Differential endocytosis magnetic nanoparticles for ablation and method for regulating the same
By measuring and regulating the endocytosis kinetic parameters of target cells and non-target cells, and calculating the safe time window and optimal action time point, the problem of tumor morphology matching in microwave ablation technology was solved. This enabled differentiated regulation of endocytosis between tumor cells and normal cells, improving ablation accuracy and protecting normal tissues.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHAANXI BAICI KANGDA MEDICAL TECH CO LTD
- Filing Date
- 2026-03-26
- Publication Date
- 2026-06-16
AI Technical Summary
Existing microwave ablation technology is difficult to match irregular tumor morphology, resulting in a mismatch between the ablation area and the tumor morphology. This may lead to residual tumor at the edge or excessive damage to normal tissue, and the distribution of nanoparticles between tumor cells and normal cells is difficult to control.
By measuring the endocytosis kinetic parameters of target cells and non-target cells, a mathematical model is established to calculate the safe time window and the optimal action time point, thereby achieving differential endocytosis regulation of magnetic nanoparticles between tumor cells and normal cells, ensuring spatial matching between the distribution of heat sources and the distribution of tumor cells.
It enables differentiated regulation of endocytosis between tumor cells and normal cells, improves ablation precision, reduces off-target toxicity, and protects normal tissues while ensuring ablation efficacy.
Smart Images
Figure CN122218073A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the interdisciplinary field of biomedicine and nanotechnology, specifically relating to a differentiated endocytic magnetic nanoparticle for ablation and its regulation method. Background Technology
[0002] Microwave ablation is a physical treatment technique that uses an ablation antenna inserted into the tissue to emit high-frequency microwaves, causing polar water molecules to rotate at high speed and generate heat through friction, leading to coagulative necrosis of cells. Compared with radiofrequency ablation, microwave ablation has advantages such as faster heating rate, larger ablation range, and less susceptibility to medium flow, and has been applied in the field of solid tissue treatment.
[0003] Current microwave ablation techniques have limitations due to the mismatch between the geometry of the ablation zone and the morphology of the tumor. The ablation zone produced by traditional microwave ablation antennas is typically ellipsoidal and may be accompanied by residual heat extending along the needle shaft. This fixed geometry is difficult to match with the diverse morphologies of tumors. To ensure complete coverage of tumor tissue, it is often necessary to expand the ablation area, which may lead to excessive damage to surrounding normal tissue; conversely, if the ablation area is controlled to protect normal tissue, tumor remnants may remain at the tumor margins.
[0004] To address this issue, existing technologies optimize antenna structures, such as multi-slot designs, water-cooling circulation, and frequency tunability, to control the thermal field distribution. However, these physical optimizations are still limited by the spatial configuration of the antenna itself, making it difficult to fundamentally match the morphology of tumors with irregular boundaries and invasive growth.
[0005] In recent years, nanomaterial-mediated microwave ablation and sensitization strategies have attracted attention. Studies have found that ferrite magnetic nanoparticles exhibit good thermal conversion efficiency under microwave fields and can be used as auxiliary heat sources to enhance ablation effects. Their potential advantage lies in the fact that the heat source can be transformed from a fixed physical antenna into distributable nanoparticles. If selective enrichment of nanoparticles in tumor tissue can be achieved, the thermal field distribution under microwave fields will be influenced by the particle distribution.
[0006] However, this strategy faces the challenge of controlling the distribution of nanoparticles among different tumor cells and normal cells. Existing nano-targeting strategies mainly rely on the enhanced permeability and retention (EPR) effect and surface-modified targeting ligands. The EPR effect can achieve passive enrichment at the tissue level, but it is difficult to distinguish between cancer cells and adjacent normal tissues in the tumor boundary region; although targeting ligands can enhance tumor cell uptake, there are problems such as receptor expression heterogeneity, ligand masking by protein corona, and non-specific uptake by normal cells.
[0007] Tumor biology research has shown that, due to alterations in oncogene signaling pathways, tumor cells exhibit differences in endocytosis dynamics compared to normal cells, including differences in endocytosis rate, total endocytosis volume, endocytosis pathway preference, and post-endocytosis fate. These intrinsic differences provide a biological basis for designing selective uptake strategies based on the cell's own characteristics.
[0008] Therefore, there is a need to develop magnetic nanoparticles and a method for controlling their distribution that can utilize the differences in endocytosis dynamics between different tumor cells and different normal cells to achieve differential endocytosis amounts. Summary of the Invention
[0009] Existing magnetic nanoparticle-mediated tumor ablation techniques typically focus on increasing the total amount of nanoparticles taken up by tumor cells or optimizing the specific absorption rate (SAR) of the nanoparticles. The underlying principle is that higher uptake or SAR equates to stronger ablation effects. However, this approach fails to adequately consider the inherent biological differences between different tumor cells and normal cells in terms of endocytosis rates and saturation endocytosis amounts. This results in a lack of temporal and spatial control over the spatial distribution of nanoparticles in vivo, making it difficult to precisely match the thermal field distribution generated by subsequent microwave ablation with the actual boundaries of the target cells. This can lead to incomplete ablation or excessive damage to surrounding normal tissues.
[0010] To address the aforementioned technical deficiencies, this application proposes a regulatory strategy aimed at maximizing the difference in endocytosis. Specifically, this application uses endocytosis kinetics parameters as the basis for regulating the distribution of magnetic nanoparticles between target and non-target cells. By establishing a mathematical model based on endocytosis kinetics, the application time point at which the difference in endocytosis between target and non-target cells reaches its maximum is calculated. Ablation is applied at this time point to achieve spatiotemporal matching between the distribution of the heat source and the distribution of tumor cells. Furthermore, based on the same principle, this application also constructs an evaluation method for screening nanomaterials based on cellular uptake kinetics.
[0011] A method for controlling differentiated endocytic magnetic nanoparticles for ablation includes the following steps: S1. Determine the endocytosis kinetic parameters of magnetic nanoparticles by target cells and non-target cells, including saturation endocytosis amount and endocytosis rate constant; S2. Based on the endocytosis kinetic parameters, a safe time window is determined, in which the amount of magnetic nanoparticles endocytosed by the target cell is always greater than the amount of non-target cell endocytosed. S3. Within the safety time window described in S2, determine the final time point at which the difference between the target cell endocytosis and the non-target cell endocytosis reaches its maximum. .
[0012] Preferably, in S2, the safe time window in which the endocytosis amount of the target cell is always greater than that of the non-target cell is determined by comparing two endocytosis time curves obtained by fitting endocytosis kinetic parameters. The endocytosis rate constant is obtained by performing exponential kinetic fitting on the data of endocytosis amount changing with time. The fitting model is as follows: (1) in, for The amount of internal throughput at any given moment. This is the saturation internalization rate. is the endocytosis rate constant.
[0013] Preferably, the final action time point described in S3 The methods for determining this include: S31, based on endocytosis kinetic parameters, construct a difference function for the amount of endocytosis between target cells and non-target cells, satisfying: (2) in, for Target cellular endocytosis volume at any given time. for Non-target cell endocytosis at any given time This represents the saturation internalization amount for the target cells. The target cell endocytosis rate constant. This represents the saturation amount of endocytosis in non-target cells. This represents the non-target cell endocytosis rate constant. S32, differentiate the difference function and set the derivative to zero to find the theoretically optimal time point. satisfy: (3) and ; S33, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, based on the theoretical optimal time point. The sign of the numerical value, and whether it falls within the safe time window described in S2, determines the final point of action. .
[0014] Preferably, in step S331, the theoretically optimal time point is determined. Whether it is within the safe time window described in S2, if the calculated If the number is positive and falls within the safe time window described in S2, then select... or a nearby time point as the final time point of action. .
[0015] Preferably, in step S332, the theoretically optimal time point is determined. Whether it is within the safe time window described in S2, if the calculated If the value is negative and not within the safety time window described in S2, the moment when the difference function reaches its maximum value within the safety time window is selected as the final action time point. .
[0016] Preferably, in step S333, the theoretically optimal time point is determined. Whether it is within the safe time window described in S2, if the calculated If the value is positive but exceeds the upper limit of the safety time window, the right endpoint of the safety time window or a nearby time point is selected as the final action time point. .
[0017] Preferably, in step S334, the theoretically optimal time point is determined. Whether it is within the safe time window described in S2, if the calculated If the value is positive but less than the lower limit of the safety time window, the left endpoint of the safety time window or a nearby time point is selected as the final action time point. .
[0018] Preferably, the S3 target cell endocytosis threshold In satisfied, At that time, the threshold ratio of target cell endocytosis to non-target cell endocytosis. Both conditions must be met simultaneously. .
[0019] A second aspect of the invention is its application in screening magnetic nanomaterials for ablation, characterized in that endocytosis kinetics parameters of target cells and non-target cells are used as screening criteria, including one or more of the following indicators: saturation endocytosis ratio. Difference in endocytosis rate constant Theoretical optimal time point Existence and its position within the safety window; .
[0020] A third aspect of the invention is a magnetic nanoparticle for ablation, said magnetic nanoparticle at the final action time point. Its endocytosis in target cells is higher than in non-target cells.
[0021] Compared with the prior art, the method of this application has the following beneficial technical effects: 1. Based on the precise regulation of differences in endocytosis dynamics, the target cell endocytosis exceeds that of non-target cells as a premise, and the maximization of the difference is taken as the optimization goal. This fundamentally avoids the negative difference that may be caused by pursuing the maximum value, i.e. the risk of normal cells taking up more.
[0022] 2. Solutions are provided for both valid and invalid theoretical formulas, and absolute value thresholds and ratio thresholds are introduced as dual screening criteria, making this method applicable to various complex and differentiated internalization dynamics scenarios, greatly enhancing the universality and operability of the technology.
[0023] 3. By scientifically calculating and finding the theoretically or practically optimal time point, the difference in endocytosis between tumor cells and normal cells can be maximized. This allows for spatial matching of heat source distribution and tumor cell distribution when a microwave field is subsequently applied, improving ablation accuracy and effectively reducing off-target toxicity. Attached Figure Description
[0024] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0025] Figure 1 Examples 1-3 of this invention show the distribution curves of endocytosis in mice after co-incubation with 75 μg / mL FVIO for 0-24 h using ICP-MS. Figure 2 For Examples 1-3 of this invention, the endocytosis distribution curves of human hepatocellular carcinoma cells HepG2 or human umbilical vein endothelial cells HUVEC were detected by ICP-MS after co-incubation of 75 μg / mL FVIO with human hepatocellular carcinoma cells HepG2 or human umbilical vein endothelial cells HUVEC for 0-24 h. Figure 3 Examples 1-3 of this invention show the distribution curves of endocytosis in human triple-negative breast cancer cells MDA-MB-231 or normal mouse hepatocytes AML-12 after co-incubation with 75 μg / mL FVIO for 0-24 h, detected by ICP-MS. Figure 4 Examples 1-3 of this invention show the distribution curves of endocytosis in cells after co-incubation with 75 μg / mL FVIO mouse hepatocellular carcinoma cells Hepa1-6 or human umbilical vein endothelial cells HUVEC for 0-24 h, detected by ICP-MS. Figure 5Examples 1-3 of this invention show the distribution curves of endocytosis in human hepatocellular carcinoma cells HepG2 or normal mouse hepatocytes AML-12 detected by ICP-MS after co-incubation of 75 μg / mL FVIO for 0-24 h. Figure 6 Examples 1-3 of this invention show the distribution curves of endocytosis in human triple-negative breast cancer cells MDA-MB-231 or human umbilical vein endothelial cells HUVEC after co-incubation with 75 μg / mL FVIO for 0-24 h using ICP-MS. Figure 7 Example 4 of the present invention, 75 μg / mL The distribution curves of endocytosis in human hepatocellular carcinoma cells Hep3B or normal human hepatocytes AML-12 were detected by ICP-MS after co-incubation for 0-24 h. Detailed Implementation
[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0027] Example 1 Material preparation and characterization: FVIOs, namely Fe3O4 nanorings, were synthesized. Transmission electron microscopy characterization showed that they are uniform nanoring structures with an outer diameter of approximately 57-70 nm. Dynamic light scattering analysis revealed a hydrated particle size of 70-80 nm, with slight variations depending on surface modification. The zeta potential was tunable, and the saturation magnetization was 58-72 emu / g, exhibiting a vortex magnetic structure. Under an alternating magnetic field of 300-400 Oe and 365 kHz, the specific absorption rate (SAR) was 2000-5000 W / gFe, demonstrating excellent magnetocaloric conversion capability, and thus suitable as the magnetic nanoparticles described in the third aspect of this invention.
[0028] S1. Determine the endocytosis kinetic parameters of magnetic nanoparticles by target cells and non-target cells, including saturation endocytosis amount and endocytosis rate constant.
[0029] Various tumor cell lines (target cells) and normal cells (non-target cells) were co-incubated with 75 μg Fe / mL FVIOs for 0–24 h. At different time points, cells were digested and counted, and intracellular iron content was measured using ICP-MS to calculate the endocytosis amount per cell (pg / cell). The cell pairs involved in this example include: Hepa1-6 and AML-12, HepG2 and HUVEC, MDA-MB-231 and AML-12, Hepa1-6 and HUVEC, HepG2 and AML-12, and MDA-MB-231 and HUVEC.
[0030] The internalization time curves of each group were nonlinearly fitted using Origin software. The endocytosis dynamics parameters of each group were obtained and summarized in Table 1.
[0031] Table 1
[0032] S2. Based on the endocytosis kinetic parameters, a safe time window is determined to be 0-24h. Within this safe time window, the amount of magnetic nanoparticles endocytosed by the target cells is always greater than the amount of non-target cells endocytosed.
[0033] By comparing the fitting curves of each pairing, it was determined that the target cell endocytosis was always greater than that of the non-target cells within a safe time window. According to Table 1, the pairings of Hepa1-6 and AML-12 cells, HepG2 and HUVEC cells, Hepa1-6 and HUVEC cells, and HepG2 and AML-12 cells all showed positive values and were all within the safe time window of 0-24h.
[0034] S3. Within the safe time window described in S2, determine the time point at which the difference between the endocytosis of the target cell and the endocytosis of the non-target cell reaches its maximum.
[0035] S31, based on endocytosis kinetic parameters, construct a difference function for the amount of endocytosis between target cells and non-target cells, satisfying: (4) in, for Target cellular endocytosis volume at any given time. for Non-target cell endocytosis at any given time This represents the saturation internalization amount for the target cells. The target cell endocytosis rate constant. This represents the saturation amount of endocytosis in non-target cells. This represents the non-target cell endocytosis rate constant. S32, differentiate the difference function and set the derivative to zero to find the theoretically optimal time point. satisfy: (5) and ; S33, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, based on the theoretical optimal time point. The sign of the numerical value, and whether it falls within the safe time window described in S2, determines the final point of action. .
[0036] S331, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, if the calculated If the number is positive and falls within the safe time window described in S2, then select... or a nearby time point as the final time point of action. .
[0037] Table 1 shows the calculation results for the Hepa1-6 and AML-12 pairing. , is a positive number, when When the value is positive and falls within the safety window defined by S2, select... Or a time point adjacent to it as the final time point of action, at which time the endocytosis of Hepa1-6 cells reached Approximately 99.43% of the data meet the absolute threshold. Furthermore, the ratio to AML-12 is approximately 1.44, which meets the ratio threshold. .
[0038] Calculation results of HepG2 and HUVEC pairing , is a positive number, when When the value is positive and falls within the safety window defined by S2, select... Or a time point adjacent to it as the final time point of action, at which the endocytosis of HepG2 cells reached Approximately 85.4% of them meet the absolute threshold. Furthermore, the ratio to HUVEC is approximately 1.30, which meets the ratio threshold. .
[0039] Calculation results of Hepa1-6 and HUVEC pairing , is a positive number, when When the value is positive and falls within the safety window defined by S2, select... Or a time point adjacent to it as the final time point of action, at which time the endocytosis of Hepa1-6 cells reached Approximately 92.1% of them meet the absolute threshold. Furthermore, the ratio to HUVEC is approximately 1.54, which meets the ratio threshold. .
[0040] Calculation results of HepG2 and AML-12 pairing , is a positive number, when When the value is positive and falls within the safety window defined by S2, select... Or a time point adjacent to it as the final time point of action, at which the endocytosis of HepG2 cells reached Approximately 86.9% of them meet the absolute threshold. Furthermore, the ratio to AML-12 is approximately 1.21, which meets the ratio threshold. .
[0041] The above four sets of effectively paired experimental data show that the target cell endocytosis reached its theoretical optimal time point. This ensures sufficient labeling or killing of target cells, with the target-to-non-target ratio between 1.21 and 1.54, significantly greater than 1, enabling effective differentiation between target and non-target cells. All absolute thresholds are met, verifying the universality and reliability of this invention.
[0042] This method demonstrates that it can maximize the differential endocytosis of target cells and non-target cells.
[0043] Example 2 This example demonstrates the calculation of the theoretically optimal time point. When the value is negative, the final action time point is determined. The same material preparation and characterization methods as in Example 1 were used, and the endocytosis kinetics parameters of the magnetic nanoparticles by target and non-target cells were measured using S1. The obtained data are shown in Table 1.
[0044] S2. Based on the endocytosis kinetic parameters, a safe time window is determined to be 0-24h. Within this safe time window, the amount of magnetic nanoparticles endocytosed by the target cells is always greater than the amount of non-target cells endocytosed.
[0045] S3. Within the safe time window described in S2, determine the time point at which the difference between the endocytosis of the target cell and the endocytosis of the non-target cell reaches its maximum.
[0046] S31, based on endocytosis kinetic parameters, construct a difference function for the amount of endocytosis between target cells and non-target cells, satisfying: (6) in, for Target cellular endocytosis volume at any given time. for Non-target cell endocytosis at any given time This represents the saturation internalization amount for the target cells. The target cell endocytosis rate constant. This represents the saturation amount of endocytosis in non-target cells. This represents the non-target cell endocytosis rate constant. S32, differentiate the difference function and set the derivative to zero to find the theoretically optimal time point. satisfy: (7) and ; S33, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, based on the theoretical optimal time point. The sign of the numerical value, and whether it falls within the safe time window described in S2, determines the final point of action. .
[0047] S332, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, if the calculated If the value is negative and not within the safety time window described in S2, the moment when the difference function reaches its maximum value within the safety time window is selected as the final action time point. .
[0048] The calculation of the pairing of MDA-MB-231 and AML-12 is shown in Table 1. This indicates that the theoretical extreme point is located in the negative time domain, and the difference function of endocytosis between target cells and non-target cells. The trend of change within the safe time window is monotonically increasing. When the difference function monotonically increases within the safe window, the maximum value is the right endpoint of the safe window. The maximum value appears at the right endpoint of the window. Combining absolute threshold and ratio threshold, select As the final point of action, it meets the absolute threshold. Furthermore, the ratio to AML-12 is approximately 1.8, which meets the ratio threshold. .
[0049] Example 3 This example demonstrates the calculation of the theoretically optimal time point. The final action time point is determined when the target cell is outside the safe time window described in S2. The same material preparation and characterization methods as in Example 1, and the endocytosis kinetics parameters of the magnetic nanoparticles by the target and non-target cells were measured in S1. The obtained data are shown in Table 1.
[0050] S2. Determine a safe time window. Based on the endocytosis kinetic parameters, determine a safe time window of 0-24h. Within this safe time window, the amount of magnetic nanoparticles endocytosed by the target cells is always greater than the amount of non-target cells endocytosed.
[0051] S3. Within the safe time window described in S2, determine the time point at which the difference between the endocytosis of the target cell and the endocytosis of the non-target cell reaches its maximum.
[0052] S31, based on endocytosis kinetic parameters, construct a difference function for the amount of endocytosis between target cells and non-target cells, satisfying: (8) in, for Target cellular endocytosis volume at any given time. for Non-target cell endocytosis at any given time This represents the saturation internalization amount for the target cells. The target cell endocytosis rate constant. This represents the saturation amount of endocytosis in non-target cells. This represents the non-target cell endocytosis rate constant. S32, differentiate the difference function and set the derivative to zero to find the theoretically optimal time point. satisfy: (9) and ; S33, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, based on the theoretical optimal time point. The sign of the numerical value, and whether it falls within the safe time window described in S2, determines the final point of action. .
[0053] S333, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, if the calculated If the value is positive but exceeds the upper limit of the safety time window, the right endpoint of the safety time window or a nearby time point is selected as the final action time point. .
[0054] The calculations for pairing MDA-MB-231 and HUVEC are shown in Table 1. The difference function between the amount of endocytosis of target cells and non-target cells far exceeds the upper limit of the safe time window. The trend of change within the safe time window is monotonically increasing, with the maximum value appearing at the right end of the window. When the difference function monotonically increases within the safe window, the maximum value is the right endpoint of the safe window. Combining the absolute threshold and the ratio threshold, select... At this final point of action, the internalization of MDA-MB-231 is close to saturation, satisfying the absolute threshold. Furthermore, the ratio to AML-12 is approximately 2.0, which meets the ratio threshold. .
[0055] Example 4 This invention provides a method for screening magnetic nanomaterials, characterized in that the endocytosis kinetics parameters of target cells and non-target cells are used as screening criteria, including one or more of the following indicators: saturation endocytosis ratio. Difference in endocytosis rate constant Theoretical optimal time point Existence and its position within the safety window; .
[0056] Material A, FVIOs nanorings, data can be found in Examples 1-2; Material B, The nanocubes, with a size of approximately 17 nm, a hydrated particle size of 20.5 nm, a zeta potential of -39.6 mV, a saturation magnetization of 42.97 emu / g, and a SAR of >1000 W / g Fe+Zn, are compared in Table 2.
[0057] Table 2
[0058] The ratio of saturated internalization of both materials satisfies The ratios of AML-12 to AML-12 were 1.44 and 1.09, respectively, both meeting the screening criteria. Both materials meet the screening criteria, and FVIOs's If the value is positive and within the window, it can be applied directly. of For negative values, the optimal time point in practice needs to be determined using the method in Example 2. The SAR value of FVIOs is higher than... For microwave ablation applications, the combination of high internalization differential and high SAR value is superior. Therefore, when the internalization differential of the two is similar, FVIOs can be regarded as the preferred material.
[0059] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be included within the protection scope of the present invention.
Claims
1. A method for controlling differentiated endocytic magnetic nanoparticles for ablation, characterized in that, Includes the following steps: S1. Determine the endocytosis kinetic parameters of magnetic nanoparticles by target cells and non-target cells, including saturation endocytosis amount and endocytosis rate constant; S2. Based on the endocytosis kinetic parameters, a safe time window is determined, in which the amount of magnetic nanoparticles endocytosed by the target cell is always greater than the amount of non-target cell endocytosed. S3. Within the safety time window described in S2, determine the final time point at which the difference between the target cell endocytosis and the non-target cell endocytosis reaches its maximum. .
2. The method for controlling differentiated endocytic magnetic nanoparticles for ablation according to claim 1, characterized in that, The safe time window in S2 where the target cell endocytosis amount is always greater than the non-target cell endocytosis amount is determined by comparing two endocytosis time curves obtained from fitting endocytosis kinetic parameters. The endocytosis rate constant is obtained by performing exponential kinetic fitting on the data of endocytosis amount changing with time. The fitting model is as follows: (1) in, for The amount of internal throughput at any given moment. This is the saturation internalization rate. is the endocytosis rate constant.
3. The method for controlling differentiated endocytosis magnetic nanoparticles for ablation according to claim 1, characterized in that, The final time point of action as described in S3 The method for determining it includes the following steps: S31, based on endocytosis kinetic parameters, construct a difference function for the amount of endocytosis between target cells and non-target cells, satisfying: (2) in, for Target cellular endocytosis volume at any given time. for Non-target cell endocytosis at any given time This represents the saturation internalization amount for the target cells. The target cell endocytosis rate constant. This represents the saturation amount of endocytosis in non-target cells. This represents the non-target cell endocytosis rate constant. S32, differentiate the difference function and set the derivative to zero to find the theoretically optimal time point. satisfy: (3) and ; S33, Determine the theoretically optimal time point Whether it is within the safe time window described in S2, based on the theoretical optimal time point. The sign of the numerical value, and whether it falls within the safe time window described in S2, determines the final point of action. .
4. The method for controlling differentiated endocytic magnetic nanoparticles for ablation according to claim 3, characterized in that, Includes the following steps: S331, determining the theoretically optimal time point. Whether it is within the safe time window described in S2, if the calculated If the number is positive and falls within the safe time window described in S2, then select... or a nearby time point as the final time point of action. .
5. The method for controlling differentiated endocytic magnetic nanoparticles for ablation according to claim 3, characterized in that, Includes the following steps: S332, determining the theoretically optimal time point. Whether it is within the safe time window described in S2, if the calculated If the value is negative and not within the safety time window described in S2, the moment when the difference function reaches its maximum value within the safety time window is selected as the final action time point. .
6. The method for controlling differentiated endocytosis magnetic nanoparticles for ablation according to claim 3, characterized in that, Includes the following steps: S333, determining the theoretically optimal time point. Whether it is within the safe time window described in S2, if the calculated If the value is positive but exceeds the upper limit of the safety time window, the right endpoint of the safety time window or a nearby time point is selected as the final action time point. .
7. The method for controlling differentiated endocytic magnetic nanoparticles for ablation according to claim 3, characterized in that, Includes the following steps: S334, determining the theoretically optimal time point. Whether it is within the safe time window described in S2, if the calculated If the value is positive but less than the lower limit of the safety time window, the left endpoint of the safety time window or a nearby time point is selected as the final action time point. .
8. A method for controlling differentiated endocytosis magnetic nanoparticles for ablation according to any one of claims 1-7, characterized in that, The S3 target cell endocytosis threshold In satisfied, At that time, the threshold ratio of target cell endocytosis to non-target cell endocytosis. Both conditions must be met simultaneously. .
9. The application of a differentiated internalization magnetic nanoparticle control method for ablation according to any one of claims 1-8 in screening magnetic nanomaterials for ablation, characterized in that, The endocytosis kinetics parameters of target cells and non-target cells on candidate magnetic nanomaterials were used as screening criteria, which included one or more of the following indicators: saturation endocytosis ratio. Difference in endocytosis rate constant Theoretical optimal time point Existence and its position within the safety window.
10. A magnetic nanoparticle for ablation, characterized in that, The final action time point determined by the differential endocytic magnetic nanoparticle modulation method for ablation according to any one of claims 1-8 is described. Its endocytosis in target cells is higher than in non-target cells.