloride, N,N-Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), all these above were purchased from Energy Chemical Co., Ltd. The water used in the experiment was ultra-pure grade water. Other chemical solvents and compounds were bought from Beijing Chemical Works and used directly.
Characterization
Nuclear magnetic resonance spectrum ('H NMR): Avance Hocky 400 (400 MHz) wavelength dispersive spectrometer, which used CDC 3, Actone-D, DMSO-D 6 as chemical agents, while TMS was interior label, measured at 25°C Transmission electron microscopy (TEM) images were tested on a JEM-2200FS microscope (JEOL, Japan) under the acceleration voltage of 100K. Generally, a 3tL droplet of the sample containing nanoparticles was dropped onto a copper grid (300 mesh). In the meantime, removing excess liquid with filter paper, then put it still and wait to observe until becoming dry naturally. Gatan multiscan CCD would record the electron microscopy images while Digital Micrograph dealt with it. Dynamic light scattering (DLS): Malvern Zetasizer Nano ZS equipped with 633 nm helium-neon laser, whose angle checking was 1730. Quartz cuvette acted as particle size test sample cell. Ultraviolet-visible spectrum (UV-Vis): Shimadzu TU1901.
Synthesis of pH-responsive prodrug
pH-responsive prodrugs were prepared in two steps as shown in Fig. 1. PEG reacted with 4-Carboxybenzaldhyde , getting the PEG-CHO. The next step is adding DOX, because of the C=N in DOX' structure. so that Schiff base bonds appeared, and DOX was embedded in PEG.
Synthesis of PEG-CHO
The chemical agent p-Eormylbenzoic acid (150 mg, 1 mmol), EDCI (191.7 mg, 1 mmol) and DMAP (61 mg, 0.5 mmol) were dissolved in ultra-dry DCM, then to the solution PEG-OH (375 mg, 0.5 mmol) was added under the atmosphere of nitrogen. After being stirred at temperature of 37°C for 24 h, the solution should be washed for 3 times by IM HCl, saturated NaHCO3 and salt water respectively. Dry and evaporate the compound with 86% yield while the organic phase was collected.
Synthesis of PEG-Schiff-DOX
PEG-CHO (100 mg, 110 tmol), Doxorubicin (50 mg, 90 tmol) and TEA (70 tL, 500 tmol) ,
which was dissolved and oscillated overnight in 3M1 anhydrous DMF. After rotary evaporation of reagents solution, diluting it by large amount of DCM. Leaching the solution by saturated salt water for 3 times, and then continuing to precipitate it with 78% yield in cold ether.
Stability and PH-responsive degradation of the nanoparticles
The nanoparticle drug was dissolved in PBS buffer solution with pH=7.4 (0.5 mg/mL) , and its particle size distribution were tested by DLS. Comparation can be observed after placing for two weeks. The nanoparticle drug was dissolved in PBS buffer solution with pH=5.0(0.5 mg/mL). After 2h in the 37C constant temperature water bath , the particle size can be test by DLS.
Principles of experimentation
Doxorubicin (DOX) itself is a chemotherapeutic drug belonging to anthracycline. By intercalating between base pairs and inhibiting topoisomerase II , thereby, prohibiting tumor cells' RNA(mostly) and DNA that they cannot live any more. However, free drug is definitely inefficient due to the pathological complexity and restriction of body condition. Not only the toxicity side effect is strong, but half period is barely long. Generally, choosing an applicable nano-drug carrier is considered full of prospective. Compared with others, Pegylated nanoparticles have amount of advantages when they are developed to deliver DOX. PEG is hydrophilic and it also equipped with targeting. Between the PEG and DOX, there should be a bond called Schiff base bond. Nucleophilic addition reaction is conducted between aldehydes containing carbonyl groups and primary amines. The Nitrogen-atom (NH2) with lone electron pair reacts with carbon-atom (CHO), whose intermedium is Schiff base after dehydration. This contrived bond is pH-reactive which plays a key role in two aspects of the experiment. It can self-assemble into acid-labile micellar nanoparticles and carry DOX at the same time. The other advantage is that prepared nano-medicine carriers are stable in neutral condition but the bond will rupture as soon as under the circumstance of acidity. As a result, DOX are released to the inner cells. Water solubility is also increased due to this bond. To summary, PEG-CHO was prepared first, then reacting with NH2-DOX to form PEG-Schiff-DOX. A complete nanomedicine delivery modality was finished. Compared with free DOX, it has good stability and the size of the nanoparticles getting larger due to the outer-connected PEG. It helped prolonging blood circulation time. Meanwhile, the stable nanoparticles enlarged the drug loading capacity. What's more, with the pH-sensitive Schiff base bond, it ensures that DOX would be released accurately while the toxicity of it would be reduced properly. The whole procedure is illustrated in Fig.2. PEG-Schiff-DOX self-assembled with free dox first, thus a polymer with an empty cavity appeared. The nanoparticles penetrated into tumor tissues via EPR effect, then they were internalized by tumor cells via endocytosis. Once entering the acidic environment of intracellular endosomal/lysosomal compartments, pH-triggered cleavage of Schiff base bonds led to the nanoparticles' dissociation. In this way, encapsulated DOX would be released accurately and rapidly, subsequently the previously invisible Schiff-base bonds were exposed to the acidic environment while the conjugated PTX released completely at last.
Experimental Results and Discussion
Analysis of synthetic results
PEG-CHO synthesis PEG-CHO 1H NMR spectrum is shown in Figure 1, the analysis showed that benzene ring hydrogen (e,f) in the synthesized PEG-CHO was corresponds to the methyl peak (a) ratio at the end of the PEG, is a:e:f=3:2:2, can indicat the successful synthesis of PEG-CHO. PEG-Schiff-DOX synthesis PEG-Schiff-DOX H NMR spectrum (Figure 2) shows the peak shape of the drug molecule is messy and short. And using PEG end methyl as the starting point, the methyl peak (a) corresponds to the (b) area of the main chain peak, the peak (c+d+e) of the low-field region is derived from eight Hydrogen atom, on the benzene ring and Schiff bond. The integral area ratio basically corresponds, indicating the successful preparation of the PEG-Schiff-DOX.
PEG-Schiff-DOX morphology and degradation behavior of nanoparticles
As shown in Figure 3, PEG-Schiff-DOX spherical micelles below 200 nm can be assembled in pH=7.4 aqueous solution. When the nanoparticles are placed in an aqueous solution of pH=5.0
, the morphology and structure of the nanoparticles are obviously destroyed and amorphous. According to this phenomenon, PEG-Schiff-DOX nanoparticles can exist stably under neutral conditions and disintegrate under acidic conditions.
Nanometer drug stability and drug release behavior
pH responsiveness (stability) of nanopharmaceuticals by 37°C in buffer pH=5.0 particle size change results after two hours of oscillation are given. Figure 4 shows that PEG-Schiff-DOX particle size changes obviously before and after acid treatment, some nanoparticles have completely disintegrated. The narrow particle size distribution indicates that the heterogeneous nanoparticles disintegrate under the action of acid and release the drug. The test results of drug release behavior are more intuitive and can be seen from ultraviolet detection results. The PEG-Schiff-DOX nanoparticles loaded at pH=7.4 hardly released the drug, as shown in Figure 5, while the release behavior was significantly enhanced at pH=5.0. These results suggest that PEG-Schiff-DOX nanoparticles will reduce DOX leakage in the neutral environment of blood circulation, reduce toxicity to normal cells, and can rapidly disintegrate in the acidic environment of tumor tissue and intracellular endosomes/lysosomes compartment. It can achieve rapid drug release and kill tumor cells.
Claims (2)
1. A method of preparing of PH-sensitive drug delivery nanoparticles, characterized in that, including: the conjugated DOX we designed achieve to prolong drug circulation time via PEG, which can reduce the uptake by the reticuloendothelial system.
2. According to method of claim 1, wherein using the Schiff base bond to link DOX and PEG helps to accurately calculate the drug load rate and specifically release DOX in the acidic tumor microenvironment, thus improving batch repeatability of the loading system and reducing DOX-induced toxicity, respectively.
Figure 1
Figure 2
Figure 3
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113712939A (en) * | 2021-09-16 | 2021-11-30 | 浙江海洋大学 | Nanoparticle of adriamycin coupled chitosan oligosaccharide |
| CN114644665A (en) * | 2022-04-20 | 2022-06-21 | 湖南工程学院 | light/pH dual-response coupled prodrug compound and preparation method and application thereof |
| CN115444941A (en) * | 2022-09-06 | 2022-12-09 | 山西大学 | Double-drug nano-diamond drug releasing drug in response to pH as well as preparation method and application thereof |
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2020
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113712939A (en) * | 2021-09-16 | 2021-11-30 | 浙江海洋大学 | Nanoparticle of adriamycin coupled chitosan oligosaccharide |
| CN114644665A (en) * | 2022-04-20 | 2022-06-21 | 湖南工程学院 | light/pH dual-response coupled prodrug compound and preparation method and application thereof |
| CN114644665B (en) * | 2022-04-20 | 2023-05-12 | 湖南工程学院 | photo/pH dual-response coupled prodrug compound and preparation method and application thereof |
| CN115444941A (en) * | 2022-09-06 | 2022-12-09 | 山西大学 | Double-drug nano-diamond drug releasing drug in response to pH as well as preparation method and application thereof |
| CN115444941B (en) * | 2022-09-06 | 2024-05-28 | 山西大学 | Double-drug nano diamond drug capable of releasing drug in pH response mode and preparation method and application thereof |
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