CN115252804A - Lalotataxel-fatty alcohol small molecule prodrug and construction of self-assembled nanoparticles thereof - Google Patents

Lalotataxel-fatty alcohol small molecule prodrug and construction of self-assembled nanoparticles thereof Download PDF

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CN115252804A
CN115252804A CN202110478650.7A CN202110478650A CN115252804A CN 115252804 A CN115252804 A CN 115252804A CN 202110478650 A CN202110478650 A CN 202110478650A CN 115252804 A CN115252804 A CN 115252804A
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prodrug
fatty alcohol
larotaxel
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罗聪
王永军
杨金诚
马宏达
孙进
何仲贵
冯尧
马志宁
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Suzhou Yutai Pharmaceutical Technology Co ltd
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Abstract

The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, and relates to synthesis of a larotaxel-fatty alcohol micromolecule prodrug with a tumor reduction response characteristic, construction of self-assembled nanoparticles, and application of the larotaxel-fatty alcohol micromolecule prodrug in preparation of a medicament delivery system. The invention further provides a larotaxel-stearyl alcohol micromolecule prodrug, and the larotaxel-stearyl alcohol micromolecule prodrug is prepared from the larotaxel-stearyl alcohol micromolecule prodrug Cheng Laluo, and the larotaxel-fatty alcohol prodrug nano-particles can be non-PEGThe drug-loaded larotaxel-fatty alcohol prodrug nanoparticles and the active targeting larotaxel-fatty alcohol prodrug nanoparticles are prepared from the larotaxel-fatty alcohol prodrug nanoparticles modified by PEG, the drug-loaded larotaxel-fatty alcohol prodrug nanoparticles and the active targeting larotaxel-fatty alcohol prodrug nanoparticles. The synthesis steps of the larotaxel-fatty alcohol prodrug are few, the process is simple, the synthesis cost is reduced, the yield is high, the purification is easy, the particle size of nanoparticles formed by self-assembling the larotaxel-fatty alcohol micromolecule prodrug is ultra-small, the curative effect of the larotaxel is improved, and meanwhile, the toxic and side effects are reduced.

Description

Lalotataxel-fatty alcohol small molecule prodrug and construction of self-assembled nanoparticles thereof
Technical Field
The invention belongs to the field of new auxiliary materials and new dosage forms of medicinal preparations, and relates to synthesis of a larotaxel-fatty alcohol micromolecule prodrug with a tumor reduction response characteristic, construction of self-assembled nanoparticles, and application of the larotaxel-fatty alcohol micromolecule prodrug in preparation of a medicament delivery system.
Background
Larotaxel (Larotaxel, XRP9881, PRP 109881) is a new taxane cell cycle specific chemotherapeutic developed by Sanofi-Aventis through a semisynthetic method, and has a broad tumor suppression spectrum. Until now, the medicine has no preparation with definite curative effect at home and abroad to be sold on the market. The therapeutic effect of raloxistaxel is similar to other taxanes, acts on spindle tubulin in during cell division, combines with free tubulin, promotes the assembly of tubulin into stable microtubules and inhibits microtubule depolymerization, thereby inhibiting the mitosis of cancer cells. Different from other taxane compounds, the ralfatsia can effectively kill drug-resistant cells, can pass through a blood brain barrier, and has good anti-tumor application prospect. In vitro studies show that the anti-tumor activity of the larotaxel is stronger than that of the taxol, and the larotaxel has stronger inhibiting and killing effects on multidrug resistant tumor cells. The existing clinical research results show that after the larotaxel is dissolved by the Tween, the larotaxel is used as a second-line treatment or remedial treatment drug, and the curative effect of treating metastatic breast cancer is better than that of docetaxel and doxorubicin.
Although raltitrexed has good antitumor effect and clinical therapeutic prospect, raltitrexed has the defect of poor water solubility as other taxanes. In order to overcome the defect, the preparation of the larotaxides used in clinical trials abroad is generally added with polysorbate on the surface for solubilization treatment. For example, injection formulations used by Sanodi-Avents in their second-phase clinical trials have used polysorbate (Tween-80) as a solubilizing agent. Although the solubility enhancer solves the problem of difficult solubility of larotaxel to a certain extent, the introduction of the solubility enhancer often causes severe allergic reaction of patients, and the simple anticancer drug solution can cause further harm to the body of cancer patients who are weak due to the toxicity of the anticancer drug. Therefore, how to design a high-efficiency and low-toxicity raloxiracetam preparation is still the key point of the preparation for clinically exerting good anti-tumor effect.
Disclosure of Invention
Aiming at the technical background, the invention solves the technical problem of overcoming the defect of low solubility of the larotaxel and better exerting the antitumor effect of the larotaxel so as to achieve the aims of synergy and attenuation. The ralfataxel-fatty alcohol prodrug provided by the invention is characterized in that the ralfataxel and the fatty alcohol are connected together through chemically sensitive connecting arms, and the chemically sensitive bonds can be rapidly broken in tumor cells and a tumor microenvironment to release drugs. The raloxiracetam-fatty alcohol prodrug has tumor reduction response characteristics. Meanwhile, the raloxiracetam-fatty alcohol prodrug can be self-assembled into nanoparticles with ultra-small particle size (60-100 nm) in water. The prodrug of the prodrug nanoparticle system is used as a carrier material and a coated drug, so that the drug loading is very high and exceeds 50%.
The invention realizes the purpose through the following technical scheme:
the invention provides a raloxixel-fatty alcohol small molecule prodrug with tumor reduction response characteristics or pharmaceutically acceptable salts, isomers and solvates thereof:
Figure BDA0003048290380000021
wherein R is C3-C30A saturated or unsaturated chain hydrocarbon group;
further, the air conditioner is characterized in that,
Figure BDA0003048290380000022
or R is C3-C22An alkenyl group; the alkenyl contains 1-5 olefinic bonds;
p＝7-29；
n＝1-3；
further, when
Figure BDA0003048290380000023
When p =11-27;
further, when
Figure BDA0003048290380000024
When p =11-17;
when R is C3-C22When alkenyl, R includes, but is not limited to, propenyl, allyl, 2-butenyl, 4-pentenyl, 2-hexenyl, 4-decenyl, 2-dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraenyl, docosapentaenyl, linolyl.
Further, the present invention prefers raloxixel-fatty alcohol small molecule prodrugs of the following structure or pharmaceutically acceptable salts, isomers, solvates thereof:
Figure BDA0003048290380000031
the invention provides a synthesis method of a raloxiracetam-fatty alcohol prodrug, which comprises the following steps:
(1) Dissolving dithiodiglycolic acid in acetic anhydride, reacting for 2-4 hours at room temperature under the protection of nitrogen, and removing redundant acetic anhydride;
(2) Dissolving the product obtained in the step (1) in dichloromethane, adding fatty alcohol, adding 4-Dimethylaminopyridine (DMAP) as a catalyst, stirring at room temperature for 12-18 hours, and separating by using a cyclohexane-acetone elution system through column chromatography after the reaction is finished to obtain an intermediate product; dissolving the intermediate product, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt) and 4-Dimethylaminopyridine (DMAP) in anhydrous dichloromethane, activating for 2-4 hours in an ice bath, adding raltitrexed, reacting for 48-60 hours at 25-30 ℃ under the protection of nitrogen, and separating and purifying the obtained product by a preparation liquid phase.
The reaction formula is as follows:
Figure BDA0003048290380000032
r is C3-C30A saturated or unsaturated chain hydrocarbon group; n =1-3.
The fatty alcohol in the step (2) may be C3-C30Saturated or unsaturated fatty alcohols, such as n-dodecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, stearyl alcohol, 1-nonadecanol, 1-eicosanol, 1-docosanol, 1-hexacosanol, oleyl alcohol, linoleyl alcohol, or linolenyl alcohol, and the like.
Further, the invention provides nanoparticles of the larotaxel-fatty alcohol small molecule prodrug, wherein the larotaxel-fatty alcohol prodrug nanoparticles can be non-pegylated larotaxel-fatty alcohol prodrug nanoparticles, PEG modifier-modified larotaxel-fatty alcohol small molecule prodrug nanoparticles, drug-loaded larotaxel-fatty alcohol small molecule prodrug nanoparticles and actively targeted larotaxel-fatty alcohol small molecule prodrug nanoparticles.
The raltitrexed-fatty alcohol prodrug nanoparticle is prepared by the following method:
(1) The preparation method of the non-PEG small molecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug; the preparation of ultra-small nanoparticles can also be carried out by using a microfluidic device: preparing an ethanol solution containing the raltitrexed-fatty alcohol prodrug as an organic phase, taking ultrapure water as a water phase, and mixing according to the proportion of the water phase and the organic phase to prepare the raltitrexed-fatty alcohol prodrug nano-particles.
(2) The preparation method of the PEG modified micromolecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of PEG modifier and prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug; the preparation of ultra-small nanoparticles can also be carried out using microfluidic devices: preparing an ethanol solution containing a PEG modifier and a Larataxel-fatty alcohol prodrug as an organic phase, taking ultrapure water as a water phase, and mixing the water phase and the organic phase according to the proportion to prepare the Larataxel prodrug nanoparticles.
The PEG modifier is selected from but not limited to DSPE-PEG, TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA, and can be preferably DSPE-PEG2k、DSPE-PEG5k、TPGS2KThe mass ratio of the prodrug to the PEG modifier is 90-70.
(3) The preparation method of the hydrophobic drug-entrapped small molecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of PEG modifier, hydrophobic drug and prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles from the prodrug; the PEG modifier is selected from DSPE-PEG2k、DSPE-PEG5k、TPGS2KThe hydrophobic drugs include, but are not limited to, the aforementioned raltitrexed and other taxane-fatty alcohol prodrugs.
(4) The preparation method of the active targeting small molecule prodrug self-assembly nanoparticle comprises the following steps: dissolving a certain amount of PEG modifier, PEG modified by hydrophobic target head and prodrug into a proper amount of ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug; what is needed isThe PEG modifier is selected from DSPE-PEG2k、DSPE-PEG5k、TPGS2KThe target head modified PEG includes but is not limited to cRGD-PEG-PLL, DSPE-PEG2K-Pep-1、DSPE-PEG-CREKA。
The larotaxel-fatty alcohol small molecule prodrug disclosed by the invention is found to be capable of self-assembling to form a uniform nano system for the first time. The advantages of the nano-drug delivery system are:
(1) A series of novel Lalotasirox-fatty alcohol small molecule prodrugs are provided, and the prodrugs can be self-assembled into nanoparticles;
(2) The synthesis steps of the raltitrexed-fatty alcohol prodrug are few, the raltitrexed-fatty alcohol prodrug with an oxidation-reduction bond can be synthesized by only two steps, the process is simple, the synthesis cost is reduced, the yield is high, the purification is easy, the purity after the purification reaches up to 99.5 percent, and the process has strong process amplification advantages;
(2) Nanoparticles formed by self-assembly of the larotaxel-fatty alcohol micromolecule prodrug have ultra-small (about 60-100 nm) and uniform particle size, and are beneficial to being enriched on tumor parts through an EPR (ethylene propylene rubber) effect, so that the anti-tumor effect is improved;
(3) The medicine has ultrahigh medicine-loading rate and good stability, and is beneficial to reducing adverse reactions caused by auxiliary materials and biological materials;
(4) The surface modification is easy, the uptake of reticuloendothelial system can be effectively avoided and the uptake of tumor cells to nanoparticles can be improved through PEG and active targeting modification, and the circulation time of larotaxel in blood can be effectively prolonged;
(5) The sensitivity of the prodrug to the intracellular environment of a tumor part is increased by reducing the sensitive chemical connecting arm, so that the specific drug release of the larotaxel in the tumor cells and the tumor microenvironment is realized, the curative effect is improved, and the toxic and side effects are reduced.
Drawings
FIG. 1 is a drawing of the disulfide-linked Lalottasai-stearyl alcohol prodrug (LTX-SS-SA) of example 1 of the present invention1HMR spectrum.
FIG. 2 is a mass spectrum of a disulfide-linked Lalotaxel-stearyl alcohol prodrug (LTX-SS-SA) of example 1 of the present invention.
Fig. 3 is a graph of particle size versus storage time for pegylated small molecule prodrug self-assembled nanoparticles of example 3 of the present invention.
Fig. 4 is a blood concentration-time curve diagram of the pegylated small molecule prodrug self-assembled nanoparticle of example 3 of the present invention.
Fig. 5 is a graph of tumor volume change of the pegylated small molecule prodrug self-assembled nanoparticle of embodiment 3 of the invention in an anti-tumor experiment.
Fig. 6 is a graph of the change in body weight of mice in an in vivo anti-tumor experiment of PEG-based small molecule prodrug self-assembled nanoparticles of example 3 of the invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
Example 1: synthesis of tumor reduction sensitive disulfide-linked Lalotaside-stearyl alcohol prodrugs (LTX-SS-SA)
Figure BDA0003048290380000061
5mmol dithiodiglycolic acid was added to a 50mL eggplant-shaped bottle, dissolved in 10mL acetic anhydride, reacted at room temperature for 2 hours under nitrogen protection, and then distilled under reduced pressure to remove excess acetic anhydride. The resulting product was dissolved in 30mL of dichloromethane, and 5mmol of stearyl alcohol and 2mmol of dmap were added thereto, stirred at 25 ℃ for 12 hours, and purified by silica gel column chromatography using cyclohexane-acetone (12-15). Finally, the intermediate product, 5mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 5mmol of 1-hydroxybenzotriazole (HOBt) and 1mmol of 4-Dimethylaminopyridine (DMAP) are dissolved in 50mL of anhydrous dichloromethane, ice bath is carried out for 1 hour, then a proper amount of larotaxel is added, reaction is carried out at room temperature for 24 hours under the protection of nitrogen, the final product is separated and purified by a preparation liquid phase and an acetonitrile-water (90-99. Measurement by nuclear magnetic resonance1H-NMR Hydrogen spectroscopy and LC-MS were used to determine the structure of the prodrug of example 1, as shown inAs shown in fig. 1 and 2.
Example 2: preparation of non-PEGylated Larataxel-stearyl alcohol prodrug small molecule prodrug self-assembly nanoparticles
The prodrug of example 1, 8mg, was weighed accurately, dissolved in 800. Mu.L of ethanol, and the ethanol solution was added dropwise slowly to 4mL of deionized water with stirring to spontaneously form uniform nanoparticles.
Example 3: preparation of PEG modified Lalotaside-stearyl alcohol prodrug small molecule prodrug self-assembly nanoparticles
Accurately weighing DSPE-PEG2K1.4mg and 8mg of the prodrug of example 1, dissolved in 800. Mu.L of ethanol, and the ethanol solution was slowly added dropwise to 4mL of deionized water with stirring to spontaneously form PEG-modified nanoparticles having a uniform particle size. When the dosage of PEG is 10-30%, more stable nanoparticles with the particle size of 80nm can be obtained.
Altering prodrugs with DSPE-PEG2KThe results show that when DSPE-PEG is used2KWhen the dosage is 10% -30%, the prodrug and DSPE-PEG are2KIn a ratio of 90:10-70: at 30, the grain diameter of the prepared nano-particle is 70-100 nm, and the grain diameter polydispersity is less than 0.2.
The DSPE-PEG2KAlternatively, amphiphilic polymers such as TPGS, PLGA-PEG, PE-PEG or DSPE-PEG-AA, or targeting groups may be used instead.
Example 4: the microminiature raloxitol small molecule prodrug nanoparticles were prepared using a microfluidic device:
preparation of a composition containing DSPE-PEG2000And ethanol solution of Laratarettol small molecule prodrug is used as an organic phase, wherein the concentration of Laratarettol prodrug is 10mg/ml, and DSPE-PEG20002mg/ml; ultrapure water is used as a water phase, and the flow speed ratio of the water phase to an organic phase is 5:1, and finally obtaining the raloxitol small molecule prodrug nano-particles.
After the nanoparticles were diluted by 50 times, 1ml of the diluted sample was placed in a particle size cup, and the particle size and dispersion index of the nanoparticles were measured by a Malvern Zetasizer particle sizer, and the results are shown in fig. 3.
Example 5: pharmacokinetics research of small molecule prodrug self-assembled nanoparticles
12 healthy male rats with a body weight of 200-250g were randomly divided into 2 groups, fasted for 12h before administration, and allowed free drinking water. The solution of larotaxel and the pegylated small molecule prodrug self-assembled nanoparticles (particle size 80 nm) prepared in example 3 were injected intravenously, respectively. The dosage of larotaxel was 4mg/kg. Orbital bleeds were performed at defined time points of 0.083h, 0.25h, 0.50h, 1.00h, 2.00h, 4.00h, 8.00h, 12.00h, 24.00h and 48.00h, and plasma was isolated. The drug concentration in plasma was determined by liquid chromatography-mass spectrometer.
The results are shown in fig. 4, the circulation time of the PEGylated small molecule prodrug is obviously prolonged, the bioavailability is obviously improved, and the stability is better compared with the solution. Experimental results show that the PEG small-molecule prodrug self-assembly nanoparticles can obviously prolong the circulation time of larotaxel in blood.
TABLE 1 pharmacokinetic parameters of LTX-SS-SAL prodrug nanoparticles and LTX solutions
Figure BDA0003048290380000071
Example 6: in vivo anti-tumor experiment of PEG (polyethylene glycol) -modified small-molecule prodrug self-assembled nanoparticles
Mouse breast cancer cell suspension (4T1, 5x10)6cells/100 ul) were inoculated ventral subcutaneous female BALB/c mice. When the tumor volume grows to 100-120mm3Tumor-bearing mice were randomly divided into five groups of five mice each: a blank control group (PBS), a larotaxel solution group (8 mg/kg), an LTX-SS-SA nanoparticle low dose group (4 mg/kg), an LTX-SS-SA nanoparticle medium dose group (8 mg/kg) and an LTX-SS-SA nanoparticle high dose group (12 mg/kg). The nanoparticles used for administration were PEG-modified small molecule prodrug self-assembled nanoparticles prepared in example 3. The administration was 1 time every 1 day and 5 times continuously. Mice were observed daily for survival after dosing, weighed, and tumor volume measured. Data were collected and analyzed after mice were sacrificed one day after the last dose.
The results are shown in FIG. 5, blank controlThe tumor volume of the group increased rapidly and reached 600-700mm on day 103. In contrast, the raloxistaxel solution group (Free-LTX) was able to retard tumor growth, while the nanoparticle formulation group was able to significantly inhibit tumor growth, with the tumor volume of the high dose formulation group being only 130mm3. This reflects that the raloxitol nanoparticle designed by us has good anti-tumor effect.
The results are shown in FIG. 6, and the body weight of each group of mice was not significantly changed. The result shows that the PEG micromolecule prodrug self-assembly nanoparticles have obvious anti-tumor effect, do not cause remarkable non-specific toxicity to organisms, and are a safe and effective anti-cancer drug delivery system.

Claims (10)

1. A larotaxel-fatty alcohol small molecule prodrug of the structure:
Figure FDA0003048290370000011
wherein R is C3-C30A saturated or unsaturated chain hydrocarbon group;
preference is given to
Figure FDA0003048290370000012
Or R is C3-C22An alkenyl group; the alkenyl contains 1-5 olefinic bonds;
p＝7-29；
n＝1-3。
2. the larotaxel-fatty alcohol small molecule prodrug of claim 1, or a pharmaceutically acceptable salt, isomer, solvate thereof,
wherein,
Figure FDA0003048290370000013
and p =11-27, preferably p =11-17; or R is propenyl, allyl, 2-butenyl, 4-pentenyl,2-hexenyl, 4-decenyl, 2-dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 9-octadecenyl, eicosatetraenyl, docosapentaenyl, linoleic acid.
3. The raloxixel small molecule prodrug or a pharmaceutically acceptable salt, isomer, solvate thereof of claim 1 or 2:
Figure FDA0003048290370000014
n =1-3, preferably 1.
4. The method of preparing a Lalotasitol small molecule prodrug as claimed in claim 1,
(1) Dissolving dithiodiglycolic acid in excessive acetic anhydride, reacting at room temperature under the protection of nitrogen, and removing the excessive acetic anhydride;
(2) Reacting the product obtained in the step (1) with fatty alcohol by using 4-dimethylamino pyridine as a catalyst, and separating by using column chromatography after the reaction is finished to obtain an intermediate product; dissolving the intermediate product, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-dimethylaminopyridine in anhydrous dichloromethane, activating under ice bath, adding raltitrexed under the protection of nitrogen, reacting at 25-30 ℃, and separating and purifying the obtained product by a prepared liquid phase to obtain the compound;
the fatty alcohol is C3-C30Saturated or unsaturated fatty alcohols.
5. The self-assembled nanoparticles of raloxiracetam-fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt, isomer, solvate thereof according to any one of claims 1 to 3, comprising non-pegylated raloxiracetam-fatty alcohol prodrug nanoparticles, PEG-modified raloxiracetam-fatty alcohol prodrug nanoparticles, drug-loaded raloxiracetam-fatty alcohol prodrug nanoparticles, and actively targeted raloxiracetam-fatty alcohol prodrug nanoparticles, wherein the PEG modifier is preferably a PEG selected from the group consisting of TPGS, DSPE-PEG, PLGA-PEG, PE-PEG, and DSPE-PEG-AA, and the mass ratio of the raloxiracetam-fatty alcohol small molecule prodrug to the PEG modifier is 90 to 70.
6. The self-assembled nanoparticles of a larotaxel-fatty alcohol small molecule prodrug or a pharmaceutically acceptable salt thereof of claim 5, prepared by a method comprising:
dissolving Larotaxel-fatty alcohol micromolecule prodrug or a mixture of the Larotaxel-fatty alcohol micromolecule prodrug and PEG modifier into ethanol, slowly dripping the ethanol solution into water under stirring, and spontaneously forming uniform nanoparticles by the prodrug;
or taking an ethanol solution containing the PEG modifier and the Lalotasite-fatty alcohol micromolecule prodrug as an organic phase, taking ultrapure water as a water phase, and preparing by adopting a microfluidic device.
7. Use of the raloxiracetam-fatty alcohol small molecule prodrug of any of claims 1-3, or a pharmaceutically acceptable salt, isomer, solvate thereof, or the small molecule prodrug self-assembling nanoparticle of claim 5 for the preparation of a drug delivery system.
8. Use of the larotaxel-fatty alcohol small molecule prodrug or the pharmaceutically acceptable salt, isomer, solvate or the small molecule prodrug self-assembled nanoparticle of claim 5 of any one of claims 1 to 3 in the preparation of an antitumor drug.
9. Use of the raloxiracetam-fatty alcohol small molecule prodrug of any of claims 1-3, or a pharmaceutically acceptable salt, isomer, solvate thereof, or the self-assembled nanoparticle of the cabazitaxel fatty alcohol prodrug of claim 5, for the preparation of a drug that increases the therapeutic efficacy and reduces the toxicity.
10. Use of the raloxiracetam-fatty alcohol small molecule prodrug of any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, solvate thereof, or the small molecule prodrug self-assembling nanoparticle of claim 5 for the preparation of an injectable, oral, or topical delivery system.
CN202110478650.7A 2021-04-30 2021-04-30 Lalotataxel-fatty alcohol small molecule prodrug and construction of self-assembled nanoparticles thereof Pending CN115252804A (en)

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