Gel material for radiofrequency ablation and use

Abstract

The application relates to the technical field of tumor treatment, and discloses a gel material for radiofrequency ablation and application. The gel material for radiofrequency ablation adopts an alginate gel to form a local wrapping isolation belt between tumor tissues and blood vessels, a hydrated platinum solution is injected at the middle position of the alginate gel, and a coordination gel is formed by in-situ coordination of alginate and platinum ions. The hydrated platinum solution is prepared by fully reacting a platinum-based drug, silver nitrate and water. The application of the gel material in preparing a tumor drug for treating tumors located beside large blood vessels. The alginate gel and the hydrated platinum solution are respectively injected between tumor tissues and adjacent large blood vessels, and a stable gel is formed in the tissue gap, without the need of an additional crosslinking agent. Through the design of the material structure and the control of the application path, precise auxiliary ablation of tumors beside large blood vessels and blood vessel protection are realized in RFA ablation treatment, which constitutes the core technical advantage of the application.

Description

Technical Field

[0001] This application relates to the field of tumor treatment technology, and in particular to a gel material and its application for radiofrequency ablation of liver tumors. Background Technology

[0002] Radiofrequency ablation (RFA) is a mature, minimally invasive technique for treating hepatocellular carcinoma (HCC) and liver metastases, particularly suitable for early-stage lesions with a tumor diameter ≤3 cm. RFA involves generating a high-frequency current within the tissue, causing localized high-temperature thermal coagulation necrosis of the lesion, thus achieving the therapeutic goal. Clinical studies have shown that RFA can achieve a complete ablation rate exceeding 90% for small HCCs, with a 5-year survival rate of 40%-70%, characterized by its minimally invasive nature, repeatability, and rapid recovery. The latest guidelines for liver cancer diagnosis and treatment have listed thermal ablation alongside surgery as first-line treatments. However, in clinical application, the local recurrence rate of RFA for HCC is 2%-60%, especially for tumors adjacent to major blood vessels in the liver, where the local recurrence rate is approximately 12.4%. A retrospective, multicenter, matched cohort study showed that compared to surgical resection, RFA significantly reduced progression-free survival and overall survival for small HCCs (≤3 cm) adjacent to major blood vessels. Therefore, the efficacy of ablation therapy for liver tumors located near liver blood vessels has received increasing attention.

[0003] Traditional radiofrequency ablation (RFA) technology has significant limitations in treating liver tumors located near major blood vessels. Due to the high-velocity blood flow within these vessels (such as the hepatic vein, portal vein, and their branches), heat is often continuously carried away from the area adjacent to the vessel after the radiofrequency electrode releases energy, resulting in the so-called "heat-sink effect." This phenomenon means that the temperature of the tumor tissue on the side adjacent to the vessel cannot reach a level sufficient to induce cell necrosis, leading to incomplete ablation or tumor residue. Further research has shown that the heat-sink effect not only reduces the effectiveness of local treatment but also significantly increases the postoperative recurrence rate. Figure 1 This is especially pronounced when the tumor is closely attached to the blood vessel wall. Furthermore, to achieve sufficient ablation coverage, operators often need to increase the power or extend the heating time, which can lead to the opposite problem—high-temperature damage to the large blood vessel wall, causing bleeding, thrombosis, or biliary complications. In severe cases, it can lead to liver ischemia and liver necrosis. Figure 2 Therefore, how to ensure the therapeutic effect of ablation while avoiding thermal damage to important vascular structures is one of the key challenges in radiofrequency ablation technology.

[0004] To address the limitations of RFA treatment and overcome local tumor recurrence caused by the "heat sink effect," a series of targeted technologies have been developed clinically. Existing technology one: multi-polar, multi-point ablation technology, primarily targeting large tumors or irregularly shaped lesions. By repeatedly changing the puncture point or adjusting the electrode position, overlapping ablation is performed at different sites of the tumor to achieve full-area coverage and effective boundary clearance. Figure 3 Studies have explored the feasibility of using multipolar radiofrequency ablation electrodes to overlap thermal fields in liver tissue using in vivo porcine liver experiments. Results showed that multipolar, multi-point ablation treatment can expand the ablation range. Although multipolar / multi-point radiofrequency ablation technology can expand the area of ​​tissue necrosis and improve local control rates for large tumors or tumors adjacent to liver vessels, it still has certain limitations in practical application. Firstly, the procedure is more complex, with the planning of the puncture path, electrode placement, and radiofrequency energy control relying more heavily on the operator's experience. Secondly, the overlapping needle placement method increases the number of punctures and the difficulty of electrode placement, potentially increasing the risk of vascular injury during electrode placement. Similarly, multipolar / multi-point radiofrequency ablation technology increases the overall power and time during the ablation process; higher radiofrequency energy and treatment time increase the probability of damage to large liver vessels adjacent to the tumor. More importantly, the overlapping needle placement method may create more irregularly shaped and incompletely fused ablation areas, potentially containing "non-fusion" dead zones, making it impossible to achieve the ideal ablation safety boundary, and ultimately potentially leading to tumor residue or local recurrence.

[0005] Existing Technology Two: RFA combined with Transarterial Chemoembolization (TACE) to improve the efficacy of RFA and reduce local recurrence rate. RFA combined with TACE is a commonly used local comprehensive treatment strategy for intermediate-to-advanced or specially located hepatocellular carcinoma (HCC). It combines the advantages of two local treatment methods, showing a higher local control rate, especially in cases where the tumor diameter is large, close to blood vessels or bile ducts, or where complete ablation in one session is not possible. TACE involves injecting chemotherapeutic drugs (such as doxorubicin) and carrier oils (such as lipiodol) through an arterial catheter, followed by embolization to inhibit tumor blood supply and induce ischemic necrosis. TACE reduces tumor blood supply and decreases the impact of the "heat sink effect" on the tumor, indirectly improving the thermal effect and necrosis range of RFA. Currently, there are no clear standardized treatment guidelines for RFA combined with TACE in the clinical treatment of liver tumors; implementation mainly relies on literature reports and individual physician experience. Although this combined regimen has certain efficacy advantages in specific situations, it still has several limitations in practical application. RFA and TACE are typically not performed simultaneously, resulting in a prolonged treatment cycle and requiring multiple interventional procedures for patients. This increases the financial burden and carries the potential risk of lesion progression or metastasis. Furthermore, TACE also causes some damage to liver tissue; if combined with RFA to further impair liver function, it may lead to liver failure, especially in patients with multiple lesions or those who have undergone multiple treatments. In addition, while TACE can induce partial tumor necrosis, residual tumor cells can still be distributed in the perivascular region, making RFA treatment susceptible to heat sink effects, leading to incomplete ablation. Some studies have also found that the hypoxic environment following TACE may activate the hypoxia-inducible factor (HIF-1α) pathway, accelerating the progression of residual tumor cells and further exacerbating the technical difficulty and failure risk of RFA treatment.

[0006] Existing technology three: Radiofrequency ablation alternative, namely, using irreversible electroporation (IRE) to treat perivascular tumors of the liver. IRE is a non-thermal local ablation technique that involves inserting multiple electrodes into the tumor tissue and releasing short-duration high-voltage pulse currents (typically 1000-3000 volts) to create permanent nanopores in the cell membrane, disrupting the membrane's selective permeability, thereby causing cellular electrolytic imbalance, apoptosis, or programmed cell death, without damaging the extracellular matrix, blood vessels, bile ducts, or neural structures. Because IRE is not affected by the "heat sink effect," it is considered a particularly suitable ablation method for lesions near large blood vessels, bile ducts, or organ boundaries. Figure 4Although intravascular resurfacing (IRE) can kill tumor cells without damaging blood vessels, bile ducts, and connective tissue, it has been widely studied for the treatment of tumors near major blood vessels in the liver. However, it still has several limitations in clinical practice. First, the ablation area of ​​IRE is usually small, suitable for lesions with a diameter ≤3cm. For larger tumors close to major blood vessels, a single IRE may not achieve complete coverage, requiring multi-polar combined operation, which is complex and riskier in the perivascular area. Second, during IRE treatment, the electrode needles need to be arranged parallel and equidistantly to form a regular electric field. However, in the perivascular area (such as at the junction of portal vein branches and hepatic veins), the vascular structure obstructs the optimal electrode placement path, easily causing uneven electric field and leading to local ablation failure. Although IRE is a non-thermal ablation treatment, its high-voltage pulsed current (usually 1000V–3000V) may cause non-target tissue stimulation in the perivascular area, including electrolytic damage to the diaphragm, biliary smooth muscle, or blood vessel walls, leading to complications such as arrhythmias and bile duct stenosis. In addition, unlike thermal ablation which creates a clear coagulation zone, IRE cannot monitor the necrotic area in real time, making it difficult to confirm the completeness of ablation during the procedure. Evaluation is only conducted via MRI / CT after the ablation is completed, which increases the risk of incomplete ablation.

[0007] Existing technology four: RFA combined with percutaneous ablation ethanol (PEI) therapy. This approach combines thermal ablation with chemical ablation. Under image guidance, percutaneous ethanol is injected locally into the tumor. Its chemical properties cause dehydration of tumor cells, protein denaturation, and microvascular obstruction, leading to local necrosis. It can be used as an adjunct to thermal ablation, especially suitable for lesions that are difficult to completely ablate with a single technique, such as large tumors, those with irregular borders, or those near large blood vessels. Multiple clinical studies have shown that the local control rate of RFA+PEI combined therapy is higher than that of RFA or PEI alone, especially in HCC lesions larger than 3 cm. Although percutaneous ethanol injection (PEI) combined with radiofrequency ablation (RFA) has advantages in liver tumor treatment, such as ease of operation, high reproducibility, and low cost, its clinical application still has significant limitations, mainly due to the uncontrollable diffusion behavior of ethanol as a liquid drug. First, after injection into tumor tissue, PEI is prone to uneven diffusion within the tumor due to the heterogeneity of its internal structure, degree of fibrosis, and differences in tissue gaps. This uncertainty in distribution may result in some tumor areas not being adequately covered by ethanol, thus hindering effective cell necrosis. This is especially true in areas near large blood vessels, where the uncontrollable diffusion of ethanol further increases the risk of local residue. Second, the high-contrast area formed in the tissue after ethanol injection may interfere with the precise placement of the electrode needle under image guidance during subsequent RFA procedures, affecting the determination of the puncture path. Simultaneously, echo changes or local artifacts formed after ethanol injection may also obscure the true ablation boundary, making it difficult for the operator to accurately assess the integrity and edge coverage of the ablation area. Third, the chemical properties of PEI can cause red blood cell destruction and vascular endothelial cell damage, leading to local inflammatory reactions, endothelial shedding, and activation of the coagulation system. If ethanol is accidentally injected into the blood vessel lumen during puncture, it can cause local thrombosis or even embolism in distant organs (such as the lungs or brain), which is one of the most serious complications of PEI. Therefore, although PEI can enhance the therapeutic effect of RFA to a certain extent, due to its strong diffusion, uncontrollable distribution and interference with imaging monitoring, there are still potential risks of incomplete ablation, residual tumor and recurrence. Especially in cases with complex anatomical structures or special tumor locations, it may not be able to achieve the goal of protecting blood vessels while improving the efficacy of radiofrequency ablation. Summary of the Invention

[0008] To address the aforementioned technical issues, this application provides a gel material and its application for radiofrequency ablation of liver tumors, which protects blood vessels, inhibits tumor growth, and improves the efficacy of radiofrequency ablation.

[0009] In a first aspect, this application provides a gel material for radiofrequency ablation, which uses alginate gel to form a local encapsulation and isolation zone between tumor tissue and blood vessels, and injects a hydrated platinum solution into the middle position of the alginate gel, thereby forming a coordination gel through in-situ coordination of alginate and platinum ions.

[0010] Furthermore, the hydrated platinum solution is prepared by fully reacting a platinum-based drug, silver nitrate, and water, wherein the platinum-based drug is a divalent cationic chemotherapy drug, including cisplatin, carboplatin, or oxaliplatin.

[0011] Furthermore, by mass fraction, the raw materials of the coordination gel include 0.1%-0.5% of the platinum-based drug and 1.8%-3.5% of the alginate.

[0012] Secondly, this application provides the use of any of the above-mentioned gel materials in the preparation of drugs for treating tumors located next to large blood vessels.

[0013] Furthermore, the alginate gel and the hydrated platinum solution are injected between the tumor tissue and the adjacent large blood vessels, respectively, to form a stable gel in the interstitial space without the need for additional cross-linking agents.

[0014] Furthermore, the injection process includes first injecting the alginate gel to form a local encapsulation barrier between the tumor tissue and the blood vessel, and then injecting the hydrated platinum solution at the middle position of the local encapsulation barrier.

[0015] Furthermore, the application specifically includes the following steps: (1) Prepare the hydrated platinum solution and the alginate gel separately. (2) Assess the number, location, size, and spatial relationship of the tumors to the adjacent blood vessels. (3) First, inject the alginate gel to form a local encapsulation isolation zone between the tumor tissue and the blood vessel. Then, inject the hydrated platinum solution at the middle position of the local encapsulation isolation zone to form the coordination gel, and confirm the injection effect. (4) Perform radiofrequency ablation.

[0016] Furthermore, the injection process can utilize a single-tube syringe, a dual-lumen premixing system, or a dedicated interventional puncture needle.

[0017] Furthermore, the amount of the platinum-based drug used in the injection process does not exceed 10 mg.

[0018] Furthermore, the tumor is a liver tumor.

[0019] In the treatment of liver tumors using radiofrequency ablation (RFA), effectively protecting adjacent major blood vessels and preventing vascular wall necrosis and intraluminal thrombosis caused by high temperatures, thereby preventing secondary ischemic necrosis of liver tissue, is a significant safety issue currently facing the application of RFA in areas adjacent to large blood vessels. Currently, the physical properties (such as mechanical strength and thermal insulation) of conventional alginate gels are unsuitable for RFA treatment, while the gel material of this application, through specific proportions and application methods, can be used in RFA treatment.

[0020] The beneficial effects of this application include at least the following: 1. This application achieves precise auxiliary ablation and vascular protection of tumors near large blood vessels in RFA ablation therapy through the design of material structure and control of application path, which constitutes the core technical advantage of this application.

[0021] 2. This application addresses key issues faced by existing RFA techniques in treating tumors adjacent to large liver vessels, such as the "heat sink effect," easy damage to vascular tissue, incomplete ablation, and high recurrence rate, by injecting an alginate-platinum ion coordination gel complex between the tumor and blood vessels before radiofrequency ablation (RFA). The gel material in this application exhibits excellent biocompatibility, biodegradability, and gel-forming ability. The alginate-platinum ion coordination gel features sustained release and precise local release, avoiding drug toxicity caused by high doses in a short period and extending the drug's action window.

[0022] 3. In this application, cisplatin serves as both a cross-linking agent and an anti-tumor active ingredient in the system, which greatly simplifies the operation process and improves the controllability and precision of the injection operation.

[0023] 4. The application of this application can stably protect vascular tissue from thermal damage and avoid vascular injury or thrombosis during RFA ablation, thereby improving the tissue safety of the treatment process.

[0024] 5. The application of this application can suppress the "heat sinking effect" and improve the uniformity of thermal ablation by constructing an in-situ gel barrier with directional thermal insulation, thus solving the technical difficulty of incomplete ablation in the vicinity of blood vessels in traditional RFA.

[0025] 6. The application of this application has significant technical advantages in enhancing tumor suppression effects and delaying or preventing recurrence through the combined effect of cisplatin's sustained drug efficacy coverage in the gel and RFA-mediated in situ immune activation. Attached Figure Description

[0026] Figure 1The imaging findings of a 53-year-old male patient who underwent radiofrequency ablation (RFA) for perihepatic colon cancer with liver metastases are shown below. A) Axial T2-weighted MRI image shows a 2.6 cm high-signal lesion (arrow) in segment 8 before ablation, adjacent to the hepatic vein. B) Axial enhanced MRI image shows clearance of the lesion (arrow) during the equilibrium phase. C) Preoperative ultrasound image shows the lesion (arrow) in contact with the hepatic vein. The patient underwent RFA, and the technique was effective one month post-procedure. D) Axial enhanced MRI image six months after RFA shows local tumor progression around the ablation area.

[0027] Figure 2 This is a 53-year-old male patient with liver necrosis following radiofrequency ablation (RFA) for hepatocellular carcinoma. A shows an enhanced MRI scan taken one week before RFA, revealing a tumor located near the portal vein (white arrow). B shows an enhanced MRI scan two days after RFA, showing necrosis of liver tissue outside the ablation zone (asterisk), with the portal vein not visible. C and D are enhanced CT scans taken one month after RFA, C in the coronal plane and D in the axial plane. The ablation zone and distal necrotic liver tissue have fused together, forming a wedge-shaped non-enhancing area (asterisk) with gas formation inside (red arrow), indicating liver infection.

[0028] Figure 3 These are schematic diagrams of multi-electrode / multi-point radiofrequency ablation technology. A shows a schematic diagram using two electrode needles for ablation. B shows a schematic diagram using three electrode needles for ablation. C shows a schematic diagram using two electrode needles with overlapping ablation points. D shows a schematic diagram using three electrode needles with overlapping ablation points.

[0029] Figure 4 This patient is a 22-year-old male with a non-seminomatous testicular tumor and two liver metastases. Image a is an enhanced CT image before IRE treatment, showing a low-density metastatic lesion in liver segment V, with a long diameter of 1.8 cm (thick arrow); this metastatic lesion is located between a branch of the portal vein (thin arrow) and the right hepatic vein (arrow). Enhanced CT images b and c, taken one day after IRE ablation, show a low-density area in the venous phase (thick arrow) with peripheral enhancement in both phases. Note the presence of air bubbles within the lesion (thin arrow). The right hepatic vein (arrow) and its branch are patent, with no signs of thrombosis. PV = portal vein.

[0030] Figure 5 This is a schematic diagram of the process of using alginate-platinum ion coordination gel in radiofrequency ablation of liver tumors.

[0031] Figure 6 Equipment used for drug injection.

[0032] Figure 7 It is a hydrated platinum solution.

[0033] Figure 8 This is sodium alginate gel. A is a front view of the sodium alginate gel. B is a side view of the sodium alginate gel.

[0034] Figure 9 These are alginate-platinum ion coordination complex gels. A is an alginate-platinum ion coordination gel formed by the coordination of alginate and hydrated platinum; it is milky white and shows no obvious flow (white arrow). B is an alginate-platinum ion coordination gel that forms immediately after injection in in vitro experiments; it is milky white and shows no obvious flow (white arrow). C is an alginate-platinum ion coordination gel that exhibits some viscosity after formation; the coordination gel shown by the white arrow adheres to the needle tip.

[0035] Figure 10 These are electron micrographs of alginate and alginate-platinum ion coordination gels. Image A shows a layered network structure of alginate. Image B shows a dense network structure of alginate-platinum ion coordination gels with attached particles.

[0036] Figure 11 On day 11 after drug injection, alginate-platinum ion coordination gel remained in the xenograft. A is alginate gel (black arrow). B is alginate-platinum ion coordination gel (black arrow).

[0037] Figure 12 This is an infrared image of the thermally insulated alginate-platinum ion coordination gel. A shows the ablation zone (white arrow) and the thermally insulated zone (where the radiofrequency ablation needle tip temperature is set to 60℃). (Number). B represents the ablation zone (white arrow) and the insulation zone, where the radiofrequency ablation needle tip temperature is set to 65℃. (Number). C represents the ablation zone (white arrow) and the heat insulation zone, where the radiofrequency ablation needle tip temperature is set to 70℃. (No.) D represents the control group, where no alginate-platinum ion coordination gel was injected, and the ablation zone (white arrow) was set to 70°C at the radiofrequency ablation needle tip temperature.

[0038] Figure 13 The graphs show the intratumoral temperature changes after injection of alginate-platinum ion coordination gel. A shows the temperature changes at the ablation needle tip (blue curve) and the alginate-platinum ion coordination gel (yellow curve) when the radiofrequency ablation needle tip temperature is set to 60℃. B shows the temperature changes at the ablation needle tip (blue curve) and the alginate-platinum ion coordination gel (yellow curve) when the radiofrequency ablation needle tip temperature is set to 70℃. C shows the temperature changes at the ablation needle tip (blue curve) and the same injection site (yellow curve) in the control group (without alginate-platinum ion coordination gel injection) when the radiofrequency ablation needle tip temperature is set to 60℃.

[0039] Figure 14 The ultrasound images show the post-injection appearance of alginate-platinum ion coordination gel under ultrasound monitoring. In the ultrasound images, the alginate gel appears as an anechoic area (white arrow), while the alginate-platinum ion coordination gel forms isoechoic clusters (red). Number).

[0040] Figure 15 Images include gross pathology, H&E staining, and immunofluorescence. The PT+RFA group (alginic acid-platinum ion coordination gel combined with radiofrequency ablation) was included; RFA only (radiofrequency ablation only) was included; and the control group (negative control, receiving no treatment) was included. Compared to the combined treatment and the negative control group, radiofrequency ablation alone caused vascular damage and thrombosis.

[0041] Figure 16 To prevent liver ischemia and necrosis in live animal experiments using alginate-platinum ion coordination gel. A represents the protection of liver blood vessels after injection of the ablation zone (…). Blood flow to the distal liver tissue was not affected in section B. Section B involved simple radiofrequency ablation of tissue adjacent to major liver vessels. (arrow) The blood vessels were affected by the high temperature, and ischemic necrosis occurred in the distal liver tissue.

[0042] Figure 17 For comparison of radiofrequency ablation range. RFA+PT: alginate-platinum ion coordination gel combined with radiofrequency ablation treatment group; RFA only: radiofrequency ablation treatment group alone; RFA high low: high and low power control group. The ablation range of the radiofrequency ablation group alone was significantly smaller than that of the alginate-platinum ion coordination gel combined with radiofrequency ablation group.

[0043] Figure 18 The combination of alginate-platinum crosslinked gel and radiofrequency ablation significantly inhibited tumor growth. A shows a comparison of tumor size in each group on day 11 after alginate-platinum crosslinked gel injection. B shows a comparison of survival time in mice of different treatment groups. C shows a comparison of tumor growth curves in different treatment groups. D shows the weight change curve of mice after drug injection. E shows immunohistochemical staining of tumor proliferation in different treatment groups. F shows immunofluorescence staining of tumor necrosis in different treatment groups. Control: negative control group; RFA only: radiofrequency ablation alone; PT only: alginate-platinum gel alone; PT+RFA: alginate-platinum gel combined with RFA. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application are described clearly and completely below. The following embodiments are used to illustrate this application, but are not intended to limit the scope of this application.

[0045] A gel material for radiofrequency ablation utilizes an alginate gel to form a localized encapsulation barrier between tumor tissue and liver blood vessels. A hydrated platinum solution is injected into the center of the alginate gel, allowing for in-situ coordination between alginate and platinum ions to form a coordination gel. The hydrated platinum solution is prepared by fully reacting a platinum-based drug, silver nitrate, and water. The platinum-based drug is a divalent cationic chemotherapeutic agent, including cisplatin, carboplatin, or oxaliplatin. By mass fraction, the coordination gel comprises 0.1%-0.5% platinum-based drug and 1.8%-3.5% alginate, with the remainder being solvent. The gelling properties and good biocompatibility of alginate enable it to encapsulate and release drugs. Platinum-based drugs (such as cisplatin) form cross-linked structures with DNA (especially acting on the guanine N7 site), blocking DNA replication and repair, thereby inducing tumor cell apoptosis. This application achieves a good balance between physical properties (such as mechanical strength and thermal insulation) and precise local release through material structure design.

[0046] Injecting a 5% glucose solution or a 0.9% sodium chloride solution between the liver tumor and major blood vessels creates an artificial liquid barrier, which can provide some degree of local cooling and protection for the blood vessels. This method is simple to operate and low in cost, but the liquid form is unstable, easily diffused or absorbed, and does not easily remain for a short period of time. The duration of thermal protection is limited, and it does not have the ability to synergistically fight tumors with drugs.

[0047] The application of the aforementioned gel material in the preparation of drugs for treating tumors located next to large blood vessels specifically includes the following steps ( Figure 5 ): (1) Prepare hydrated platinum solution and alginate gel respectively.

[0048] (2) Assess the number, location, size and spatial relationship of the tumor to adjacent blood vessels.

[0049] (3) First, inject alginate gel to form a local encapsulation barrier between the tumor tissue and liver blood vessels. Then, inject hydrated platinum solution in the middle of the local encapsulation barrier and confirm the injection effect. No additional cross-linking agent is required. Compared with relying on exogenous cross-linking agents to build a stable structure, this application achieves self-cross-linking through the intrinsic interaction between the material and the drug (e.g., cisplatin). The injection process can use a single-tube syringe, a dual-lumen premixing system, or a dedicated interventional puncture needle.

[0050] (4) Perform radiofrequency ablation.

[0051] Example 1 I. Composition and Component Description 1. Sodium alginate gel Sodium alginate gel is the main component of the gel in this application, with a concentration of 25%. This material has good biocompatibility, injectability, and in-situ gelation ability.

[0052] 2. Cisplatin chemotherapy drugs Cisplatin was added to the alginate gel solution in the form of a hydrated platinum solution with a concentration of 20 mg / mL. It served not only as an antitumor drug but also as a divalent cation crosslinking source, reacting with alginate in situ to form a gel.

[0053] 3. Hybrid Injection System This system is used to inject sodium alginate gel and platinum hydrate solution separately into the tissue space between the tumor and blood vessels, mixing to form a new coordination gel. The system can be a single-tube syringe, a dual-lumen premixing system, or a dedicated interventional puncture needle.

[0054] 4. Radiofrequency ablation system The system uses the Mianyang Lide radiofrequency ablation instrument, with a radiofrequency electrode needle diameter of 16G and a tip exposed 2.0cm-4.0cm. It can provide an ablation range of about 2.5cm-4.5cm along the long axis of the electrode needle. When the radiofrequency electrode needle is inserted into the tumor area, it can provide 70-90 watts of energy to form a local high temperature and induce coagulative necrosis of the tumor tissue.

[0055] 5. Drug injection equipment Drug injection equipment ( Figure 6 The procedure includes an interventional puncture needle, a 5mL syringe, and a 2mL syringe. The interventional puncture needle used is the Japanese Hachiko Type B PTC interventional puncture needle, with a diameter of 18G and a length of 20cm. The needle tip is specially treated to allow for real-time ultrasound monitoring of the needle tip's insertion position. The puncture needle consists of a core and a sheath. After the needle is placed in the designated position, the core is removed, and the sheath is used to deliver the medication between the tumor and the blood vessel. Sodium alginate gel and platinum hydrate require separate syringes with different dosages; the 5mL syringe is used for sodium alginate injection, and the 2mL syringe is used for platinum hydrate injection. The PTC puncture needle is placed between the tumor and the liver blood vessel. The core is removed, and sodium alginate is injected first, followed immediately by platinum hydrate.

[0056] II. Technical Process Steps Step 1: Preoperative drug preparation 1. Preparation method of 20 mg / mL hydrated cisplatin solution: (1) Accurately weigh 20.00 mg of cisplatin and 22.64 mg of silver nitrate into a vial. Then add 1 mL of deionized water and stir for 1 hour in the dark while heating at 60 °C.

[0057] (2) Remove the magnetic ball and centrifuge the reaction system at 15000 rpm for 10 minutes.

[0058] (3) Carefully aspirate the supernatant after centrifugation using a syringe, filter it using a 0.22 μm pore size syringe filter, and finally obtain a platinum hydrate solution with a concentration of 20 mg / mL. Figure 7 ).like Figure 7 As shown, the obtained hydrated platinum solution is a colorless, transparent liquid with fluidity.

[0059] 2. Preparation method of 2.5% sodium alginate gel: (1) Accurately weigh 250 mg of sodium alginate onto weighing paper.

[0060] (2) Add 10 mL of deionized water to the vial, and add sodium alginate under vigorous stirring. After the addition is complete, continue stirring for 20 min to obtain a 2.5% sodium alginate gel solution. Figure 8 ).like Figure 8 As shown, the obtained sodium alginate gel is a pale milky white transparent colloid with certain fluidity and viscosity. A is a front view of the sodium alginate gel. B is a side view of the sodium alginate gel.

[0061] Step Two: Preoperative Imaging Assessment and Pathway Planning 1. One week before surgery, enhanced CT or MRI scans are performed to determine the number, location, size, and spatial relationship of liver tumors with adjacent blood vessels.

[0062] 2. On the day of treatment, ultrasound or contrast-enhanced ultrasound is used to assess the condition of the liver tumor and to plan a reasonable puncture path and injection site.

[0063] 3. The assessment of the puncture path requires avoiding important organs, such as the diaphragm, intestines, gallbladder, and stomach wall.

[0064] Step 3: Delivery of the coordination gel complex 1. Use a 5mL syringe to draw 5mL of sodium alginate gel solution.

[0065] 2. Use a 2mL syringe to draw 0.5mL of platinum hydrate solution.

[0066] 3. Under the guidance of ultrasound or contrast-enhanced ultrasound, monitor in real time the PTC interventional puncture needle to reach the designated position between the tumor and the liver blood vessels.

[0067] 4. After the PTC interventional puncture needle reaches the predetermined position, inject 2mL-5mL (generally depending on the size of the tumor along the vascular axis; for example, if the tumor along the vascular axis is about 2.0cm, inject about 2mL of sodium alginate gel solution) into the designated position to form a local encapsulation isolation zone.

[0068] 5. After the sodium alginate injection is completed, place the tip of the PTC interventional puncture needle in the center of the sodium alginate-wrapped isolation zone, and then quickly inject 0.2mL-0.5mL of hydrated platinum solution (the dosage depends on the size of the tumor, and the total amount should not exceed 0.5mL).

[0069] 6. During drug injection, ultrasound is used to monitor in real time whether a stable "anechoic" area is formed in the designated region by the sodium alginate solution. If an "anechoic" area is formed, it proves that the sodium alginate gel solution has been successfully injected at the designated location. When injecting hydrated platinum, ultrasound is used to monitor in real time whether a "medium-echoic" cluster is formed in the "anechoic" area of ​​the sodium alginate gel solution. If it is formed, it proves that the alginate-platinum ion coordination gel injection has been successful.

[0070] Step 4: Perform radiofrequency ablation treatment After successful injection of alginate-platinum ion coordination gel, radiofrequency electrode needles are placed in the center of the tumor using real-time monitoring with ultrasound or contrast-enhanced ultrasound, and treatment is performed according to clinical standard radiofrequency ablation procedures.

[0071] Step 5: Postoperative observation and follow-up Immediately after RFA, ultrasound contrast imaging technology is used to observe the morphology and extent of the "non-enhanced area" in the radiofrequency ablation zone in real time, and to assess whether the tissue necrosis area and alginate-platinum gel still exist in the designated area after ablation treatment.

[0072] Enhanced CT or MRI imaging was performed 1 week and 1 month postoperatively to observe the extent of tumor necrosis and residual tumor cells. The continuous release of cisplatin in the gel further inhibited residual tumor cells and reduced the recurrence rate.

[0073] III. Results and Analysis 1. The gel system possesses excellent absorbability, stability, and sustained-release properties. To verify the formation of a stable coordination structure between hydrated platinum and sodium alginate, 50 μL of hydrated cisplatin was injected into 100 μL of sodium alginate. This immediately resulted in the formation of a milky white flocculent sodium alginate-platinum coordination complex. Figure 9 ).like Figure 9 As shown, hydrated platinum, upon injection into sodium alginate gel, immediately forms a milky white, opaque new coordination complex gel with no obvious flowability and a certain viscosity. Characterization experiments clarified the changes in gel properties before and after the addition of platinum. Cryo-scanning electron microscopy (Cyro-SEM) images show that the addition of hydrated platinum leads to intermolecular cross-linking between cisplatin and alginate, thereby transforming the layered gel structure into a particulate cross-linked structure. Figure 10 Compared to traditional Ca 2+The cross-linked system, with its uniform cross-linking and moderate ionic strength, significantly improved the structural stability and hydrolysis resistance of the gel in the interstitial tissue space. Similarly, the introduction of platinum hydrate significantly affected the flow properties of the alginate gel. Figure 9 Crosslinking of cisplatin with alginate significantly delayed cisplatin release in neutral media. In vitro experiments showed that less than 10% of cisplatin was released from the gel system within 10 days. Mouse xenograft experiments showed that the drug remained within the tumor on day 11 after RFA treatment. Figure 11 Therefore, this complex effectively maintains the drug concentration in the local tumor area, enhances the local effect of cisplatin, and reduces systemic toxicity.

[0074] 2. Improves the thermal protection effect on large blood vessels. The gel system used in this application has low thermal conductivity, as shown in in vitro experiments. Figure 12 , Figure 13 This effectively absorbs and buffers the heat generated during RFA (Radioactive Acid Fusion), thereby blocking direct radiation and conduction of high temperatures to the blood vessel walls. Furthermore, the gel injected between the major liver blood vessels and the tumor can form an ultrasound-monitorable area. Figure 14 The success rate of gel formation can be measured in real time. Simultaneously, the gel system exhibits short-term stability, is not prone to large displacement, and is not easily absorbed or diffused, remaining within a localized area for a certain period, effectively addressing the problems of short-term thermal insulation and poor stability associated with traditional liquid materials. In vivo experimental results show that alginate gel can effectively reduce the impact of radiofrequency ablation on large blood vessels in the liver. Figure 15 ), and also prevent liver tissue necrosis caused by vascular damage ( Figure 16 ).

[0075] Therefore, the in-situ gel technology adopted in this application can stably protect vascular tissue from thermal damage and avoid lumen contraction or thrombosis during RFA ablation, thereby improving the tissue safety of the treatment process.

[0076] 3. Reduced the "heat sink effect" and improved the ablation efficiency of RFA. This application utilizes an alginate-platinum ion coordination composite gel injected between blood vessels and tumors to form a "heat insulation zone," preventing heat loss along the blood vessel direction and enhancing the heat retention capacity of the ablation process within the tumor itself. The gel's high specific heat and gel-like viscous structure work together to create a localized heat reflection and retention interface, increasing the temperature at the periphery and expanding the effective ablation area. In vivo experimental results confirmed that after injection of the alginate-platinum ion coordination composite gel, the area of ​​tissue necrosis resulting from thermal ablation was greater than that in the radiofrequency ablation treatment group alone. Figure 17 ).

[0077] Therefore, the technical solution of this application can suppress the "heat sinking effect" and improve the uniformity of thermal ablation by constructing an in-situ gel barrier with directional thermal insulation, thus solving the technical difficulty of incomplete ablation in the vicinity of blood vessels in traditional RFA.

[0078] 4. Enhances tumor suppression effects and reduces the risk of recurrence. This application utilizes cisplatin's anti-DNA synthesis mechanism to further kill residual tumor cells at the periphery through sustained-release cisplatin, building upon RFA-induced thermal damage to tumor cells, thus compensating for minor residues caused by insufficient temperature during thermal ablation. Combined with RFA-induced release of damage-associated molecular patterns (DAMPs), this gel system may also activate a local immune response, enhancing the toxic sensitivity of cisplatin to tumor cells.

[0079] Evidence from mouse xenograft experiments suggests that alginate-platinum ion coordination composite gel combined with radiofrequency ablation can significantly inhibit tumor growth. Figure 18 A, C, E), immunofluorescence staining results showed that combined treatment could significantly induce apoptosis in tumor cells ( ). Figure 18 F) prolongs the survival time of mice ( Figure 18 B, D).

[0080] Therefore, this application has significant technical advantages in enhancing tumor suppression effects and delaying or preventing recurrence through the combined effect of cisplatin's sustained drug efficacy coverage in the gel and RFA-mediated in situ immune activation.

[0081] The above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit it. Although this application has been described in detail above with general descriptions and specific embodiments, some modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of this application fall within the scope of protection claimed in this application.

Claims

1. A gel material for radiofrequency ablation, characterized in that, The gel material is composed of sodium alginate gel solution and hydrated platinum solution; The volume of the sodium alginate gel solution is 2 mL to 5 mL; the volume of the hydrated platinum solution is 0.2 mL to 0.5 mL. In this process, the sodium alginate gel solution is first used to form a local encapsulation isolation zone between the tumor tissue and blood vessels, and then the hydrated platinum solution is added to the middle position of the local encapsulation isolation zone formed by the sodium alginate gel solution. The concentration of the hydrated platinum solution is 20 mg / mL. The hydrated platinum solution is prepared by fully reacting a platinum-based drug, silver nitrate, and water. The platinum-based drug is a divalent cationic chemotherapy drug, specifically cisplatin.

2. The gel material according to claim 1, characterized in that, During the radiofrequency ablation procedure, the tip temperature of the radiofrequency ablation needle is 60°C. .

3. The use of the gel material according to any one of claims 1-2 in the preparation of a drug, wherein the drug is a drug for treating tumors located next to large blood vessels; wherein, The tumor is a liver tumor.

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