A method for preparing a polymer nanoparticle

Abstract

The application discloses a kind of ultrasonic microreactor preparation methods of polymer nanoparticles, comprising the following steps: (1) configuration organic solution (2) ultrasonic mixing (3) solvent removal, by organic-organic mutual solution nanometer precipitation system preparation monodisperse polymer nanoparticles, expand the preparation system of polymer nanoparticles;Using ultrasonic microreactor to mix, prevent blockage and the operation flexibility is high, energy utilization is strong, reduce its preparation cost, easy to realize the continuous long time production of product, with wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of nanoparticle synthesis, and more specifically to a method for preparing polymer nanoparticles. Background Technology

[0002] Polymer nanoparticles, with their small particle size and large specific surface area, have wide and important applications in biomedicine, environment, catalysis, electronics, and aerospace. In biomedicine, polymer nanoparticles are primarily used as carriers for nanomedicines. Nanomedicines are a new type of drug that uses nanomaterials as delivery carriers to carry active pharmaceutical ingredients such as nucleic acids and small molecules. They possess characteristics such as high absorption and utilization rates and targeted delivery, making them important tools for cancer treatment and gene therapy, and are considered next-generation drugs.

[0003] Specifically, polymer nanoparticles as drug carriers have the following advantages: (1) The large molecular weight of polymers allows drugs to remain at the lesion site for a longer period of time; (2) Drugs can achieve sustained or controlled release within polymer particles through diffusion or degradation of the polymer itself; (3) Functional components with targeting effects or those that control drug release can be chemically bonded to the surface of polymer particles; (4) If biodegradable polymer materials are selected, the accumulation of carrier materials in human organs and tissues after drug release can be avoided, preventing toxic side effects. Currently, the polymer particles used as drug carriers reported in the literature are typically between 1 and 1000 nm in size, and their morphological structures are mainly microspheres and microcapsules. Drugs can be physically embedded or chemically bonded into polymer nanoparticles.

[0004] There are various methods for preparing polymer nanoparticles, among which the emulsification-solvent evaporation method and the nanoprecipitation method are the most commonly used. The emulsification-solvent evaporation method first dissolves the polymer in a soluble, benign solvent, using a good fluid solution. This solution is then dispersed into a dispersion medium containing a surfactant using high-speed homogenization, ultrasonication, strong mechanical stirring, or membrane dispersion, forming O / W or dual emulsion droplets to obtain polymer nanoparticles with a particle size ranging from 10 to 1000 nm. However, this method yields a wide particle size distribution, and the surfactant removal process is complex and prone to product contamination. The nanoprecipitation method, due to its simple preparation process and high product quality, is widely used by researchers. In the nanoprecipitation method, the polymer is dissolved in an organic solvent, and through rapid mixing with a poor solvent, the polymer precipitates under supersaturation. After a series of treatments, polymer nanoparticles are obtained.

[0005] Monodispersity is a crucial criterion for evaluating the quality of nanoparticles. Monodisperse particles refer to a dispersion system with uniform size, shape, and chemical composition. However, due to the complexity and stringent conditions required for preparing monodisperse particles, truly monodisperse particle groups do not exist. Generally, monodispersity refers to a group of particles with uniform shape and composition and a very narrow particle size distribution. Highly monodisperse particles exhibit uniform morphology, size, and crystal form, resulting in consistent overall particle properties. To prepare highly uniformly dispersed polymer nanoparticles, devices with excellent mixing properties, such as microreactors and microjets, are often used. The mixing of the good solvent and antisolvent containing the polymer precursor must be sufficiently rapid, with the mixing time shorter than the nucleation time. However, polymer nanoparticles have high viscosity, making them prone to clogging microchannels. Conventional passive methods rely on complex channel structures, resulting in poor operational flexibility and further increasing the risk of clogging. To address the problems of easy clogging and difficulty in enhancing mixing and mass transfer in microreactors, external energy needs to be introduced into the microreactor to disrupt and prevent clogging, thereby further enhancing mixing and mass transfer. Due to its advantages such as good penetration, high energy density, and safety and reliability, ultrasound is widely used in process intensification. By introducing ultrasonic energy into microreactors and integrating them into ultrasonic microreactors, the problem of solid blockage in microreactors can be effectively solved, and the mixing and mass transfer of fluids can be enhanced.

[0006] Therefore, ultrasonic microreactors have broad application prospects in the field of nanoparticle preparation. Due to the special properties and applications of polymer nanoparticles, how to obtain a monodisperse polymer nanoparticle is also of great research significance. Summary of the Invention

[0007] The purpose of this invention is to solve the technical problems existing in the prior art, such as low mixing efficiency of the preparation system, large average particle size and poor monodispersity of polymer nanoparticles, easy clogging of the system, poor operational flexibility, and difficulty in achieving continuous scale-up production. The purpose of this invention is to provide a method for preparing polymer nanoparticles using an ultrasonic microreactor. Through an organic-organic miscible nanoprecipitation system, the mechanical stirring effect of ultrasonic cavitation bubbles is more easily triggered, enabling instantaneous mixing performance and preparing monodisperse polymer nanoparticles. This expands the preparation system of polymer nanoparticles, prevents clogging, has high operational flexibility, strong energy utilization, reduces preparation costs, and facilitates continuous long-term production of the product, thus having broad application prospects.

[0008] To achieve the above-mentioned objectives, the technical solution adopted by the present invention is as follows: a method for preparing polymer nanoparticles, wherein the polymer nanoparticles are copolymers, block copolymers, or polymer prodrugs.

[0009] A method for preparing polymer nanoparticles, the method comprising the following steps:

[0010] (1) Prepare organic solutions:

[0011] Anti-solution fluids: organic solvents, or organic solutions containing stabilizers;

[0012] Good solution fluid: an organic solution containing a polymer precursor, or an organic solution containing a polymer precursor and a stabilizer, wherein the mass concentration of the polymer precursor is 0.1-20%;

[0013] (2) Ultrasonic mixing: The reverse solution fluid and the good solution fluid containing polymer precursor are simultaneously transported to a tubular reactor for ultrasonic-enhanced instantaneous mixing. The residence time in the tubular reactor is 0.1s-60s to obtain the crude product.

[0014] (3) Solvent removal: The organic solvent is removed from the crude product to obtain the polymer nanoparticle product;

[0015] In the above method, the polymer precursor is dissolved in a solvent with excellent solubility for it, i.e., a good solution fluid. Then, the entire solution is added to a solution with poor solubility for the polymer, i.e., a reverse solution fluid. When the two fluids are mixed, local supersaturation occurs, which leads to the precipitation of nanoparticles. The organic solvent on the surface of the precipitated nanoparticles is removed to obtain the polymer nanoparticle product. A tubular reactor is used for fluid mixing and ultrasonic-enhanced mixing. Under the action of ultrasound, a large number of cavitation bubbles are generated in the pipe. These cavitation bubbles (and bubble groups) undergo violent translational motion, surface oscillation, collision tearing, and merging and agglomeration, generating strong eddies and flow field disturbances. Each cavitation bubble becomes a miniature stirrer, which significantly enhances the liquid mixing in the pipe and avoids the problems of weak convective mixing and easy blockage by solids in tubular reactors. At the same time, in the organic-organic phase fluid system under the action of ultrasound, the ultrasonic energy is more likely to excite cavitation bubbles, so that the violent movement and stirring of cavitation bubbles achieve an instantaneous mixing effect. The resulting polymer nanoparticles are smaller and more uniform.

[0016] In this invention, the reverse solution fluid refers to a polymer precursor with a solubility of less than 0.1 mg / L in an organic solvent or an organic solution containing a stabilizer. Correspondingly, a good solution fluid is defined as one with a polymer precursor solubility of 10 mg / mL or higher. When a good solution fluid and a reverse solution fluid are mixed, polymer nanoparticles precipitate under the influence of supersaturation. Better mixing results are more conducive to preparing small-sized, uniformly distributed nanoparticles.

[0017] Preferably, the concentration of the stabilizer is 0.01-5%, more preferably 0.03-3%.

[0018] The stabilizer is at least one of mannitol, polyvinyl alcohol, and polyvinylpyrrolidone.

[0019] Adding stabilizers to the fluid can, on the one hand, form a protective layer on the surface of polymer nanoparticles, effectively inhibiting their aggregation and improving their dispersibility and stability. On the other hand, stabilizers can also be adsorbed during the nucleation process of polymer nanoparticles, influencing their nucleation kinetics to some extent. This results in ultrasonic mixing time being shorter than the nucleation time, making it easier to prepare small-sized, monodisperse polymer nanoparticles.

[0020] Preferably, the tubular reactor used to apply ultrasound in step (2) is an ultrasonic microreactor, which uses a transducer as the ultrasonic source; the tubular reactor is combined with the ultrasonic generating device by one or more of the following methods: adhesive bonding, welding, or mechanical structure fixation, so as to introduce ultrasound into the fluid pipeline.

[0021] Preferably, in the above preparation method, the ultrasonic microreactor used in step (2) includes:

[0022] An ultrasonic transducer for generating ultrasonic waves;

[0023] An amplitude transformer, one end of which is connected to the ultrasonic transducer;

[0024] The tool head has a columnar structure along its length, and one end of the tool head is connected to the other end of the amplitude transformer.

[0025] A fluid conduit is provided inside the tool head on the side away from the amplitude transformer, or the fluid conduit is connected to the outer side of the tool head away from the amplitude transformer. The amplitude transformer is used to transmit the ultrasonic waves generated by the ultrasonic transducer to the tool head, and the tool head is used to concentrate the ultrasonic energy within the tool head into the fluid conduit. This arrangement can enhance the mixing of the fluid within the fluid conduit.

[0026] This invention utilizes a self-developed ultrasonic microreactor for its fabrication process. The ultrasonic microreactor employs a columnar toolhead structure, with the fluid conduit positioned inside the toolhead on the side away from the amplitude transformer, or connected to the outer side of the toolhead away from the amplitude transformer. This design reduces the processing cost of the fluid conduit, facilitates easier connection between the fluid conduit and the toolhead, and ensures that dispersed ultrasonic energy is concentrated within the fluid conduit despite its large length and volume. The specific structure of the self-developed ultrasonic microreactor used in this invention is detailed in Chinese patent application CN 202110953049.9.

[0027] Preferably, the hydraulic diameter of the fluid pipe is 0.1mm-50mm, preferably 0.2-10mm; the ultrasonic frequency is 10kHz-2000kHz, preferably 20-200kHz; and the power is 10W-1000W, preferably 20-200W.

[0028] Under ultrasonic stimulation, numerous cavitation bubbles are generated in the pipe. These bubbles (and bubble swarms) undergo violent translational motion, surface oscillation, collisional tearing, and coalescence. These cavitation phenomena generate strong eddies and flow field disturbances, making each cavitation bubble a miniature stirrer, significantly enhancing fluid mixing in the channel. Depending on the bubble radius and ultrasonic power, each bubble (bubble swarm) exhibits different cavitation modes, such as volumetric oscillation, shape oscillation, and transient cavitation. Cavitation behavior is most intense near the resonance size, resulting in transient cavitation; the further the bubble radius is from the resonance size, the weaker its cavitation behavior becomes, gradually transitioning from shape mode to volumetric mode and oscillation. With increasing ultrasonic power, the bubbles change from volumetric oscillation to regular surface wave oscillation, and finally to chaotic wave oscillation. These oscillation behaviors exhibit a significant confinement effect: the smaller the pipe size and the tighter the gas-liquid interface bound by the pipe wall, the more difficult it is to excite surface wave oscillations, and the smaller the oscillation amplitude under the same ultrasonic power. Violent acoustic flow also appears near the oscillating bubbles, which couples and superimposes with the internal circulation in the liquid blast, significantly enhancing convective mixing in the liquid. Therefore, it is necessary to combine the fluid properties of good solution fluid and reverse solution fluid, and select a pipe ultrasonic microreactor with appropriate power, frequency and suitable hydraulic diameter to help obtain polymer nanoparticles with uniform and controllable particle size.

[0029] Preferably, the flow rate ratio of the good solution fluid to the reverse solution fluid used in step (2) is 1:(0.1-10).

[0030] When good and bad solutions are mixed in different proportions, the mixing intensity and number of cavitation bubbles triggered by ultrasonic energy vary, leading to differences in mixing time. Simultaneously, different proportions of good and bad solutions also affect the nucleation and growth process of polymer nanoparticles, especially at ratios of 1:(0.1-10). Controlling different mixing ratios to achieve excellent instantaneous mixing can produce polymer nanoparticles with small size and good dispersibility.

[0031] Preferably, the solvent removal method in step (3) is at least one of centrifugation, drying or rotary evaporation under reduced pressure.

[0032] The principle of centrifugal washing is to remove residual solvent from the crude product, ensuring minimal impurities remain in the nanoparticles. The principle of vacuum rotary evaporation is to remove low-boiling-point organic solvents from the crude product. Specifically, the reduced pressure in the equipment causes the solvent to boil at a lower temperature than normal. Rotating the flask increases the surface area of ​​the liquid, thereby increasing the evaporation rate. Solvent vapor condenses upon contact with the condenser and drips into a receiving device. When the organic solvent is removed, the desired product is obtained.

[0033] Preferably, the drying method is any one of blower drying, vacuum drying, freeze drying, or spray drying.

[0034] Drying refers to the process of using heat energy to vaporize the moisture in wet materials and remove the steam, thereby obtaining drier materials, or using freezing methods to remove moisture by sublimation after freezing. Among these methods, forced-air drying uses a chamber to circulate hot air to achieve the drying purpose; vacuum drying works by reducing the pressure around the liquid in a vacuum, thereby lowering the liquid's boiling point and increasing the evaporation rate; spray drying works by spraying a solution into fine droplets in hot air, where the moisture evaporates as the droplets fall, resulting in a powdered or granular product; in freeze-drying, the product is first pre-frozen, and then sublimated under vacuum, allowing the moisture to directly transform from ice into vapor, thus achieving dryness.

[0035] Preferably, when the organic solvent used in the reverse solution fluid and / or the good solution fluid is a solvent with a high saturated vapor pressure, the solvent can be removed directly by drying, specifically by any one of the following methods: forced air drying, vacuum drying, or spray drying.

[0036] Preferably, the polymer precursor in step (1) is one or more of the following polymers: polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), poly(D,L-glycolic acid) (PLG), polycaprolactone (PCL), polymethylpropionamide (PMAA), polyethylene glycol-polylactic acid-glycolic acid copolymer (PEG-PLGA), polycaprolactone-polyethylene glycol copolymer (PCL-PEG); polymethacrylic acid-polyethylene glycol (PHPMA-PEG), polyethylene glycol-polycarbonate block copolymer (DG-MPEG); PAMAM-PEG-DOX prodrug; PEG-SS-PASP-Hyd-DOX prodrug; polymethacrylic acid-hydrazone-doxorubicin (PHPMA-Hyd-DOX). Among them, PLGA has been certified by the U.S. Food and Drug Administration (FDA) and is officially included in the United States Pharmacopeia as a pharmaceutical excipient.

[0037] Compared with the prior art, the present invention has achieved beneficial technical effects:

[0038] This invention prepares monodisperse polymer nanoparticles through an organic-organic miscible two-phase nanoprecipitation system, expanding the preparation system of polymer nanoparticles. The use of an ultrasonic microreactor for mixing avoids the problems of weak convective mixing and easy solid blockage in tubular reactors. Furthermore, based on the organic-organic miscible system, the movement of cavitation bubbles is more intense and the stirring effect is better, resulting in smaller, more uniform polymer nanoparticles with high energy utilization, reduced preparation costs, and easy continuous long-term production, showing broad application prospects. The polymer nanoparticles prepared by this invention have a small average particle size, a PDI as low as 0.04, and a uniform particle size distribution, indicating good monodispersity.

[0039] Attached Figure

[0040] Figure 1 The present invention describes the preparation process of polymer nanoparticles.

[0041] Figure 2 Dynamic light scattering particle size and distribution of the copolymer nanoparticles prepared in Example 1;

[0042] Figure 3 Comparison of dynamic light scattering particle size and distribution of nanoparticles prepared in Example 1 and Comparative Example 1;

[0043] Figure 4 This is a scanning electron microscope image of the polymer nanoparticles prepared in Example 1. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. However, the scope of protection of this invention is not limited to the specific embodiments described below.

[0045] In the following embodiments,

[0046] PLGA (polylactic acid-glycolic acid copolymer, Mw: 38000-54000) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0047] PVP-K30 (polyvinylpyrrolidone, Mw: 40000) was purchased from Siegfried and from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0048] Anhydrous ethanol and acetone were of analytical grade and purchased from China National Pharmaceutical Group Co., Ltd.

[0049] mPEG5K-PLGA10K (methyl polyethylene glycol 10k polylactic acid-hydroxyacetic acid 5k-block copolymer) was purchased from Shanghai Yayi Biotechnology Co., Ltd.

[0050] Dichloromethane and diethyl ether were of analytical grade and purchased from China National Pharmaceutical Group Co., Ltd.

[0051] The ultrasonic microreactor used in the following embodiments includes:

[0052] An ultrasonic transducer for generating ultrasonic waves;

[0053] An amplitude transformer, one end of which is connected to the ultrasonic transducer;

[0054] The tool head has a columnar structure along its length, and one end of the tool head is connected to the other end of the amplitude transformer.

[0055] A fluid conduit is disposed inside the tool head on the side away from the amplitude transformer; the amplitude transformer is used to transmit the ultrasonic waves generated by the ultrasonic transducer to the tool head, and the tool head is used to concentrate the ultrasonic energy inside the tool head into the fluid conduit.

[0056] Examples 1-4: Preparation of a copolymer nanoparticle

[0057] The concentrations of polymer precursors in the good solution fluids used in Examples 1-4, the total flow rates of the reverse solution fluid and the good solution fluid, and the power of the ultrasonic microreactor are shown in Table 1 below. Figure 1 The preparation steps for polymer nanoparticles are as follows.

[0058] A solution of PLGA dissolved in acetone was used as the good solution fluid, and an ethanol solution containing 0.1% PVP-K30 was prepared as the reverse solution fluid. The reverse solution fluid and the good solution fluid containing the polymer precursor were simultaneously fed into an ultrasonic microreactor for ultrasonic-enhanced instantaneous mixing. The flow ratio of the good solution fluid to the reverse solution fluid was 2:1. The residence time in the ultrasonic microreactor was 1 s at room temperature, the hydraulic diameter of the fluid conduit was 1 mm, and the ultrasonic frequency was 20.3 kHz. The mixed product was then subjected to rotary evaporation under reduced pressure for 10 min, followed by vacuum drying to obtain PLGA nanoparticles.

[0059] Examples 5-8: Preparation of Block Copolymer Nanoparticles

[0060] The concentrations of polymer precursors in the good solution fluids, the reverse solution fluids, and the good solution fluids used in Examples 5-8, and the power of the ultrasonic microreactors are shown in Table 1. (Refer to...) Figure 1 The preparation steps for polymer nanoparticles are as follows.

[0061] A solution of PEG5K-PLGA10K dissolved in dichloromethane was used as the good solution fluid, and anhydrous diethyl ether was used as the reverse solution fluid. The reverse solution fluid and the good solution fluid containing the polymer precursor were simultaneously transported to an ultrasonic microreactor for ultrasonic-enhanced instantaneous mixing. The volume ratio of the good solution fluid to the reverse solution fluid was 3:1. At room temperature, the residence time in the ultrasonic microreactor was 0.5 s, the hydraulic diameter of the fluid conduit was 1 mm, and the ultrasonic frequency was 40 kHz. The mixed product was then centrifuged, washed multiple times with water, and dried by forced air to obtain polymer nanoparticles.

[0062] Comparative Example 1: Preparation of copolymer nanoparticles in an acetone-water system

[0063] Under the same conditions as in Example 1, acetone containing PLGA was used as the good solution fluid, and an aqueous solution of PVP-K30 was used as the reverse solution fluid to prepare PLGA polymer nanoparticles.

[0064] Performance testing

[0065] The average particle size and monodispersity of the polymer nanoparticles prepared in Examples 1-8 and Comparative Example 1 were tested. The test methods are as follows, and the test data are recorded in Table 1.

[0066] Average particle size and PDI test: A small amount of polymer nanoparticles were added to 1 mL of deionized water, ultrasonically dispersed, and then characterized by dynamic light scattering at 25 °C for average particle size and polydispersity index (PDI).

[0067] Table 1. Total flow rate, concentration, ultrasonic microreactor power, and nanoparticle characterization of raw materials in Examples 1-8 and Comparative Example 1

[0068]

[0069] The test results show that the PDI of Comparative Example 1 is higher than that of Example 1, with an average particle size of 142.6 nm and a PDI of 0.222. This indicates that the preparation of nanoparticles using an ultrasonic microreactor with an organic-organic hybrid system can yield high-quality polymer nanoparticles with small average particle size and narrow distribution.

[0070] A comparison of the dynamic light scattering particle size distribution data between Comparative Example 1 and Example 1 is shown in the figure. Figure 3 It can be seen that, based on the ultrasonic microreactor and using an organic-organic hybrid system, high-quality polymer nanoparticles with small average particle size and narrow distribution can be synthesized.

[0071] Based on the disclosure and teachings of the foregoing specification, those skilled in the art can make changes and modifications to the above embodiments. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the invention should also fall within the protection scope of the claims of the present invention. Furthermore, although some specific terms are used in this specification, these terms are only for convenience of explanation and do not constitute any limitation on the invention.

Claims

1. A method for preparing polymer nanoparticles, characterized in that, The method includes the following steps: (1) Prepare organic solution: Anti-solution fluids: organic solvents, or organic solutions containing stabilizers; Good solution fluid: an organic solution containing a polymer precursor or an organic solution containing a polymer precursor and a stabilizer, wherein the mass concentration of the polymer precursor is 0.1-20%; (2) Ultrasonic mixing: The reverse solution fluid and the good solution fluid are simultaneously transported to a tubular reactor for ultrasonic-enhanced instantaneous mixing. The residence time in the tubular reactor is 0.1s-60s to obtain the crude product. (3) Solvent removal: The organic solvent is removed from the crude product to obtain the polymer nanoparticle product. The tubular reactor used in step (2) to apply ultrasound is an ultrasonic microreactor, which uses a transducer as the ultrasonic source. The tubular reactor is combined with the ultrasonic generating device through one or more methods, such as adhesive bonding, welding, or mechanical structural fixation, to introduce ultrasound into the fluid pipeline. The ultrasonic microreactor used in step (2) includes: An ultrasonic transducer for generating ultrasonic waves; An amplitude transformer, one end of which is connected to the ultrasonic transducer; The tool head has a columnar structure along its length, and one end of the tool head is connected to the other end of the amplitude transformer. A fluid conduit is provided inside the tool head on the side away from the amplitude transformer, or the fluid conduit is connected to the outer side of the tool head away from the amplitude transformer; the amplitude transformer is used to transmit the ultrasonic waves generated by the ultrasonic transducer to the tool head, and the tool head is used to focus the ultrasonic energy within the tool head into the fluid conduit. The fluid pipeline has a hydraulic diameter of 0.2-10 mm; an ultrasonic frequency of 20-200 kHz; and a power of 20-200 W. The flow rate ratio of the good solution fluid to the reverse solution fluid used in step (2) is 1:(0.1-0.5).

2. The method for preparing polymer nanoparticles according to claim 1, characterized in that, The concentration of the stabilizer is 0.01~5%.

3. The method for preparing polymer nanoparticles according to claim 1 or 2, wherein the stabilizer is at least one selected from mannitol, polyvinyl alcohol, and polyvinylpyrrolidone.

4. The method for preparing polymer nanoparticles according to claim 1, characterized in that, The total flow rate of the reverse solution fluid and the good solution fluid used in step (2) is 0.1-10000 mL / min.

5. The method for preparing polymer nanoparticles according to claim 1, characterized in that, The solvent removal method in step (3) is at least one of centrifugation, drying or rotary evaporation under reduced pressure.

6. The method for preparing polymer nanoparticles according to claim 5, characterized in that, The drying process can be any one of the following: forced-air drying, vacuum drying, freeze drying, or spray drying.

7. The method for preparing polymer nanoparticles according to claim 1, characterized in that, In step (1), the polymer precursor is one or more of the following: polylactic acid-glycolic acid copolymer PLGA, polylactic acid PLA, poly(D,L-glycolic acid) PLG, polycaprolactone PCL, polymethylpropionamide PMAA, polyethylene glycol polylactic acid-glycolic acid copolymer PEG-PLGA, polycaprolactone-polyethylene glycol copolymer PCL-PEG; polymethacrylic acid-polyethylene glycol PHPMA-PEG; polyethylene glycol-polycarbonate block copolymer DG-MPEG; and polymethacrylic acid-hydrazone-doxorubicin PHPMA-Hyd-DOX.

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