TWI504413B - Composite polymer contrast agent and drug carrier in nano-scale - Google Patents

Description

Nano-sized composite polymer developer and drug carrier

The present invention relates to a nano-sized composite polymer and a method for producing the same, and more particularly to a developer or a drug carrier having both magnetic and acoustic properties.

Currently used in drug release control systems, mostly composed of acid-base and heat-sensitive materials, the above materials can only achieve efficacy in certain parts of the body, and can not widely meet most of the conditions that need to control drug release.

However, most drug delivery systems or drug carriers have a loose and unstable structure. When transported in vivo, the structure is very susceptible to damage, and it is easy to leak during delivery, and thus it is impossible to release specific drugs at specific locations, especially It is a heat sensitive polymer, such as a polymer Pluronic is a triblock polymer composed of polyethylene oxide (PEO) and polypropylene oxide (PPO), which is temperature sensitive. characteristic. If the drug carrier is simply produced by using Pluron, the structure is loose and unstable, and it is easy to be dissolved back into the aqueous solution when stored at room temperature. Please refer to Figure 1(a) - Figure 1(c). Figure 1 (a) - Figure 1 (c) shows the structure of Pluronic Pluronic F127 (PEO _n -PPO _m -PEO _n ) as a function of temperature. At room temperature, the structure of the solution state of Pluronic F127 (indicated by an arbitrary unit of f127, the following) is loose (as shown in Fig. 1(a)). If the temperature is raised by heating f127 (as shown in Fig. 1(b)), f127 is emulsified and its structure is compact and the volume is reduced. However, once the temperature of the solution drops (as shown in Figure 1 (c)), the structure of f127 appears loose again. That is, although f127 can be agglomerated at a low temperature due to aggregation at a non-polar end to reduce the interface, a stable nano-ultrasonic microbubble structure cannot be formed.

The drug carrier synthesized by the general heat sensitive polymer, if the chemical crosslinking agent is not used, makes the structure of the heat sensitive drug carrier unstable and difficult to prepare, but the use of the chemical crosslinking agent is often poor in biocompatibility. Therefore, how to effectively and without using a chemical cross-linking agent, a stable heat-sensitive drug carrier can be prepared, thereby achieving a property of reducing the natural drug leakage before the drug release system or the drug carrier reaches the target position. Moreover, after reaching the target position, the technical means of controlling the release of the drug by means of additional energy is a primary problem in the art. In addition, most of the ultrasonic developers are prepared by the conventional polymer materials, and the defects are as follows: the ultrasonic microbubbles are unstable, the preparation process is complicated, and there is no similar method at present, and the doped type can be synthesized in a simple step. The meter ultrasonic microbubbles, as well as the ultra-sonic developer, can be applied to both tumor imaging and drug release control.

Taiwan Patent No. 201113040 discloses a preparation method of magnetic nano particles, which comprises first reacting folic acid and pluronic F127 polymer into a folic acid-Pluronic F127 polymer; then reacting polyacrylic acid and ferric chloride into Polyacrylic acid-bonded iron oxide; finally, the folic acid-Pluronic F127 polymer and the polyacrylic acid-bonded iron oxide are esterified into a folic acid-polymer-polyacrylic acid bond under the control of a crosslinking agent. Water-soluble iron oxide particles, which are magnetic nano particles. When the magnetic nanoparticles are coated with Nile Red, they can be used as a drug carrier and a developer of nuclear magnetic resonance images. However, the magnetic nanoparticles need to use a crosslinking agent to form a stable drug carrier, and the developer cannot be used for ultrasonic imaging. Above the way.

The main purpose of this case is to reveal a functional polymer which is made of polyvinyl acid and a temperature-sensitive type with biocompatibility, doped in a specific ratio, and added oil phase iron oxide, and then utilizes interface chemistry. The characteristics are self-assembled into nano-ultrasonic microbubbles having a hollow structure by transformation within a temperature gradient. The above process is simple and rapid, and can construct a nano-sonic microbubble with high stability and magnetic resonance image and ultrasonic image sensitivity.

Another object of the present invention is to disclose a method for synthesizing composite magnetic nano ultrasonic microbubbles comprising the steps of dissolving a magnetic nanoparticle in an organic solvent to form an organic phase solution. A water soluble polymer and a temperature sensitive polymer are dissolved in water to form an aqueous phase solution. The organic phase solution and the aqueous phase solution are oscillated together to form a mixture; and within a temperature gradient, the mixture is first subjected to a temperature rising process and then subjected to a cooling process, after which a gas is blown The mixture is allowed to self-assemble to form the composite magnetic nano ultrasonic microbubbles.

Another object of the present invention is to disclose an ultrasonic developer which can be produced by a method of synthesizing composite magnetic nano ultrasonic microbubbles.

Another object of the present invention is to disclose a method for synthesizing a composite magnetic nano hollow drug carrier comprising the steps of dissolving a drug and a magnetic nanoparticle in an organic solvent to form an organic phase solution. A water soluble polymer and a temperature sensitive polymer are dissolved in water to form an aqueous phase solution. The organic phase solution and the aqueous phase solution are oscillated together to form a The mixture; and within a temperature gradient, the mixture is subjected to a temperature rising process followed by a cooling process to self-assemble the mixture to form the composite magnetic nano hollow drug carrier.

Another object of the present invention is to disclose a pharmaceutical carrier prepared by a method of synthesizing a composite magnetic nano hollow drug carrier, wherein when a focused ultrasonic wave is applied to the drug carrier, the structure of the drug carrier is changed, thereby releasing the The drug in a pharmaceutical carrier.

F127, F127‧‧ ‧Prannik F127

F68, F68‧‧ ‧Prannik F68

PEO‧‧‧polyethylene oxide

PPO‧‧‧polypropylene oxide

Hb‧‧‧ hydrogen bond

Pfp‧‧‧perfluoride

Sol‧‧‧solvent

Paa, PAA‧‧‧ polyacrylic acid

PVA‧‧‧Phenol

Spio‧‧‧Superparamagnetic iron oxide

Car‧‧‧ carrier

Med‧‧‧drug

Coa‧‧‧shell

Nb‧‧‧Nei ultrasonic microbubbles

Hs‧‧‧ hollow structure

This case can be further explained by the detailed description of the following drawings:

Figure 1 (a) - Figure 1 (c) shows the structure of Pluronic as a function of temperature.

Fig. 2(a) - Fig. 2(c) show the change in structure of pluronic with polyacrylic acid as a function of temperature.

3(a) to 3(c) are examples of a method of synthesizing a nano-sized composite polymer.

Figure 4 shows the change in diameter of the nano-ultrasonic microbubbles of Pluronic F127 and (PAA + Pluronic F127) at different temperatures.

Figure 5 shows the average grayscale value (dB) of nano-ultrasonic microbubbles of different compositions under the corresponding ultrasound image.

6(a) to 6(d) show an embodiment of a composite magnetic nanosonic microbubble synthesis method.

Figure 7 (a) shows the average gray scale value (dB) in an ultrasonic image of a nano-ultrasonic microbubble containing iron oxide.

Figure 7(b) shows the percent enhancement of nano-ultrasonic microbubbles of different compositions under the corresponding ultrasound image.

Figures 8(a)-8(c) show transmission electron microscopy images of nano-ultrasonic microbubbles under different concentrations of iron oxide nanoparticles.

Figure 9 is a graph showing the inverse of the relaxation time constant under nuclear magnetic resonance versus the concentration of iron ions.

Figure 10 (a) shows composite magnetic nano ultrasonic microbubbles with different SPIO concentrations under the application of focused ultrasound, exhibiting different release characteristics.

Fig. 10(b) shows the case of focusing ultrasonic stimulation of composite magnetic nano ultrasonic microbubbles.

Fig. 10(c) - Fig. 10(d) show the structural changes of the composite magnetic nano ultrasonic microbubbles in the case of focused ultrasonic stimulation under a transmission electron microscope.

Figure 11 shows an embodiment of a method of synthesizing composite magnetic nano ultrasonic microbubbles.

In this paper, a method for synthesizing nano-composite polymer npp with a hollow structure and its application by using pluronic and dopants is proposed. Please refer to Figure 2(a) - Figure 2(c). Fig. 2(a) - Fig. 2(c) show the structure change of pluronic with polyacrylic acid (PAA) as a function of temperature. Figure 2 (a) shows the use of temperature-sensitive polymer tp, such as Pluronic F127 (represented by f127) or Pluronic F68 (represented by f68), and another water-soluble polymer wp (such as a unit of high The principle of the interaction of molecular polyacrylic acid paa). In one embodiment, paa is added to the f127 solution to enhance internal hydrogen bond hb bonding. And by controlling the temperature, change the polarity of f127. Fig. 2(b) shows that after the emulsification temperature rise, the PPO bond in f127 is converted into a hydrophobic state (non-polar), and thus starts to agglomerate in the inner core, and paa is coated on the outer shell because it is a highly polar polymer. Figure 2(c) shows that when cooling, the carboxyl group of paa forms a hydrogen bond with the PEO segment of f127, while the PPO segment of f127 in the core of the nanoparticle begins to turn into hydrophilicity (polarity) and expands due to cooling. The nano-composite polymer npp having a hollow structure hs is formed.

The hollow structure of the nano-composite polymer npp can also be used as a composite magnetic nano hollow drug carrier with highly acoustic-sensitive nano-ultrasonic microbubbles, which can be constructed by mixing and mixing the above two polymers. Nano-composite high scores with high stability and ultrasonic sensitivity To achieve rapid release of drug release using ultrasonic waves of a specific frequency, and to control the carrier structure by the process technology of nanomaterials. In one embodiment, first, magnetic nanoparticles and a drug (for example, one of a fluorescent molecule, a hydrophilic molecule, a biomolecule, or other functional substance having a concentration of 0.1% by weight) are dissolved in an organic solvent (for example, Dichloromethane (2 mL) treated with ice bath to form an organic phase solution. However, in another embodiment, the drug and perfluorinated solution are also soluble in the water soluble solvent. In this embodiment, a temperature-sensitive polymer of Pluronic F127 with a concentration of 2% by weight and 12 mL is additionally dissolved in a water-soluble polymer, a 5% by weight concentration, and a 3 mL polyacrylic acid (PAA). It was about 1 hour in water until the aqueous phase solution showed a clear state. The aqueous phase solution is mixed with the organic phase solution. The ratio of the volume of the aqueous phase to the volume of the organic phase solution is fixed in a range of ratios, such as 15:2. After mixing, the mixture was shaken for 1 minute using a strong ultrasonic wave to produce a mixed solution of a uniform emulsion phase. Thereafter, the mixed solution was slightly heated to 29-32 ° C, stirred for about half an hour, and then heated to 55-70 ° C to completely evaporate the organic phase solution. The uncoated drug and the polymer are removed by centrifugation, and the mixed solution is allowed to stand for a period of time, and after the temperature of the mixed solution is balanced with the room temperature, the mixed solution is self-assembled to form a shell and A hollow polymer composite polymer, that is, a composite magnetic nano hollow drug carrier.

Please refer to Figure 3(a). Figure 3 (a) is an embodiment of a method of synthesizing a nano-sized composite polymer, comprising the following steps:

As shown in step S3101, a gas such as perfluorinated or sulfur hexafluoride is first dissolved in an organic solvent such as dichloromethane treated with an ice bath to form an organic phase solution. As shown in step S3102, a water-soluble polymer (such as polyvinyl acid or polyvinyl alcohol) and a temperature-sensitive polymer (such as pluronic) are then dissolved in water to form an aqueous phase solution. As shown in step S3103, the organic phase solution is then oscillated together with the aqueous phase solution to form Into a mixture. As shown in step S3104, the mixture is first subjected to a temperature rising process and then subjected to a cooling process within a temperature gradient to self-assemble the mixture to form the nano-sized composite polymer.

Please refer to Figure 3(b). Figure 3 (b) is an embodiment of a method of synthesizing a nano-sized composite polymer, comprising the following steps:

First, as shown in step S3201, a gas such as perfluorinated or sulfur hexafluoride is dissolved in an organic solvent such as dichloromethane treated with an ice bath to form an organic phase solution. Immediately, as shown in step S3202, an aqueous phase solution is formed. Finally, as shown in step S3203, the organic phase solution and the aqueous phase solution are oscillated together to form the nano-sized composite polymer having a hollow structure.

Please refer to Figure 3(c). Figure 3 (c) is an embodiment of a method of synthesizing a nano-sized composite polymer, comprising the following steps:

As shown in step S3301, a mixture solution is formed. The mixture solution is heated as shown in step S3302. And as shown in step S3303, the heated mixture solution is cooled, and the mixture is self-assembled to form the nano-sized composite polymer.

Please refer to Figure 4. Figure 4 shows the change of particle diameter at different temperatures of pure Pluronic F127 (F127) and polyacrylic acid PAA-doped Pluronic F127 (PAA+F127) nano-ultrasonic microbubbles. The pure ultrasonic microbubbles of the Pluronic F127 will dissolve directly back into the aqueous solution at low temperatures, and the particle size cannot be detected. The polyacrylic acid PAA is doped with the nano-ultrasonic microbubbles of Pluronic F127, which can be scaled by different temperature cycles (two pairs of arrows in Figure 4 to indicate temperature rise or decrease), close to body temperature. Has a hollow structure. The response of such ultrasonic-sensitive nano-ultrasonic microbubbles to ultrasonic waves also varies with the composition ratio. The same changes.

In another embodiment, FIG. 5 shows the average gray scale value (dB) of the nano-ultrasonic microbubbles of different compositions under the corresponding ultrasonic image, wherein the horizontal axis is the composition ratio by weight percentage concentration, and the vertical axis Is the brightness (dB) of the corresponding ultrasound image. In this embodiment, three sets of nano-ultrasonic microbubbles with different compositional conditions were considered, namely: doping polyacrylic acid PAA and pluronic F127 at 55 ° C; and doping polyvinyl alcohol Polyvinyl Alcohol at 70 ° C ( PVA) and Pluronic F127; and doped polyvinyl alcohol PVA and Pluronic F127 at 55 °C. The average grayscale value of the image increases with the increase of the ratio of Pluronic F127 to PAA (1/4, 2/3, 3/2). Until F127/PAA=3/2, the average grayscale value of the image reaches After the 50dB highest, it begins to decline. In addition, when the Pluronic F127 solution was added to different proportions of the less polar polyvinyl alcohol PVA polymer, it was found that similar functional nano ultrasonic microbubbles could be synthesized, but it is necessary to raise the temperature to 70 ° C to cause polarity. Differences, which in turn form nano-ultrasonic microbubbles.

On the other hand, this paper proposes a synthetic magnetic nano-ultrasonic microbubble developer synthesis method. Temperature-sensitive polymer Pluronic F127, high molecular polyacrylic acid (PAA), and a magnetic nanoparticle, superparamagnetic iron oxide (SPIO) nanoparticle, together form a supersonic and magnetically sensitive property. Rice capsule hollow structure. The composite magnetic nano-ultrasonic microbubble-based iron oxide nano-particles are dispersed in a polymer shell.

Figure 6 (a) shows, in one embodiment, a magnetic nanoparticle having a drug (weight percent concentration of 0.1%) and a diameter between 2 and 30 nanometers (nm), such as superparamagnetic iron oxide (SPIO, Expressed as spio) with 5 μL of gaseous perfluorinated acid (PFP, expressed as pfp) (or sulphur hexafluoride (SF ₆ )) dissolved in an ice bath-treated organic phase solution (eg 2 mL of dichloromethane solvent sol ), forming a single organic phase solution. In other implementations, the magnetic nanoparticles may include a ferroferric oxide (Fe ₃ O ₄ ), a ferric oxide (Fe ₂ O ₃ ), a cobalt iron oxide (CoFe ₂ O ₄ ), a One of manganese iron oxide (MnFe ₂ O ₄ ) and cerium oxide (Gd ₂ O ₃ ), and its precursors may include, but are not limited to, chlorides, nitrates, acetates, and the like.

In addition, a weight percent concentration of 2%, 12 mL of temperature-sensitive polymer pluronic F127 (expressed as f127) and a concentration of 5% by weight, 3 mL of polyacrylic acid (PAA, expressed as paa) were placed in water for about 1 hour until water The phase solution assumes a clear state. The aqueous phase solution is mixed with the organic phase solution, and the ratio of the aqueous phase to the volume of the organic phase solution is fixed at a ratio of, for example, 15:2. After mixing, a strong ultrasonic wave was shaken for 1 minute to produce an emulsion phase solution.

See Figure 6(b) - Figure 6(c). Figure 6 (b) - Figure 6 (c) shows that the mixed solution is slightly heated to 29 ~ 32 ° C, stirred for about half an hour, when the temperature-sensitive polymer Pluronic F127 begins to shrink (Figure 6 (b) The four inward arrows are shown, and the internal perfluorinated gas begins to vaporize, gradually accumulating in the inner core, and pushing the superparamagnetic iron oxide to the outer casing (as shown in Figure 6(b). Short arrow number). It is then heated to 55 ° C to volatilize the organic phase solution (as indicated by the long outward arrow in Figure 6(b)).

Fig. 6(d) shows the removal of the uncoated drug and the polymer by centrifugation, that is, the nano-ultrasonic microbubble containing the outer shell of the iron oxide nanoparticle, and the nano-ultrasonic microbubble has a hollow The structure wherein the hollow structure has a diameter between 150 nm and 500 nm and a shell thickness of between 5 nm and 100 nm. The box in Figure 6(d) illustrates the compressed enclosure.

In another embodiment, Figure 7(a) shows the addition of superparamagnetic iron oxide to nano-ultrasonic microbubbles of different compositions, the average grayscale value (dB) in the corresponding ultrasound image, where the horizontal axis is oxidized. The iron concentration and the vertical axis are the brightness (dB) of the corresponding ultrasonic image. In this implementation, three sets of cases were considered, namely: doping polyacrylic acid (PAA) and pluronic F127 at 55 ° C; at 70 ° C Under-doped polyvinyl alcohol (PVA) and Pluronic F127; and doped polyvinyl alcohol (PVA) and Pluronic F127 at 55 °C. It can be found that when Pluronic F127 is doped with acrylic acid (PAA) (F127/PAA=3/2), the addition effect of nano-ultrasonic microbubbles on ultrasonic images (95dB) can be greatly increased after the addition of iron oxide.

In another embodiment, FIG. 7(b) shows the percentage of enhancement of the nano-ultrasonic microbubbles of different compositions under the corresponding ultrasonic image, wherein the horizontal axis is the composition ratio distinguished by the weight percentage concentration, and the vertical axis is Percentage of enhancement (%) of the corresponding ultrasound image. In this embodiment, three sets of cases are considered, namely: doping polyacrylic acid (PAA) and pluronic F127 at 55 ° C; doping polyacrylic acid (PAA) and pluronic F68 at 55 ° C; Polyvinyl alcohol (PVA) and Pluronic F68 were doped at 70 ° C; polyvinyl alcohol (PVA) and Pluronic F127 were doped at 55 ° C. It can be found that when Pluronic F68 replaces Pluronic F127, it can also enhance the development contrast of nano-ultrasonic microbubbles in ultrasonic images. It can be seen that such temperature-sensitive polymers have similar effects.

Figure 8(a) - Figure 8(c) show the transmission electron microscopy images of nano-ultrasonic microbubbles under different concentrations of iron oxide nanoparticles (low, medium and high concentrations), The iron oxide nanoparticles are uniformly surrounded by the outer shell of the nano ultrasonic microbubbles. The size of the nano-ultrasonic microbubbles is between 190 nm and 230 nm. The addition of different concentrations of iron oxide nanoparticles can form composite magnetic nano-ultrasonic microbubbles with different shell thicknesses; the higher the concentration of iron oxide nanoparticles, the higher the shell thickness of the composite magnetic nano-ultrasonic microbubbles formed. Thick, the smaller the kernel, and vice versa. The most important thing is that you can use iron oxide to strengthen the structure of the outer casing, which can be enhanced to over 95dB in ultrasonic image comparison.

Figure 9 is a graph showing the concentration of 1/T ₂ to iron ion concentration under nuclear magnetic resonance, wherein the horizontal axis is the iron ion concentration (M) and the vertical axis is the reciprocal of T ₂ . T ₁ and T ₂ are parameters for the longitudinal or lateral direction of the magnetization, respectively. After NMR, the composite magnetic nano-ultrasonic microbubbles are a good developer, corresponding to different concentrations of 28.8mg/mL, 18.8mg/ml and 9.4mg/ml of SPIO solution, the formation of nano-composite The polymer developers have r2 values of 208, 183 and 164, respectively. R2 is the parameter of shimming.

In addition, the composite magnetic nano-ultrasonic microbubbles developed in this case have good supersonic characteristics due to their hollow structure, and can be used to induce the instantaneous compression of microbubbles by the manipulation of focused ultrasound (HIFU), resulting in the outer shell structure. Destruction, which in turn releases a large amount of drug quickly and accurately, as a drug carrier. In addition, when the drug carrier is not focused on the ultrasound, the carrier can continue to coat the drug well in the inner core. This feature is very helpful for long-term drug control, and then after applying ultrasonic energy, it can pass through the nuclear magnetic resonance device. To monitor changes in the magnetic properties of nearby tissues.

Fig. 10(a) shows a composite magnetic nanosonic microbubble (nb) with different SPIO concentrations and different shell thicknesses under the application of fixed-focus focused ultrasonic HIFU, showing the release characteristics of different drugs, wherein the horizontal axis is time. The vertical axis is the cumulative release amount. The HIFU can be set such that a 400 KHz pulse is turned on at 0.001 seconds and turned off at 0.999 seconds. Nano-ultrasonic microbubbles containing 9.4 mg/mL of SPIO, with the physical properties of a thinner shell, exhibit the strongest supersonic response, while the drug concentration rises rapidly. In one embodiment, Carmustine or paclitaxel is used as a simulated drug, which is coated in the nano-ultrasonic microbubble to test its sensitivity to the ultrasonic wave. The state before the supersonic wave is added, only a very small amount of release, indicating that the drug can be stored in the core of the nano-ultrasonic microbubbles; and after the application of HIFU, the drug is quickly released from the inner core.

Figure 10 (b) shows that during HIFU stimulation, the composite magnetic nano-ultrasonic microbubbles containing a hollow structure hs will first agglomerate and then blast into fragments of the drug med and the outer shell coa, which is a good drug carrier car and release system. The fragment of the outer shell coa may further comprise a temperature sensitive polymer tp and a water soluble polymer wp. Figure 10 (c) shows that the composite magnetic nano-ultrasonic microbubbles in the HIFU stimulation begin to agglomerate first, and the scale of this figure is 200 nm. Fig. 10(d) shows the rupture of the composite magnetic nano-ultrasonic microbubbles after HIFU stimulation, in which the circle shape, the arrow and the concave disk are partially illustrated, and the scale of this figure is 100 nm.

Please refer to Figure 11. Figure 11 is an embodiment of a method of synthesizing a composite magnetic nano ultrasonic microbubble comprising the following steps:

As shown in step S1101, a magnetic nanoparticle is dissolved in an organic solvent to form an organic phase solution, wherein the magnetic nanoparticle comprises a ferroferric oxide (Fe ₃ O ₄ ), a ferric oxide. One of (Fe ₂ O ₃ ), a cobalt iron oxide (CoFe ₂ O ₄ ), a manganese iron oxide (MnFe ₂ O ₄ ), and cerium oxide (Gd ₂ O ₃ ), the organic solvent including Dichloromethane.

As shown in step S1102, a water-soluble polymer and a temperature-sensitive polymer are dissolved in water to form an aqueous phase solution, wherein the water-soluble polymer comprises a polyacrylic acid (PAA) and a polyethylene. One of the polyvinyl alcohol (PVA), the temperature-sensitive polymer includes one of Pluronic F68 and one Pluronic F127.

The organic phase solution and the aqueous phase solution are shaken together to form a mixture as shown in step S1103.

As shown in step S1104, the mixture is subjected to a temperature rising process and then subjected to a temperature decreasing process within a temperature gradient, and the temperature increasing process includes the following steps: slowly heating the mixture to 29-32 degrees Celsius, stirring After about half an hour, the mixture is then heated to 55-70 degrees Celsius to volatilize the organic phase solution. After the cooling process, a gas is driven into the mixture, and the mixture is self-assembled to form the composite magnetic nano ultrasonic microbubble, wherein the gas comprises a perfluoropentane (PFP, C ₅ F ₁₂ ) and One of the sulfur hexafluoride (SF ₆ ); the composite magnetic nano ultrasonic microbubble further comprises a casing having the magnetic nanoparticle, the outer casing surrounding the composite magnetic nano ultrasonic microbubble A hollow structure is formed, the diameter of the magnetic nanoparticle is between 2 nm and 15 nm, and the diameter of the composite magnetic nano ultrasonic microbubble is between 150 nm and 500 nm.

In summary, this paper discloses a composite polymer with high stability and high temperature sensitivity, which is a valuable invention. It can be applied to the following industries: drug carriers, cancer target treatment, nuclear magnetic resonance imaging, ultrasound imaging, biomedical materials for tissue engineering, and biomedical components. The composite polymer can be developed as a product of a smart drug carrier, a biochip, a developer of nuclear magnetic resonance or ultrasonic imaging, and the like.

In detail, in the synthesis of composite polymers, high molecular polyacrylic acid plays a role as an auxiliary and stable outer shell. This polymer can provide a large number of stable structure hydrogen bonds, making nano ultrasonic microbubbles have the following characteristics: stable nai Rice structure: When the polyacrylic acid content is too low, the hydrogen bonding force of the nano-ultrasonic microbubble shell is not strong, and the pluronic F127 is easily dissolved back into the aqueous solution. When the proportion of polyvinyl alcohol is increased, a large number of hydrogen bonds can stabilize the nanostructure, but because the content of Pluronic F127 is less, the volume change of the core is too small, which affects the formation of hollow structure of nano ultrasonic microbubbles. . If nano-ultrasonic microbubbles are applied to drug carriers, because of their ultra-sonic sensitivity, the drug can be quickly and accurately controlled under the control of externally focused ultrasound. However, the accumulated energy does not cause the drug to be damage. In addition, in nano-sound micro The synthesis of the bubbles does not require the use of any chemical crosslinking agent, so the microbubble drug carrier has low toxicity properties. Furthermore, the process of nano-ultrasonic microbubbles can be synthesized at 55 ° C without causing damage to the activity of the drug. Finally, the composite polymer has high biocompatibility and low toxicity and can be used as the preferred developer for ultrasonic imaging or nuclear magnetic resonance imaging.

The embodiments and many modifications presented herein will be familiar with the inventions made by those skilled in the art, however, these inventions have been directed to the teachings set forth in the above description and related drawings. Therefore, it is understood that the invention is not limited to the specific embodiments disclosed, and the modifications and other embodiments are included in the scope of the appended claims. An exemplary embodiment that includes some combinations of elements and/or functional examples, it should be understood that combinations of different elements and/or functions may be provided by different embodiments without departing from the scope of the appended claims. . In this regard, various combinations of elements and/or functions are also included in some of the derived claims, for example, not only as specifically described above. Although specific nouns are used herein, they are used for general purposes only and are not intended to be limiting.

F127‧‧ ‧Prannik F127

Spio‧‧‧Superparamagnetic iron oxide

Pfp/sol‧‧‧perfluorinated and solvent

Paa‧‧‧poly acrylic

Claims (7)

A method for synthesizing composite magnetic nano ultrasonic microbubbles comprises the steps of: dissolving a magnetic nanoparticle in an organic solvent to form an organic phase mixed solution; and a water soluble polymer and a temperature sensitive type The molecules are doped in a specific ratio to form an aqueous phase solution; the organic phase is mixed into a solution and the aqueous phase solution is shaken together at room temperature to form a mixture; and within a temperature gradient, the mixture is first After a temperature rising process, a cooling process is performed. After the cooling process, a gas is driven into the mixture to self-assemble the mixture to form the composite magnetic nano ultrasonic microbubble, wherein the gas comprises perfluorinated ( One of Perfluoropentane, PFP, C ₅ F ₁₂ ) and sulfur hexafluoride (SF ₆ ), the temperature-sensitive polymer comprising one of Pluronic F68 and one Pluronic F127, The water-soluble polymer comprises one of polyacrylic acid (PAA) and one polyvinyl alcohol (PVA), and the organic solvent comprises a dichloromethane, and the magnetic nanoparticle package A triiron tetroxide (Fe ₃ O _4), a ferric oxide (Fe ₂ O _3), a cobalt-iron oxide (CoFe ₂ O _4), a manganese iron oxide (MnFe ₂ O ₄₎ and nitrous oxide One of 釓(Gd ₂ O ₃ ). The method of claim 1, wherein the composite magnetic nano ultrasonic microbubble further comprises a casing having the magnetic nanoparticle, the outer casing surrounding the composite magnetic nano ultrasonic microbubble to form a The hollow structure has a diameter of between 2 nm and 15 nm, and the diameter of the composite magnetic nano ultrasonic microbubble is between 150 nm and 1000 nm. The method of claim 1, wherein the heating process comprises the following steps: The mixture is slowly heated to 29-32 degrees Celsius, stirred for about half an hour, and then the mixture is heated to 55-70 degrees Celsius to volatilize the organic phase to form a solution. A composite magnetic nano ultrasonic microbubble synthesized by the method of claim 1, wherein the composite magnetic nano ultrasonic microbubble can be used as an ultrasonic developer. A method for synthesizing a composite magnetic nano hollow drug carrier, comprising the steps of: dissolving a drug and a magnetic nanoparticle in an organic solvent to form an organic phase mixed solution; and sensitizing a water soluble polymer and a temperature The polymer is dissolved in water to form an aqueous phase solution; the organic phase is mixed into a solution and shaken together to form a mixture; and the mixture is subjected to a temperature rising process in a temperature gradient. a cooling process, the mixture is self-assembled to form the composite magnetic nano hollow drug carrier, wherein the temperature sensitive polymer comprises one of Pluronic F68 and a Pluronic F127, the water solubility The polymer comprises one of polyacrylic acid (PAA) and a polyvinyl alcohol (PVA), and the magnetic nanoparticle comprises a ferroferric oxide (Fe ₃ O ₄ ), a trioxide One of two iron (Fe ₂ O ₃ ), one cobalt iron oxide (CoFe ₂ O ₄ ), one manganese iron oxide (MnFe ₂ O ₄ ), and cerium oxide (Gd ₂ O ₃ ). The method of claim 5, wherein the drug comprises one of Carmustine and paclitaxel. A pharmaceutical carrier synthesized by the method of claim 8, wherein when a focused ultrasound is applied to the drug carrier, the structure of the drug carrier is altered to release the drug in the drug carrier.