CN117982664A - Magnetic alginic acid microsphere and preparation method and application thereof - Google Patents
Magnetic alginic acid microsphere and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of magnetic alginic acid microspheres, which belongs to the technical field of polymer functional material preparation and comprises the following steps: (1) formulating an inner phase, an outer phase fluid and a receiving fluid; (2) preparing magnetic alginic acid microspheres: including preparing droplets and cross-linking curing of the droplets; (3) The preparation method has the advantages of simple steps, easy operation and lower production cost, can continuously and controllably produce microspheres with different sizes, and the magnetic alginic acid microsphere prepared by the method contains Fe 3O4 nano particles, has good sphericity and uniform size, and can be used in CT and nuclear magnetic development in the tumor embolism treatment process.
Description
Technical Field
The invention belongs to the field of polymer functional material preparation, and relates to a magnetic alginic acid microsphere, a preparation method and application thereof.
Background
At present, tumors are one of major diseases which are harmful to human health, common tumor treatment methods comprise surgery, radiotherapy and chemotherapy, embolism treatment and the like, but as most tumors are already in middle and late stages when being diagnosed, only few tumors have the opportunity of surgical excision, and radiotherapy and chemotherapy have systemic toxicity and poor patient compliance, and the use of the tumors is limited. The embolism treatment is an important strategy for treating middle and late stage tumors at present, and the principle is that an embolism material is injected into a blood supply artery of the tumor through minimally invasive surgery, so that a nutrition supply channel of the tumor is blocked, and the tumor gradually apoptosis.
The current commonly used embolic materials are embolic microspheres, spring rings, liquid suppositories and the like, wherein the microspheres are the most widely used embolic materials, and have two major categories of biodegradable and non-biodegradable microspheres, and the biodegradable embolic materials comprise gelatin sponge, starch, PLGA, alginic acid and the like, wherein the alginic acid microspheres have good biodegradability and biocompatibility and are used as the degradable suppositories for tumor embolism treatment at present, but the current alginic acid embolic microspheres need to be mixed with a developer before use, the flow of the contrast agent is checked through DSA to indirectly judge the position of the embolic microspheres and the end point of the embolism, the real condition of the embolism cannot be comprehensively reflected, a great difficulty is caused to clinical operations, in addition, the position of the embolic microspheres needs to be checked after operation, the treatment cost is increased, and the excessive contrast agent can also produce toxic and side effects on human bodies. In addition, the current clinical alginic acid embolism microsphere adopts a homogeneous emulsification method, and has poor size uniformity, so that the shunt ratio is too large or the embolism is ectopic, and the accurate embolism to the target position is difficult. Therefore, the preparation of the embolic microsphere with self-development function and uniform size has important clinical significance.
The ferroferric oxide (Fe 3O4) nano-particles have CT and nuclear magnetic development functions and can be loaded on embolic microspheres, so that alginic acid microspheres loaded with Fe 3O4 nano-particles can endow the alginic acid microspheres with self-development functions, and related researches on the seaweed magnetic materials are carried out at present, for example, the publication number is: in the preparation method of the alginic acid magnetic material disclosed in the patent application document of CN101461945A, firstly, an alginic acid aqueous solution and a Fe 3O4 suspension aqueous solution are prepared, then the two solutions are mixed, slowly stirred and dispersed in an ultrasonic manner under the inert gas atmosphere, and then the mixture is dripped into a divalent metal ion cross-linking agent solution by adopting a syringe to prepare the ionic cross-linking gel particle of alginic acid/Fe 3O4 nano particles. However, in the microsphere forming process, the injector is mainly used for dripping, the control precision of the preparation process is poor, the size is difficult to control accurately, the size of the injector dripping is large, the requirement of embolism cannot be met, and the preparation efficiency is low.
As another example, publication No.: in the CN104257631A patent application, firstly, 1.5% sodium alginate is prepared, then Fe 3O4 nano particles are mixed with sodium alginate solution, and then the mixture is dripped into calcium chloride solution with the mass concentration of 1.1% by an electrostatic method by using a high-frequency pulse microcapsule forming instrument for crosslinking and curing. The method has the advantages that the equipment is complex and expensive, the liquid drop speed is high during high-frequency pulse, the alginic acid crosslinking speed is high, the alginic acid liquid drop is sprayed to the surface of the calcium chloride aqueous solution to be impacted inevitably, so that the sphericity of the crosslinked alginic acid microspheres is poor, the alginic acid microspheres can be successfully prepared only by controlling a certain voltage within a certain range, the preparation efficiency is inevitably reduced, the size range of the alginic acid microspheres which can be prepared by the method is shortened, and the method is not beneficial to mass production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the magnetic alginic acid microsphere which can be used as a carrier of a tumor therapeutic drug and also can be used in CT and nuclear magnetic examination processes and has CT and nuclear magnetic developing functions. Meanwhile, the method for preparing the magnetic alginic acid microsphere is simpler in step, easy to operate and lower in production cost, and continuous and controllable preparation of the magnetic alginic acid microsphere is realized.
The invention is realized by the following technical scheme:
The preparation method of the magnetic alginic acid microsphere comprises the following steps:
(1) Preparing internal phase and external phase fluid and receiving liquid
Preparing an internal phase fluid: dissolving Fe 3O4 nano-particles and sodium alginate in water to obtain an internal phase fluid, wherein: the mass fraction of the sodium alginate is 1% -3%, and the mass fraction of the Fe 3O4 nano-particles is 0.5% -5%;
Preparing an external phase fluid: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain an external phase fluid, wherein the external phase fluid comprises the following components: the mass fraction of the oil-soluble surfactant is 0.5% -20%, and the mass fraction of the calcium iodide is 0.05% -1%;
Preparing a receiving solution: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain a receiving solution, wherein the receiving solution comprises the following components: the mass fraction of the oil-soluble surfactant is 0% -20%, and the mass fraction of the calcium iodide is 0.05% -5%;
(2) Preparation of magnetic alginic acid microspheres
① And (3) liquid drop preparation: injecting an internal phase fluid and an external phase fluid into a syringe and a receiving tube of the microfluidic device respectively by using a syringe pump, controlling the size of droplets by adjusting the flow rate of the syringe pump, and forming water-in-oil droplets in the receiving tube;
② Crosslinking and curing: the droplets undergo a crosslinking reaction in a receiving pipe, and flow into the receiving liquid along with the external phase fluid, and are further crosslinked and molded to obtain a crude product of the magnetic alginic acid microsphere;
(3) Washing
And (3) cleaning the crude magnetic alginic acid microsphere product obtained in the step (2) by using a detergent to remove n-octanol residual liquid on the microsphere surface, and obtaining the magnetic alginic acid microsphere after washing, dispersing the magnetic alginic acid microsphere in water and storing the magnetic alginic acid microsphere in water.
Further, in step (1), the oil-soluble surfactant in the external phase fluid and the receiving liquid is any one of Span20, span40, span60 and Span 80.
Further, the droplet size is adjusted by adjusting the flow rates of the inner phase fluid and the outer phase fluid in step (2) ①.
Further, the flow rate of the internal phase fluid is 100-1000 mu L/h, and the flow rate of the external phase fluid is 0.3-7 mL/h.
Further, the detergent in the step (3) is ethanol or isopropanol.
Further, in the step (2), the droplets are pre-crosslinked in the receiving tube under normal temperature conditions.
Further, the microfluidic device in the step (2) is a single-stage capillary microfluidic device, and comprises a syringe, a connecting pipe and a receiving pipe, wherein the syringe is used for circulating internal phase fluid, the syringe is made of a cylindrical glass capillary, and one end of the syringe is conical; the connecting pipe is used for circulating outward fluid, the connecting pipe is made of square glass pipes, a square channel is arranged in the middle of the connecting pipe, a flat-mouth needle is arranged at the inlet end of the connecting pipe, the flat-mouth needle is connected with the injection pump again, and the non-inlet end of the connecting pipe is sealed; the receiving pipe is used for circulating receiving liquid, the receiving pipe is made of cylindrical glass capillary, and the conical head of the injection pipe is inserted into the tail of the receiving pipe and connected through a connecting pipe.
Further, the diameter of the conical head outlet of the injection tube is 60-250 mu m.
A magnetic alginic acid microsphere is prepared by the above preparation method.
The magnetic alginic acid microsphere can be applied to CT and nuclear magnetic detection and tumor drug carriers in the tumor treatment process.
Compared with the prior art, the invention has the following advantages:
1. In the invention, the magnetic alginic acid microsphere prepared by the method can be used for CT and nuclear magnetic detection in the tumor treatment process and/or a tumor drug carrier, when the magnetic alginic acid microsphere is used for CT and nuclear magnetic detection in the tumor treatment process, the ferroferric oxide (Fe 3O4) nanoparticle in the magnetic alginic acid microsphere has CT and nuclear magnetic development functions, the magnetic alginic acid microsphere has good biodegradability and biocompatibility, the magnetic alginic acid microsphere is directly used for treating or carrying medicine and is used for treating tumors, no additional developer is needed, and the magnetic alginic acid microsphere is developed by the ferroferric oxide (Fe 3O4) nanoparticle in the microsphere, so that medical staff is assisted in judging the position and the embolism end point of the embolism microsphere, and when the position of the embolism microsphere is reexamined after operation, the re-radiography is not needed, the treatment cost is obviously reduced, and the safety risk problems of toxic and side effects and the like caused by excessive contrast agent on human bodies are well solved.
2. According to the invention, a microfluidic technology is combined, the preparation process is optimized, the liquid drops prepared by the microfluidic technology are introduced into the receiving pipe for preliminary crosslinking, the liquid drops further complete the crosslinking process along with the inflow of the external phase fluid into the receiving liquid, the flowing process is more gentle, the shape change caused by the impact of the liquid drops on the liquid level of the receiving liquid when the liquid drops directly enter the receiving liquid is avoided, so that good sphericity is maintained in a wider flow range, and the production difficulty is reduced.
3. In the invention, in the process of preparing the microspheres, the magnetic alginic acid microspheres with different sizes can be accurately and controllably prepared by adjusting the flow rate and the flow rate ratio of each phase of fluid, the diameter of the conical mouth of the injection tube or the inner diameter of the receiving tube, so that the flexible regulation and control of the sizes of magnetic alginic acid drops are realized, and the sizes of alginic acid drops generated in the receiving tube are quite uniform, so that the prepared magnetic alginic acid is quite uniform in size.
4. According to the invention, the microfluidic device in the scheme can be used for continuously preparing the monodisperse water-in-oil liquid drops, the liquid drops are gradually crosslinked in the receiving pipe, and the magnetic alginic acid microspheres are further crosslinked and solidified in the receiving liquid, so that the continuous preparation of the magnetic alginic acid microspheres is realized, and the mass production is facilitated.
5. According to the invention, the magnetic alginic acid microsphere with uniform shape and wide controllable size range can be prepared without using expensive instruments such as a high-frequency pulse microcapsule forming instrument, the preparation process is continuous, the related equipment cost is lower, and the production cost can be reduced.
Drawings
Fig. 1 is a schematic diagram of a single stage capillary microfluidic device.
FIG. 2 is an optical electron microscope image of the magnetic alginic acid microsphere prepared in group 1 of example 1.
FIG. 3 is an optical electron microscope image of the magnetic alginic acid microsphere prepared in group 2 of example 1.
FIG. 4 is a graph showing the magnetic characteristics of the magnetic alginic acid microspheres prepared in group 3 of example 1.
FIG. 5 is an optical electron microscope image of the magnetic alginic acid microsphere prepared in the 7 th group of example 2.
FIG. 6 is an optical electron microscope image of the magnetic alginic acid microsphere prepared in group 8 of example 2.
Wherein, 1, a syringe; 2. a connecting pipe; 3. a receiving tube.
Detailed Description
The method for preparing the magnetic alginic acid microsphere provided by the invention and the magnetic alginic acid microsphere prepared by the method are further described below by examples. It is to be noted that the following examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, since numerous insubstantial modifications and variations of the present invention may be made by those skilled in the art in light of the above teachings, and still fall within the scope of the invention.
In the following examples, a single stage capillary microfluidic device is used, the structure of which is shown with reference to fig. 1, comprising a syringe 1, a connection tube 2 and a receiver tube 3. The injection tube 1 is made of a cylindrical glass capillary, the head of the cylindrical glass capillary is pulled into a cone shape by a needle pulling instrument, and then the cone is rolled and polished on abrasive paper to a flat mouth with the cone opening inner diameter of about 60-250 mu m, and the outer diameter of a circular tube section is 960 mu m and the inner diameter is 550 mu m.
The receiving tube 3 is made of a cylindrical glass capillary, two ends of the cylindrical glass capillary are polished and flattened, the outer diameter of the receiving tube 3 is 960 mu m, and the inner diameter of the receiving tube is 200-700 mu m.
The connecting pipe 2 is a square glass pipe, two ends of the square glass pipe are polished smoothly and flatly, a square channel is arranged in the center of the square glass pipe, and the cross section size of the channel is 1X 1mm.
After the injection tube 1, the connecting tube 2 and the receiving tube 3 are manufactured, the injection tube 1, the connecting tube 2 and the receiving tube 3 are required to be placed into absolute ethyl alcohol for ultrasonic vibration for half a minute to be cleaned and dried by blowing. The head of the injection tube 1 is inserted into the tail of the receiving tube 3 and connected by the connecting tube 2. The injection tube 1, the connecting tube 2 and the receiving tube 3 are coaxially arranged and fixed on a glass slide through AB glue. The non-inlet end of the connecting tube 2 is sealed by AB glue. The inlet end of the connecting pipe 2 is respectively fixed with a flat-mouth needle through AB glue, and the flat-mouth needle is connected with the injection pump through a pipe fitting.
Example 1
In this embodiment, a method for preparing a magnetic alginic acid microsphere is provided, which specifically comprises the following steps, by changing the component ratio and flow rate of the internal phase fluid and the external phase fluid, the component ratio of the receiving liquid and the size of the device, and observing and detecting the microsphere prepared under each set of conditions after preparing the magnetic alginic acid microsphere. The conditions of each group are shown in Table 1, and the results are referred to Table 2.
The preparation method of the magnetic alginic acid microsphere comprises the following steps:
(1) Preparing internal phase and external phase fluid and receiving liquid
Preparing an internal phase fluid: dissolving Fe 3O4 nano-particles and sodium alginate in water to obtain an internal phase fluid, wherein the weight ratio of the Fe 3O4 nano-particles to the sodium alginate is shown in table 1;
Preparing an external phase fluid: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain an external phase fluid, wherein the weight ratio of the oil-soluble surfactant to the calcium iodide in the external phase fluid is shown in table 1;
preparing a receiving solution: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain a receiving solution, wherein the mass ratio of the oil-soluble surfactant to the calcium iodide in the receiving solution is shown in table 1;
(2) Preparation of magnetic alginic acid microspheres
① And (3) liquid drop preparation: selecting a proper microfluidic device, injecting an internal phase fluid and an external phase fluid into an injection tube and a receiving tube of the microfluidic device by using an injection pump respectively, and preparing magnetic alginic acid droplets according to the flow rate requirements and the device sizes of each group in table 1;
② Crosslinking and curing: the droplets are crosslinked and solidified step by step along with the flowing process of the external phase fluid, and are further crosslinked and molded in the receiving liquid to obtain a crude product of the magnetic alginic acid microsphere;
(3) Washing
And (3) washing the obtained liquid drops with ethanol serving as a washing agent to remove n-octanol on the outer surface of the crude product of the magnetic alginic acid microsphere, and dispersing the washed liquid drops in warm water for storage.
In this example, the magnetic adsorption is used to characterize the microsphere containing Fe 3O4 nanoparticles, and the size of the microsphere is observed and characterized by an optical microscope, the uniformity is represented by cv value, and the detection results of each group of magnetic alginic acid microsphere are shown in table 2. The calculation formula of cv value is as follows:
，
where d is the average diameter of the magnetic alginic acid microspheres, n is the number of samples measured and d i is the diameter of the ith microsphere. In general, microspheres are considered to have good monodispersity when the CV value is below 5%.
TABLE 1
TABLE 2
As shown in tables 1 and 2, the method can prepare the magnetic alginic acid embolic microsphere with good sphericity in a wide range of conditions, and the prepared microsphere is quite uniform and has good monodispersity. The optical electron microscope images of the magnetic alginic acid microspheres prepared in the 1 st and 2 nd groups are respectively shown in fig. 2 and 3, and the magnetic characterization of the magnetic alginic acid microspheres prepared in the 3 rd group is shown in fig. 4.
Example 2
This example further examined the effect of the flow rate of the inner phase fluid and the flow rate of the outer phase fluid on the preparation of magnetic alginic acid microspheres.
In this embodiment, the composition ratio of the inner phase fluid, the outer phase fluid and the receiving liquid in the 1 st group in the embodiment is adopted, and other preparation methods are the same as those of the 1 st group except that the flow rate of the inner phase fluid and the flow rate of the outer phase fluid are different. Experiments were conducted by adjusting the flow rate of the inner phase fluid, the flow rate of the outer phase fluid, and dividing them into 8 subgroups, and the control conditions of each subgroup, and the parameters of the prepared microspheres were referred to in table 3.
TABLE 3 Table 3
As can be seen from table 3, the magnetic alginic acid microspheres having uniform morphology and microsphere size in the range of 115 to 795 μm, each containing Fe 3O4 nanoparticles, were obtained by using the component ratios of the inner phase fluid, the outer phase fluid and the receiving fluid in the present example. As can be seen from table 3, the size of the microspheres is related to the flow rate factors of the inner and outer phases, and when the flow rate of the inner phase is fixed, the size of the prepared microspheres is gradually reduced as the flow rate of the outer phase is increased; when the flow rate of the external phase is fixed, the size of the prepared microspheres gradually increases with the increase of the flow rate of the internal phase. As can be seen from comparative groups 1 and 2 in table 3, when the flow rate of the internal phase is too high and the flow rate of the external phase is too low, the internal phase fluid is in a jet state at the cone opening, and cannot be sheared by the external phase fluid to form uniform alginic acid droplets; when the internal phase flow rate is too small and the external phase flow rate is too large, the pressure in the collection tube is too large so that the internal phase fluid cannot flow out of the cone opening, and no liquid drops are generated.
Wherein, the optical electron microscope images of the magnetic alginic acid microspheres prepared in the 7 th and 8 th groups are respectively shown in fig. 5 and 6.
As shown by a large number of experiments, the flow rate of the internal phase fluid is 100-1000 mu L/h, and the flow rate of the external phase fluid is controlled to be 0.3-7 mL/h.
Example 3
This example further examined the effect of the temperature conditions of crosslinking of the droplets in the receiving tube, the pre-crosslinking time, and the crosslinking temperature and crosslinking time in the receiving liquid on the magnetic alginic acid microspheres during the preparation of the magnetic alginic acid microspheres.
In this embodiment, the component proportions of the inner phase fluid, the outer phase fluid and the receiving liquid in the 3 rd group in the embodiment are adopted, the pre-crosslinking time of the liquid drops in the receiving pipe is changed by adjusting the length of the receiving pipe, and then conditions such as the crosslinking temperature are adjusted, so that the influence of different preparation conditions on the magnetic alginic acid microsphere is examined. According to different control conditions, the microspheres are divided into 6 groups, the specific control conditions and various parameters of the prepared microspheres are shown in Table 4, and the rest of the preparation methods are the same as those of the 3 rd group in the example 1. The flow rate of the inner phase fluid was 200. Mu.L/h, and the flow rate of the outer phase fluid was 0.3mL/h.
TABLE 4 Table 4
As can be seen from table 4, the prepared droplets were pre-crosslinked through the receiving tube, and then were continuously crosslinked as the external phase fluid slowly flowed into the receiving liquid. Because the crosslinking reaction is quicker, the length of the receiving tube has little influence on the magnetic alginic acid microsphere, and the crosslinking time in the receiving liquid has little influence on microsphere formation.
The magnetic alginic acid microsphere prepared by the preparation method of the invention contains Fe 3O4 nano particles, and can be applied to CT and nuclear magnetic detection and tumor drug carriers in the tumor treatment process.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent variation, etc. of the above embodiment according to the technical matter of the present invention fall within the scope of the present invention.
Claims (10)
1. The preparation method of the magnetic alginic acid microsphere is characterized by comprising the following steps:
(1) Preparing internal phase and external phase fluid and receiving liquid
Preparing an internal phase fluid: dissolving Fe 3O4 nano-particles and sodium alginate in water to obtain an internal phase fluid, wherein: the mass fraction of the sodium alginate is 1% -3%, and the mass fraction of the Fe 3O4 nano-particles is 0.5% -5%;
Preparing an external phase fluid: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain an external phase fluid, wherein the external phase fluid comprises the following components: the mass fraction of the oil-soluble surfactant is 0.5% -20%, and the mass fraction of the calcium iodide is 0.05% -1%;
Preparing a receiving solution: dissolving an oil-soluble surfactant and calcium iodide in n-octanol to obtain a receiving solution, wherein the receiving solution comprises the following components: the mass fraction of the oil-soluble surfactant is 0% -20%, and the mass fraction of the calcium iodide is 0.05% -5%;
(2) Preparation of magnetic alginic acid microspheres
① And (3) liquid drop preparation: injecting an internal phase fluid and an external phase fluid into a syringe and a receiving tube of the microfluidic device respectively by using a syringe pump, controlling the size of droplets by adjusting the flow rate of the syringe pump, and forming water-in-oil droplets in the receiving tube;
② Crosslinking and curing: the droplets undergo a crosslinking reaction in a receiving pipe, and flow into the receiving liquid along with the external phase fluid, and are further crosslinked and molded to obtain a crude product of the magnetic alginic acid microsphere;
(3) Washing
And (3) cleaning the crude magnetic alginic acid microsphere product obtained in the step (2) by using a detergent to remove n-octanol residual liquid on the microsphere surface, and obtaining the magnetic alginic acid microsphere after washing, dispersing the magnetic alginic acid microsphere in water and storing the magnetic alginic acid microsphere in water.
2. The method for preparing the magnetic alginic acid microsphere according to claim 1, wherein the method comprises the following steps: in the step (1), the oil-soluble surfactant in the external phase fluid and the receiving liquid is any one of Span20, span40, span60 and Span 80.
3. The method for preparing the magnetic alginic acid microsphere according to claim 1, wherein the method comprises the following steps: the droplet size is adjusted by adjusting the flow rates of the inner and outer phase fluids of ① in step (2).
4. A method for preparing a magnetic alginic acid microsphere according to claim 3, wherein: the flow rate of the internal phase fluid is 100-1000 mu L/h, and the flow rate of the external phase fluid is 0.3-7 mL/h.
5. The method for preparing the magnetic alginic acid microsphere according to claim 1, wherein the method comprises the following steps: the detergent in the step (3) is ethanol or isopropanol.
6. The method for preparing the magnetic alginic acid microsphere according to claim 1, wherein the method comprises the following steps: in the step (2), the liquid drops are pre-crosslinked in a receiving tube under the normal temperature condition.
7. The method for preparing the magnetic alginic acid microsphere according to claim 1, wherein the method comprises the following steps: the microfluidic device in the step (2) is a single-stage capillary microfluidic device and comprises an injection tube, a connecting tube and a receiving tube, wherein the injection tube is used for circulating internal phase fluid, the injection tube is made of a cylindrical glass capillary, and one end of the injection tube is conical; the connecting pipe is used for circulating outward fluid, the connecting pipe is made of square glass pipes, a square channel is arranged in the middle of the connecting pipe, a flat-mouth needle is arranged at the inlet end of the connecting pipe, the flat-mouth needle is connected with the injection pump again, and the non-inlet end of the connecting pipe is sealed; the receiving pipe is used for circulating receiving liquid, the receiving pipe is made of cylindrical glass capillary, and the conical head of the injection pipe is inserted into the tail of the receiving pipe and connected through a connecting pipe.
8. The method for preparing the magnetic alginic acid microsphere according to claim 7, wherein the method comprises the following steps: the diameter of the conical head outlet of the injection tube is 60-250 mu m.
9. A magnetic alginic acid microsphere obtained by the method according to any one of claims 1 to 8.
10. Use of the magnetic alginic acid microsphere according to claim 9 in CT and nuclear magnetic detection during tumor treatment and in tumor drug carriers.
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