Methods and compositions for cryoablation with drug delivery

Abstract

A method for cryoablation of a patient's tissue includes placing a cryoablation gel composition adjacent to the patient's tissue and cryoablation the tissue and cryoablation gel composition with a cryoprobe. The cryoablation gel composition comprises a polymer carrier and a heat transfer enhancer bound to the polymer carrier. The cryoablation gel composition may contain a therapeutic agent. By cryoablation of tissue and the cryoablation gel composition, a lethal isotherm can be achieved at a temperature of -30 to -50°C in a shorter duration compared to cryoablation of tissue without the cryoablation gel composition. By cryoablation of tissue and the cryoablation gel composition, a larger therapeutic volume can be achieved in the tissue compared to cryoablation of tissue without the cryoablation gel composition. Furthermore, by cryoablation of tissue and the cryoablation gel + drug composition, a drug can be released, and the cryoablated cells can be treated with a therapeutic agent.

Description

[Technical Field]

[0001] Priority This patent application claims priority to U.S. Provisional Patent Application No. 63 / 449,822, filed on March 3, 2023, entitled “CRYOABLATION METHODS AND COMPOSITIONS,” naming William Keun Chan Park and Damian E. Dupuy as inventors, and also claims priority to U.S. Provisional Patent Application No. 63 / 461,115, filed on April 21, 2023, entitled “CRYOABLATION METHODS AND COMPOSITIONS,” naming William Keun Chan Park and Damian E. Dupuy as inventors, and all disclosures of these applications are incorporated herein by reference in their entirety.

[0002] field Exemplary embodiments of the present invention generally relate to cryoablation, and more specifically, various embodiments of the present invention relate to enhancing the effectiveness of cryoablation using cryogels.

[0003] background Ablation is a treatment that destroys diseased tissue (e.g., cancer and / or tumors) without removing it. Ablation techniques can be used in patients with a few small tumors and when surgery is not a good option (often due to poor health or impaired liver function). In many cases, ablation can be performed without surgery by inserting a needle or probe into the tumor through the skin. The needle or probe is guided into place using imaging techniques.

[0004] In ablation, cancer can be "burned" or "frozen" using a special probe. Computed tomography (CT), ultrasound (US), or magnetic resonance imaging (MRI) can be used to guide and position the needle probe within the tumor. This requires only a small hole, usually less than 3 mm, to introduce the probe. Once the probe is inside the cancer, it is attached to a generator that "burns" or "freezes" the cancer. Cancer "freezing," also known as cryoablation, can be achieved using a cryoprobe capable of generating temperatures substantially below 0°C.

[0005] Overview of various embodiments According to one embodiment of the present invention, a method for cryoablation of a patient's tissue includes placing a cryoablation gel composition adjacent to the patient's tissue and cryoablation the tissue and the cryoablation gel composition with a cryoprobe. The cryoablation gel composition contains a heat transfer enhancer. By cryoablation of the tissue and the cryoablation gel composition, a lethal isotherm can be achieved at a temperature of -30 to -40°C in a shorter duration compared to cryoablation of the tissue without the cryoablation gel composition. By cryoablation of the tissue and the cryoablation gel composition, a larger therapeutic volume can be achieved in the tissue compared to cryoablation of the tissue without the cryoablation gel composition.

[0006] In some embodiments, the heat transfer accelerator may include a support containing albumin. The heat transfer accelerator may also include an ionic component. Furthermore, the heat transfer accelerator may also include an imaging component. The polymer support may include at least one of a-PMMA, a-PS, or a-PVC.

[0007] In some embodiments, the cryoablation gel composition may undergo a phase change as its components are rearranged in response to a decrease in temperature of the cryoablation gel composition to below 20°C. The phase change may be completed within approximately 5°C.

[0008] In some embodiments, cryoablation of patient tissue in the presence of a cryoablation gel composition may result in a faster temperature drop, lower treatment temperature, and larger ablation volume compared to cryoablation of patient tissue without the cryoablation gel composition. The increased rate of temperature drop, the decrease in treatment temperature, and the increase in cryoablation volume are due to the volume of the cryoablation gel composition.

[0009] In some embodiments, the placement of the cryoablation gel composition may include injecting the cryoablation gel composition into tissue. The cryoablation gel composition may have a viscosity value of about 500 cP to about 7000 cP. The injected cryoablation gel composition may remain at the target site.

[0010] In some embodiments, the cryoablation gel composition may further contain a drug. The drug may include a cytotoxic or immunomodulatory antitumor agent. The cytotoxic antitumor agent may directly target FcRn-overexpressing tumor cells using the interaction between albumin and the cytotoxic antitumor agent. The cytotoxic antitumor agent may contain at least one TLR-9 or STING agonist. At least one TLR-9 or STING agonist may utilize immunological surveillance APC cells, which include at least one dendritic cell, lymphocyte (B and T cells), NK cell, or macrophage.

[0011] According to another embodiment of the present invention, the cryoablation gel composition comprises a polymer and a heat transfer accelerator. The heat transfer accelerator comprises an ionic component and an imaging component. The heat transfer accelerator may also comprise a carrier containing albumin.

[0012] In some embodiments, the cryoablation gel composition may include a common contrast agent, such as iohexol, gadovist, or tantalum, to help determine the injection site of the gel. These contrast agents may also be used as imaging components.

[0013] In some embodiments, the cryoablation gel composition may further contain a drug configured to associate with a carrier. The drug may be configured to elute after the drug and carrier have been exposed to cryoablation. By eluting, the drug may directly alleviate the disease or act as a modulator of the patient's immune response, while minimizing side effects.

[0014] In some embodiments, the polymer may comprise one or more naturally occurring biopolymers, artificial biopolymers, or genetically modified biopolymers. The polymer may comprise ionic functional groups. The ionic functional groups may include amino(-NR3) + ), carboxylate (-CO2 - ), phosphate (P(O)O3 - ), sulfonium (R3S + ) or may contain one or more other ionic groups.

[0015] In some embodiments, the ionic component may include at least one alkali metal ion, alkaline earth metal ion, or transition metal ion.

[0016] In some embodiments, albumin may include human serum albumin (HSA). HSA may act as a drug delivery vehicle. The HSA drug delivery vehicle may deliver the drug via one or more non-covalent, covalent, or gene fusion strategies. The drug may further include one or more albiglutide, semaglutide, abraxane, or levemir.

[0017] The heat transfer promoter may further contain an antitumor drug. The antitumor drug may contain at least one of a STING agonist, a TLR9 agonist or a cytotoxic drug.

[0018] In some embodiments, the cryoablation gel composition may further contain a drug configured to associate with the cryoablation gel composition. The drug may be configured to elute after exposing the drug and the cryoablation gel composition to cryoablation. The drug may associate with the cryoablation gel by affinity or by being covalently linked.

[0019] According to another embodiment of the present invention, a composite therapeutic composition activated at extremely low temperatures contains a therapeutic agent and a heat transfer promoter. The heat transfer promoter agent is configured to promote ablation therapy, impregnate the therapeutic agent, and elute the therapeutic agent after exposure to the extremely low temperature from the extremely low temperature source. The composite therapeutic composition is activated at an extremely low temperature by exposure to energy from the extremely low temperature source. The therapeutic agent may associate with the heat transfer promoter by at least one of protein binding or covalent bonding.

[0020] The heat transfer promoter may be configured to coagulate after the heat transfer promoter is exposed to the cryoprobe and bind to the ablated tissue. The heat transfer promoter is configured to start eluting a part of the therapeutic agent.

[0021] The heat transfer promoter contains a carrier containing albumin, an ionic component containing at least one chaotrope, and an imaging component.

[0022] Albumin may include human serum albumin or bovine serum albumin. Chaotrope may include at least one of calcium chloride, cesium chloride, lithium chloride, potassium chloride, rubidium chloride, sodium chloride, sodium citrate, trisodium citrate, sodium tryptophanate, citric acid, octanoic acid, or a combination thereof. Imaging components may include at least one of NaCl, CsCl, iohexol, or albumin.

[0023] Those skilled in the art will better understand the advantages of various embodiments of the present invention from the following “Description of Exemplary Embodiments,” which is discussed with reference to the drawings summarized below. [Brief explanation of the drawing]

[0024] [Figure 1A] This figure schematically illustrates an experimental setup for conducting in vitro experiments using an agarose phantom according to many embodiments described herein. [Figure 1B] This is a photograph of an experimental setup in which a cryoablation gel has been added to an agarose phantom according to many embodiments described herein. [Figure 1C] This figure shows the temperature profiles of the cryoablation gel and other test gels. [Figure 1D] This figure shows the temperature profiles of the cryoablated gel and another gel at different distances from the cryoablated gel. [Figure 1E] This figure shows the temperature profile of the cryoablation gel and compares it to the temperature profile of an agarose phantom medium control located at different distances from the cryoablation gel. [Figure 2A] This is a top-down view of bovine liver tissue 10 minutes after cryoablation. [Figure 2B] This is a post-ablation photograph (3 minutes after ablation) taken from the side after the cryoablated tissue has been cut down the middle. [Figure 3] This is a phase diagram of the NaCl + H2O solution. [Figure 4A] This figure shows the measured values ​​of thermal conductivity (left axis) and calorimetry (right axis) as a function of temperature for NaCl + H2O at different NaCl concentrations. [Figure 4B] This figure shows differential scanning calorimetry measurements of a thermal gel, which give heat flow as a function of temperature. [Figure 4C] This figure shows the measured values ​​of differential scanning calorimetry of pure water, which gives the heat flow rate as a function of temperature. [Figure 5] This is a plot of the temperature-dependent thermal conductivity (TC) of three polymers: a-PMMA, a-PS, and a-PVC. [Figure 6A] This is a diagram showing the chemical structure of a-PMMA. [Figure 6B] This is a diagram showing the chemical structure of a-PS. [Figure 6C] This is a diagram showing the chemical structure of a-PVC. [Figure 7] This figure shows the involvement of FcRn in cancer biology. [Figure 8] This figure shows the therapeutic use of FcRn upregulation in cancer. [Figure 9] This figure shows a combination therapy of cryoablation using cryoablation gel + antitumor drug according to many embodiments described herein. [Figure 10] This is a schematic flowchart illustrating a method for cryoablation of patient tissue according to many of the embodiments described herein. [Figure 11] This is a schematic flowchart illustrating a method for treating tissue and a cryoablation gel composition using cryoablation with a cryoablation probe according to many embodiments described herein.

[0025] Description of Exemplary Embodiments In exemplary embodiments, cryoablation of the patient's tissue is applied by placing the cryoablation gel composition adjacent to the patient's tissue and then cryoablating the tissue and the cryoablation gel composition with a cryoprobe. Furthermore, some embodiments include the cryoablation gel composition and its preparation. Details of exemplary embodiments are discussed below.

[0026] Cryoablation Cryoablation is a procedure that uses extremely cold liquids or a device called a cryoprobe to freeze and destroy abnormal tissue. The cryoprobe is cooled with a substance such as liquid nitrogen, liquid nitrous oxide, or compressed argon gas. Cryoablation can be used to treat certain types of cancer and several conditions that can become cancerous.

[0027] Ablation involves the following three mechanisms: 1. Formation of ice crystals within cells, resulting in membrane disruption, and interruption of processes including cellular metabolism. 2. Blood coagulation, thereby blocking blood flow to tissues, followed by induction of ischemia and cell death, or 3. Induction of apoptosis, the so-called programmed cell death cascade: This is done in a frozen organization by at least one of the following:

[0028] Common uses of cryoablation include ablation of solid tumors found in the lungs, liver, breast, kidneys, and prostate. While cryoablation may sometimes be applied to cryosurgery via laparoscopic or open surgical approaches, it is most often performed percutaneously (through the skin into the target tissue, including the tumor) by a specialist such as an interventional radiologist.

[0029] Thermodynamics of cryoprobes Percutaneous cryoblation is performed by inserting a cryoprobe into malignant tissue under image guidance. After the cryoprobe is placed, it is rapidly cooled, with heat removed from the surrounding tissue by conduction through physical contact with the cryoprobe. The rapid cooling of the cryoprobe is achieved by the Joule-Thomson effect, where the rapid expansion of a gas that does no work (adiabatic expansion) results in a change in gas temperature. The cryoprobe is essentially a high-pressure, closed-loop gas expansion system. When a high-pressure room-temperature gas (typically argon) reaches the distal surface of the cryoprobe, the argon is pushed out through a throttle (narrow opening) and then rapidly expands to atmospheric pressure. The rapid expansion of argon causes a decrease in gas temperature (Joule-Thomson effect), which is rapidly transferred to the metal wall of the cryoprobe by convection and conduction. The depressurized gas is discharged from the needle hub. Warming of the cryoprobe and thawing of tissue are performed by the same system, using high-pressure helium to warm the cryoprobe during expansion to atmospheric pressure.

[0030] Heat transfer Due to the Joule-Thomson cooling effect, the temperature near the Joule-Thomson port approaches the temperature of liquid argon, i.e., -187°C, but the actual temperature at the probe surface varies between -130°C and -150°C. The cryogenic temperature at the probe surface is transmitted to the tissue in contact with it, propagating in all directions from the active tip of the probe and forming an isothermal layer over time.

[0031] lethal isotherm To destroy target tumor cells by cryoablation, the temperature must be lowered to below -30°C. Depending on the temperature, cryoablation procedures often require approximately 15 minutes or more. During this time, which is the typical progression of "ice formation," for example, 0°C and the lethal temperature are less than 2 cm and less than 1 cm from the probe, respectively, when using an agar phantom. Therefore, lethal isothermal cryoablation of tumors larger than 2 cm cannot be achieved with the same cryoablation conditions. This limitation can potentially be overcome by using multiple cryoprobes, and a larger shaft diameter (e.g., 2.4 mm instead of 1.7 mm) may help improve performance, but only to a certain extent. Another limiting factor for achieving lethal isotherms is the heat sink effect. Highly perfused organs such as the liver have numerous blood vessels carrying blood at 36.5°C in all directions, which reduces the effectiveness of cryoablation in achieving lethal isotherms (i.e., below -30°C) around target tumors larger than 2 cm in diameter.

[0032] Cryoablation gel Cryoablation gels are heat transfer enhancers containing human protein-based formulations with high ion content. High ion content compositions of cryoablation gels allow tissue to cool faster than controls, reach lower treatment temperatures than controls, and cool larger tissue volumes than can be cooled in control experiments. Heat transfer enhancers may consist of three components: 1) a polymer (natural or artificial) as a carrier, 2) an ionic component or equivalent for balancing the overall charge and / or viscosity, and 3) an imaging component.

[0033] Figure 1A schematically shows an experimental setup for performing cryoablation in an in vitro experiment using agarose phantom 10. Agarose phantoms are used in cryogenic experiments, particularly in the field of cryotherapy and / or hypothermia research, because the agarose gel can be manipulated to mimic the thermal conductivity of human tissue. This property allows researchers to simulate how heat and cold propagate through different types of tissue, helping to understand the effects of cryoablation on target tissue and surrounding structures.

[0034] An agarose phantom medium (e.g., agarose medium or agarose phantom) 10 was prepared using 1 w / v% agarose. A sample of cryoablation gel 15 was placed inside the agarose phantom 10, and a thermocouple 30 was inserted into the cryoablation gel. A cryoprobe 20 (Endocare Cryosystem, cryoprobe PCS-17), as part of the cryosystem 25, was placed 5 cm from the top of the phantom medium 10, 1 cm from the cryoablation gel and thermocouple 30. Another thermocouple 32 was inserted into the phantom agarose medium 10 and placed 1 cm from the cryoprobe 20. (The schematic diagram in Figure 1A is not to exact scale.)

[0035] When the cryoprobe 20 is cooled, the agarose phantom medium 10 freezes, forming an ice sphere 17 of the agarose phantom medium. The cryoablation gel 15 also freezes, forming a frozen ice structure 18 around the frozen cryoablation gel. Some of the agarose medium 10 may also freeze around the frozen cryoablation gel 18.

[0036] Figure 1B shows a photograph of the actual experimental setup in which cryoablation gel 15 was added to phantom agarose medium 10. A cryoprobe 20 was inserted into the bag containing the phantom agarose medium 10 and cryoablation gel 15. The cryoprobe was positioned 1 cm from the sample in the cryoablation gel. A thermocouple (not shown) was inserted into the bag. One thermocouple was inserted into the cryoablation gel 15 1 cm from the cryoprobe 20, and the other thermocouple was inserted into the agarose medium 10 1 cm from the cryoprobe.

[0037] The cryoprobe 20 was activated to cool the mixture of agarose medium 10 and cryoablation gel 15. The agarose medium 10 and cryoablation gel 15 froze, forming agarose medium ice sphere 17 and cryoablation gel ice sphere 18. The dashed ellipse 18 identifies the region where the cryoablation gel 15 froze into an ice structure (e.g., an ice sphere).

[0038] Temperature measurements of the agarose phantom (e.g., control) 10 were started 2 minutes after the start of cryoablation and continued for 10 minutes. The temperature profile 35 of the control agarose phantom is shown in Figure 1C.

[0039] Along with the agarose phantom, temperature measurements of the cryoablation gel were started 2 minutes after the start of cryoablation and continued for 10 minutes. The temperature profile of the cryoablation gel in the control agarose phantom is also shown in Figure 1C.

[0040] As shown in Figure 1C, the temperature of the cryoablation gel decreased more rapidly and to a lower temperature than the control, which was located approximately 2 cm away from the gel. The temperature profiles of both the cryoablation gel 40 and the control 35 are shown in Figure 1C. The data show that the temperature of the cryoablation gel 40 decreased rapidly to below -40°C within 5 minutes, while the data also show that the rate of temperature decrease for the control 35 was much slower under the same conditions. The lowest temperature observed for the cryoablation gel sample during a 10-minute experimental ablation duration was approximately -50°C, while the lowest temperature observed for the control sample (agarose phantom without cryoablation gel) during a 10-minute ablation duration was only approximately -15°C. This data indicates that adding cryoablation gel to an agarose phantom results in a faster temperature decrease and ultimately a lower temperature than the agarose phantom without cryoablation gel.

[0041] Figure 1D shows the temperature profiles from another experiment comparing cryoablation gel 42 with two other thermal test gels 34,36. Cryoablation gel 42 exhibits a faster temperature drop and ultimately lower temperatures than the other thermal gels. Thermal test gels 34,36 have lower pH levels than cryoablation gel 42. Addition of trisodium citrate to the experimental thermal gels increased the pH (e.g., making them more basic) and increased the ionic conductivity of the cryoablation gels compared to the previous thermal gels. Cryoablation gel 42 reaches a temperature below -35°C within 2 minutes. This is important because this temperature is considered to be tumor-killing. The temperature drops below -35°C and reaches below -50°C, whereas the other test gels did not reach -35°C during cryoablation (10 minutes).

[0042] Figure 1E shows the temperature profile of the cryoablation gel and compares it to the temperature profile of the agarose phantom medium control at different distances from the cryoablation gel. This experiment demonstrates the effect of the cooled cryoablation gel on the surrounding medium as a function of distance from the cryoablation gel. Temperature profile 39 was measured at approximately 1 cm from the cryoablation gel, and temperature profile 38 was measured at more than 1.5 cm from the cryoablation gel. Notable features here include the significantly lower temperature drop profile of the cryoablation gel 42 compared to any other location without the gel, and the decreasing thermal cooling effect of the cryoablation gel as the distance from the cryoablation gel increases.

[0043] Ex vivo cryoablation experiments were performed using bovine liver. Figure 2 shows photographs from the ex vivo cryoablation experiment using bovine liver. As shown in Figure 2A, a cryoprobe 45 (Endocare, PSC-17) was placed in the bovine liver tissue at a depth of 4 cm from the upper part of the liver surface at the entry site 48 of the cryoprobe 45. Cryoablation gel (0.7 mL) was injected at site 52 at the same depth of the cryoprobe 45, 1 cm away from the cryoprobe 45. A first thermocouple 50 was placed in the cryoablation gel at the cryoablation gel injection site 52. A second thermocouple 55 was placed on the opposite side for control (no gel). Cryoablation was performed for 10 minutes. Similar temperature profiles to those observed in the in vitro experiment described above were obtained in the bovine liver tissue and control tissue.

[0044] Figure 2A shows a top view of bovine liver tissue 10 minutes after cryoablation.

[0045] Figure 2B shows a post-ablation (3 minutes after ablation) photograph of cryoablated tissue after central section along the dashed line 56. The dashed line 58 in Figure 2B indicates a figurative boundary line formed by the cryoprobe 45, separating the lower 60 and upper 65 portions of the liver affected by the cryoprobe 45. The lower 60 portion is injected with cryoablation gel, while the upper 65 portion serves as a control, as no cryoablation gel has been injected.

[0046] When cooled by the cryoprobe 45, the temperature reached by the upper part 65 dropped to approximately -20°C. The radius of the affected area of ​​the upper part was approximately 1.1 cm.

[0047] When cooled by the cryoprobe 45, the temperature reached by the lower 60 dropped to approximately -50°C. The liver tissue in the lower 60, which was closer to the cryoablation gel, was more greatly expanded. The radius of the lower 60 was expanded to a radius of 1.7 cm compared to the upper 65, which was 1.1 cm of liver tissue acting as a control.

[0048] Furthermore, Figure 2B clearly shows a portion of the cryoablation gel 67 after treatment (e.g., cryoablation experiment). The photograph of the cryoablation gel 67 shows that it corresponds to the injection site 52 in Figure 2A.

[0049] Thermal conductivity Thermal conductivity is one of the key properties that is important in cryogenic biological applications. q=-k(T2-T1) / L Equation 1

[0050] As shown in Equation 1, the heat flux q gives the rate per unit area at which heat flows in a given direction. For many materials, it is observed that q is proportional to the temperature difference (T2-T1) and inversely proportional to the separation distance L.

[0051] Thermal conductivity of pure water and saltwater Figure 3 shows the phase diagram of a NaCl+H2O solution. In Figure 3, line 1 70: 1.2 wt% represents the temperature change from 20°C to -30°C for a diluted 1.2 wt% NaCl+H2O solution. As the temperature of the 1.2 wt% NaCl+H2O solution is decreased along line 70, starting from 20°C, a solution without phase changes is shown until the solution temperature falls below the curved red solid line, just below 0°C. At this point (e.g., 0°C), ice of pure H2O begins to grow in the solution, and the concentration of the liquid (unfrozen solution) increases until the temperature reaches the eutectic temperature of NaCl+H2O, which is -21.1°C. As the temperature drops below -21.1°C, the liquid is no longer visible, as it becomes pure water ice and NaCl·2H2O crystals (61 wt% NaCl) known as hydrohalite. Another solution with a eutectic concentration of 23.16 wt% NaCl salt yields both ice and NaCl·2H2O precipitates at a eutectic temperature of -21.1°C, according to line 2 80 in Figure 3.

[0052] When the thermal conductivity is measured for both pure water and saline systems, it is clear that heat transfer from liquid water to ice is an exothermic process, as shown in Figure 4A. Figure 4A shows the measured values ​​of thermal conductivity (left axis) and calorimetry (right axis) as a function of temperature for NaCl + H2O with different NaCl concentrations.

[0053] The blue trace 95 represents pure H2O (e.g., water), indicating that water undergoes an exothermic process at approximately 4°C. That is, as water begins to freeze into ice, it releases heat into the surrounding environment, making this process exothermic.

[0054] The pink trace 100 represents 0.6 wt% NaCl + H2O, indicating that 0.6 wt% NaCl + H2O undergoes an exothermic process at approximately 2°C.

[0055] The red trace 105 represents 1.2 wt% NaCl + H2O, indicating that 1.2 wt% NaCl + H2O undergoes an exothermic process at approximately 0°C. A second endothermic event 110 is also observed for 1.2 wt% NaCl + H2O at approximately -21°C. This exothermic event corresponds to the solidification of hydrohalite crystals of NaCl·2H2O with 61 wt% NaCl relative to H2O.

[0056] The black trace 115 represents a brine solution with a eutectic concentration of 23.16 wt% NaCl + H2O. In a eutectic brine solution (23.16 wt% NaCl + H2O), the phase change occurs at -21.1°C and has the notable characteristic of requiring less energy to form ice.

[0057] The phase transition temperature shifts to lower temperatures as the NaCl content increases. This is because increasing the concentration of NaCl in an aqueous solution lowers the freezing point of the salt-water mixture in the solution.

[0058] Furthermore, exothermic events are observed for traces 110 and 115 at approximately -21°C. These events correlate with the rearrangement of water molecules and NaCl in the salt solution, which forms hydrohalite crystals of NaCl·2H2O at 61 wt percent NaCl relative to H2O. The greater exothermic reaction of eutectic solution 115 at approximately -21°C compared to the more dilute 1.2% solution 110 indicates that the rearrangement (e.g., phase change) of H2O and NaCl molecules in the higher concentration solution released more energy into the surroundings than in the lower concentration solution, leading to the formation of hydrohalite crystals of NaCl·2H2O.

[0059] Figure 4B shows differential scanning calorimetry (DSC) measurements of a cryoablation gel, giving the heat flow as a function of temperature. The DSC scan in Figure 4B shows that as the gel components rearrange in response to the decrease in temperature at approximately -20°C, a rapid thermodynamic change (e.g., phase change) occurs in the cryoablation gel composition, and the phase change event is completed within approximately 5°C. This is also an exothermic event. Upon heating, the cryoablation gel melts at approximately -10°C.

[0060] Figure 4C shows differential scanning calorimetry measurements of water, giving heat flow as a function of temperature. Exothermic events begin when the sample cools to approximately -18°C, with phase transition events exceeding 10°C. This process is more than four times more exothermic than the crystallization of cryoablation gels, indicating that the water crystallization process is much more disordered and entropy-heavy, taking considerably longer to reach an ordered state. In contrast, cryoablation gels are more ordered materials, and the crystallization event generates less energy due to their relatively low entropy.

[0061] Thermal conductivity of nonpolar polymers When the thermal conductivity of nonpolar organic polymer materials, particularly thermoplastic resins, was investigated, it became clear that the thermal conductivity values ​​of these polymers are low, and decrease further as the temperature decreases, as shown in Figure 5.

[0062] Figure 5 shows plots of temperature-dependent thermal conductivity (TC) for three polymers: a-PMMA, a-PS, and a-PVC. The temperature dependence is calculated using Green Kubo Mode Analysis (GKMA) with quantum corrections. The solid line represents the calculation result, and the dots represent experimental values ​​reported in the literature. The chemical structures of the thermoplastic resins (e.g., polymers) used in this study are shown in Figures 6A to 6C: Figure 6A corresponds to a-PMMA, Figure 6B corresponds to a-PS, and Figure 6C corresponds to a-PVC.

[0063] Thermal diffusivity Thermal diffusivity is the value obtained by dividing the thermal conductivity at a constant pressure by the density and specific heat capacity. This allows for the measurement of the rate of heat transfer in a substance from a high-temperature end to a low-temperature end. α = k / ρc p formula 2 [In the formula, k is the thermal conductivity (W / (m·K)), c p This is the specific heat capacity (J / (kg·K)), ρ is density (kg / m³)3 ) is]

[0064] There is no organic substance that has a higher thermal conductivity than ice at 0 °C with approximately 2 W / (mK). Approximate diffusivity values of ice and brine ice are shown in Table 1 below.

[0065] **Table 1**

[0066] In pure ice, the thermal conductivity gradually increases as the temperature decreases. The increase in the diffusivity value is affected by the decrease in specific heat (asymptote towards approximately 1.3 (kJ / kgK)) accompanying the temperature decrease. In brine ice (e.g., 6 wt% NaCl solution (ice)), the trend is the same as that of pure ice, and the decrease in specific heat towards 2.33 kJ / kgK affects the diffusivity value to be approximately half that of pure water. The trends of the thermal conductivity and diffusivity of pure water are very similar to those of plasma in the temperature range (-10 to -100 °C) shown in Table 2 at the end of this book. This is because of the high water content (91 - 99%) of plasma even considering the plasma salt concentration (0.9 wt%).

[0067] ​​​​​​​​​​​​​​​The value increases to / s, indicating that the change in thermal diffusivity is greater than the change in thermal conductivity. This means that the specific heat of plasma decreases significantly over the temperature range (-10 to -100°C). More importantly, the decrease in the specific heat of plasma is more dramatic in the temperature range, i.e., 0 to -10°C.

[0069] As shown in Figure 1C, cryoablation gels, which are formulations consisting of concentrated mixtures of polymers with ionic functional groups and their counterions in aqueous solution, exhibit a much more efficient temperature decrease compared to the control. The rapid temperature decrease of the gel is presumed to be due to a sharp decrease in specific heat value in the sub-zero temperature range (0 to -10°C) compared to pure ice (control): for example, a 6 wt% NaCl solution has a specific heat value of 111.9 (kJ / kgK) at -1°C compared to 3.1 (kJ / kgK) at -10°C. This dramatic change in the gel's specific heat value may affect the change in thermal diffusivity value during the initial cryoablation (36.5 to -10°C). Key thermal properties of cryoablation gels include density, specific heat, thermal conductivity, thermal diffusivity, and enthalpy. In some embodiments, the heat transfer accelerator is a preparation of serum albumin or other albumin with a specific electrolyte that adjusts its viscosity or heat transfer accelerator properties, preferably also providing imaging under one or more medical imaging techniques such as MRI, ultrasound, or X-ray CT imaging, as further described below. By using CT for image guidance, a desired amount of heat transfer accelerator having a known CsCl concentration can be added to the cryoablation gel and deposited at the boundary of the tumor mass. Subsequently, during cooling, the injected cryoablation gel freezes into a solid of a predetermined ablation shape and volume. In this case, the cryoablation gel is cooled by a cryoprobe to reach a tumor-killing temperature (below -40°C) in the target region.

[0070] The cryoablation gel may be mixed with the drug injected for cryoablation. After ablation, the injected drug dissolves, which can directly alleviate the disease or act as a modulator of the patient's immune response, while minimizing side effects.

[0071] Another characteristic of cryoablation gels is their viscosity. Cryoablation gel compositions have a viscosity value of approximately 500 cP to approximately 7000 cP. A viscosity value of approximately 500 cP to approximately 7000 cP helps the gel remain in the target site of tissue after injection.

[0072] Polymers that can be used for the preparation of cryoablation gels include naturally occurring biopolymers: for example, protein polymers, DNA, RNA, nucleosides, carbohydrates, lipids, glycoproteins, and metalloproteins. The polymers may also include artificial or genetically modified biopolymers, such as dendrimers, or various polymers in the form of nanoparticles. The polymers herein include ionic functional groups, for example, amino(-NR3) + ), carboxylate (-CO2 - ), phosphate (P(O)O3 - ), sulfonium (R3S + The polymer may contain either natural or artificial materials, such as albumin, silk, wool, chitosan, alginates, pectin, DNA, cellulose, polysialic acid, dendritic polylysine, poly(lactic acid-coglycolic acid) (PLGA), guerlain, polysaccharides, and polyaspartic acid, as well as combinations thereof.

[0073] The ionic components may include counterions that are opposite to the charge present in the polymer and neutralize the overall charge, which can be used in cryoablation gels: any alkali metal ions, e.g., Na + , K + , Cs + , alkaline earth metal ions, for example, Ca ++ Mg ++, as well as transition metal ions of Mn, Fe, Co, Cu and Zn may be included. In the case of polymer cations such as amino and sulfonium ions, halide ions (F - Cl - , Br - , I - ), carboxylate ions (-CO2 - ), phosphate ion (P(O)O3 - ) may be a counterion. In some embodiments, the heat transfer enhancer includes a chaotrope. The chaotrope may be configured to modulate the charge distribution within the polymer. Chaotropic salts or solutions can be used as part of tissue preparation or as part of the cryoablation process to enhance the effectiveness of other active ingredients such as therapeutic agents (e.g., drugs). These ingredients can help disrupt the structure of cell membranes or proteins, making the tissue more susceptible to the effects of cryoablation.

[0074] Cryoablation gels may contain trisodium citrate, which has the chemical formula Na3C6H5O7. Trisodium citrate is sometimes simply referred to as "sodium citrate," but this can refer to any of the three sodium salts of citric acid. Trisodium citrate dihydrate is the tribasic salt of citric acid. The addition of trisodium citrate can raise the pH of the cryoablation gel to approximately pH 8, and can bring the pH of the cryoablation gel to 7.5–8.5. Furthermore, trisodium citrate increases the ionic concentration of the cryoablation gel, resulting in a high ionic conductivity. Trisodium citrate can also function as a therapeutic agent (e.g., a drug). That is, in addition to acting as a stabilizer and / or ionic component, trisodium citrate can contribute to the cryoablation gel as a therapeutic agent.

[0075] Cryoablation gels may contain caprylic acid, also known systematically as octanoic acid or C8 acid. Caprylic acid is a straight-chain saturated fatty acid and a medium-chain fatty acid. Caprylic acid is the conjugate acid of octanoate.

[0076] Trisodium citrate and caprylic acid may be included in the cryoablation gel as ionic components and may be added as stabilizers, or in combination for their use within the gel.

[0077] The cryoablation gel may contain sodium tryptophanate and / or tryptophan as stabilizers. Tryptophan is a polar molecule containing an α-amino group, an α-carboxylic acid group, and a side-chain indole, and has a non-polar aromatic β-carbon substituent.

[0078] The cryoablation gel may contain benzoic acid, an organic compound represented by the chemical formula C6H5COOH.

[0079] Imaging components can also enhance the thermal performance of cryoablation gels. For example, iohexol and / or tantalum may be included in the cryoablation gel to aid in X-ray or CT scan diagnosis or location. Iohexol and / or tantalum can also act in the cryoablation gel to achieve temperatures below -40°C within 3 minutes (see slide 15). Furthermore, cryoablation gels containing imaging components (e.g., iohexol or tantalum) may enable the achievement of tumor-killing temperatures below -35°C during cryoablation. At temperatures below -30°C during cryoablation, tumors may be difficult to visualize because they may appear as large ice spheres. However, the addition of one or more imaging agents to the cryoablation gel, in addition to the thermal effect of the imaging agents, can make the tumor visible on CT.

[0080] The aqueous medium may be a buffer solution such as a phosphate-based or citrate-based buffer solution that maintains the desired overall pH of the solution.

[0081] The concentration of the polymer in the cryoablation gel may exceed 50 g / L to achieve the desired viscosity (greater than 10 cP).

[0082] Table 2 below lists the thermal properties of biomaterials and tissues in cryogenic regimes.

[0083] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0084] Cryoablation-based drug delivery using cryoablation gel + drug In some embodiments, therapeutic agents (e.g., drugs) can be combined with the cryoablation gel. That is, the use of a combined cryoablation gel and drug composition enhances the effectiveness of cryoablation, allowing the therapeutic agent to be delivered directly to the target tissue during cryoablation and to be eluted in the target tissue over several days after ablation.

[0085] Drugs or drug combinations are, • Alkylating agent Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, Dacarbazine, Ifosfamide, Lomustine, Lurubinectedine, Mechloretamine, Melphalan, Procarbazine, Streptozocin, Temozolomide, Thiotepa, Trabectedine Platinum coordination complex Carboplatin, cisplatin, oxaliplatin ·Antibiotics, cytotoxicity Bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, plicamycin, barurubicin ·Antimetabolites • Folic acid antagonists: methotrexate, pemetrexed, pralatrexate, trimethrexate • Purine analogs: azathiopurine, cladribine, fludarabine, mercaptopurine, thioguanine • Pyrimidine analogs: azacitidine, capecitabine, cytarabine, decitabine, phloxuridine, fluorouracil, gemcitabine, trifluridine / tipiracil • Biological reaction modifiers Aldesleukin (IL-2), Denileukin difutox, Interferon γ • Histone deacetylase inhibitors Bellinostat, Panobinostat, Romidepsin, Vorinostat • Hormones • Antiandrogens: abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, nilutamide • Anti-estrogen agents (including aromatase inhibitors): anastrozole, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene Gonadotropin-releasing hormone analogs: degarelix, goserelin, histrelin, leuprolide, triptorelin • Peptide hormones: lanreotide, octreotide, pasireotide • Monoclonal antibody • Alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, semiprimab, cetuximab, daratumumab, dinutuximab, dostallimab, durvalumab, elotuzumab, gemtuzumab, inotuzumab ozogamicin, ipilimumab, mogamulizumab, moxetumomab pasdotox, necitumumab, nivolumab, ofatumumab, oraratumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tecristamab, tositumomab, trastuzumab, tremelimumab • Protein kinase inhibitors Abemaciclib, acalabrutinib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dasatinib, zvelisib, enasidenib, encorafenib, entrectinib, erdafitinib, erlotinib, fedratinib, fucibatinib, gefitinib, gilteritinib, glassegib, ibrutinib, idelalicib Imatinib, Infiglatinib, Ibosidenib, Ixazomib, Lapatinib, Lalotrectinib, Lenbatinib, Lorlatinib, Midostaurinib, Neratinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Pemigatinib, Pexidaritinib, Ponatinib, Regorafenib, Ribociclib, Lucaparib, Ruxolitinib, Selumetinib, Sonidegib, Sorafenib, Sunitinib, Talazoparib, Trametinib, Vandetanib, Vemurafenib, Bismodegib, Zanubrutinib • Taxane • Cabazitaxel, docetaxel, paclitaxel • Topoisomerase inhibitors • Etoposide, Irinotecan, Teniposide, Topotecan Vinca alkaloids Vinblastine, vincristine, vinorelbine ·others Asparaginase (Pegaspargase), Bexarotene, Eribulin, Everolimus, Hydroxyurea, Ixabepyrone, Lenalidomide, Mitotane, Omasetaxin, Pomalidomide, Taglaxofusp, Terotristat, Temsirolimus, Thalidomide, Venetoclax It may include.

[0086] Human serum albumin (HSA) serves as an excellent drug delivery vehicle via non-covalent, covalent, and gene fusion strategies. For example, HSA-based or HSA-binding drugs such as albiglutide, semaglutide, abraxane, and levemir have been successfully developed and are in clinical use.

[0087] Since the discovery of the neonatal IgG Fc receptor (FcRn), it has been found to be involved in immunoglobulin recycling and biodistribution, immune complex routing, antigen presentation, humoral immune responses, and cancer immune surveillance. Figure 7 illustrates the involvement of FcRn in cancer biology, where it plays a role in the pathophysiology of cancer. In various types of cancer, such as lung cancer and colorectal cancer, FcRn has been described as an early prognostic marker. Abnormal regulation of FcRn expression by cancer cells increases cancer cell metabolism, and this mechanism can be utilized for passive targeting of cytotoxic drugs. However, the role of this receptor depends on whether the cell population studied is tumor tissue or invasive cells, highlighting the need for further research.

[0088] Figure 8 illustrates the therapeutic applications of FcRn upregulation in cancer. Enhanced endosomal uptake of antibody-drug conjugates or albumin-drug designs by FcRn upregulation in solid tumors. Uptake of antibody-drug conjugates or albumin-drug designs. Endosome sorting. Stimulus-responsive drug release and diffusion. Antibodies and / or albumin are recycled to the cell surface. An inset shows albumin and antibody variants with tunable FcRn affinity to regulate uptake and intracellular recycling.

[0089] FcRn (neonatal Fc receptor) is expressed in antigen-presenting cells (APCs) such as dendritic cells (DCs), macrophages, and B cells. High levels of FcRn expression in these cells enable the specific intracellular transport of IgG and antigen-containing IgG immune complexes via the endolysosomal system.

[0090] Based on the mechanisms of FcRn related to HSA and IgG, combination therapies can be used as shown in Figure 9. Figure 9 shows a combination therapy of cryoablation using cryoablation gel + antitumor agent according to an embodiment of the present disclosure. The antitumor agent directly targets FcRn-overexpressing tumor cells using the interaction of albumin and the drug. The TLR-9 or STING agonist utilizes immunological surveillance APC cells such as dendritic cells, lymphocytes (B and T cells), NK cells and macrophages, all of which express the FcRn receptor.

[0091] STING (interferon-stimulating factor) is a transmembrane protein that plays a central role in innate immunity against infection and cancer. Activation of STING mediates a multifaceted type I interferon (IFN-I) response that promotes dendritic cell (DC) maturation and migration, and primes cytotoxic T lymphocytes and natural killer (NK) cells for the innate immune response. STING agonists enhance NK cell migration and death, improving therapeutic activity in patient-derived organ-type tumor spheroids.

[0092] Toll-like receptor 9 (TLR9) is a pattern recognition receptor primarily located within immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APCs). The primary ligand for the TLR9 receptor is unmethylated cytidine phosphate guanosine (CpG) oligodinucleotide (ODN). TLR9 agonists induce inflammatory processes that lead to enhanced uptake and death of microorganisms and cancer cells, as well as the generation of adaptive immune responses.

[0093] In other words, a cryoablation gel may consist of three components: 1) a polymer (natural or artificial) as a carrier, 2) an ionic component or equivalent for balancing the overall charge and / or viscosity, and 3) an imaging component. This may include a stabilizer. The polymer may be either natural or artificial, and may include, for example, albumin, silk, wool, chitosan, alginate, pectin, DNA, cellulose, polysialic acid, dendritic polylysine, poly(lactic acid-coglycolic acid) (PLGA), guerine, polysaccharides and polyaspartic acid, and combinations thereof. The ionic component may include M+X- or M2+Y2- (as the generalized formula Mn+Yn-), where M belongs to an alkali metal or alkaline earth metal such as Li, Na, K, Rb, Cs, X represents a halide, acetate, and other equivalent counterbalances to M+, and Y may be X2, or a mixed halide, acetate, carbonate, sulfate, phosphate, and other equivalent counterbalances to M2+, as well as formic acid, glycolic acid, lactic acid, propionic acid, caproic acid, oxalic acid, malic acid, citric acid, benzoic acid, uric acid, and their corresponding conjugate bases. Other organic components may be independently substituted as described in Wang, S. et al, Mol. Pharmaceutics 2015, 12, 4478-4487.

[0094] For imaging including CT imaging (e.g., computed tomography), cesium, tantalum, iopamidol, iohexol, ioxiran, iopromide, iodixanol, ioxagrate, diatrizoate, metrizoate, yotalamate, ethiodinated polymers such as PLGA, PEG, albumin, DNA, RNA, ionic polycarbohydrates, and combinations thereof can be used. Additional CT contrast agents that may be included in the cryoablation gel include ioversol, iodixanol, iopromide, or iopamidol.

[0095] Additional contrast agents that may be used include gadoterate, gadobutrol, gadopentetate, gadobenate, or gadoteridol. These may include MR contrast agents for MR imaging (e.g., magnetic resonance imaging).

[0096] Albumin itself can be a contrast enhancer for US imaging (e.g., ultrasound) by forming microbubbles. In ultrasound imaging, polymers are generally hypoechoic.

[0097] Figure 10 shows a schematic flowchart 1000 illustrating a method for cryoablation of a patient's tissue. Step 1010 involves placing the cryoablation gel composition adjacent to the patient's tissue. The tissue is the target of the cryoablation therapy, and the cryoablation gel composition is placed adjacent to the tissue, injected into the tissue, or both. That is, in embodiments, the cryogenic gel may be placed on or around the tissue, or injected into the tissue, or placed around the tissue and injected into the tissue.

[0098] In step 1020, the tissue is cryoablated with a cryoprobe. After inserting the cryoprobe into the tissue and the cryoablation gel composition, the cryoprobe is manipulated to perform the cryoablation. The cryoprobe can be rapidly cooled to temperatures below -10°C. In experiments using the cryoablation gel composition, the agarose phantom, along with the cryoablation gel composition, reached temperatures below -40°C.

[0099] Figure 11 shows a schematic flowchart 1100 illustrating a method for treating tissue and a cryoablation gel composition using cryoablation with a cryoprobe. Step 1110 involves injecting the cryoablation gel composition into the patient's tissue. Injection of the cryoablation gel composition into the tissue may include injecting the cryoablation gel composition adjacent to or around the tissue. The tissue is the target of the cryoablation therapy, and the cryoablation gel composition is positioned adjacent to the tissue, injected into the tissue, or both. That is, in embodiments, the cryogenic gel may be positioned on or around the tissue, or injected into the tissue, or positioned around the tissue and injected into the tissue.

[0100] In step 1120, the cryoprobe is inserted into the tissue. Imaging can be used to guide the insertion of the cryoprobe into the target area of ​​the tissue. Alternatively, this can be done without imaging. Computed tomography (CT), ultrasound (US), or magnetic resonance imaging (MRI) can be used to guide and position the cryoprobe within the tumor. This requires only a small incision, usually less than 3 mm, to introduce the cryoprobe.

[0101] In step 1130, tissue is treated with a cryoablation gel composition using cryoprobe cryoablation. The cryoprobe enters the tumor and is then attached to a generator that "ablates" or "freezes" the tumor. The "freezing" of the tumor is called cryoablation and can be achieved using a cryoprobe capable of generating temperatures substantially below 0°C.

[0102] In step 1140, the cryoablation probe is removed from the patient's tissue. The cryoprobe is removed at the end of the cryoablation procedure.

[0103] The embodiments of the present invention described above are intended to be illustrative only. Numerous changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to fall within the scope of the present invention as defined by any of the appended claims.

Claims

1. A method for cryoablation of patient tissue, The cryoablation gel composition is placed adjacent to the patient's tissue, The tissue and cryoablation gel composition are cryablated with a cryoprobe. Includes, The cryoablation gel composition contains a heat transfer accelerator. method.

2. The aforementioned heat transfer accelerator, A carrier containing albumin, Ionic components, Imaging components and The method according to claim 1, including the method described in claim 1.

3. As the temperature of the cryoablation gel composition is lowered to below -20°C, the components of the cryoablation gel composition are rearranged, causing the cryoablation gel composition to undergo a phase change. The phase change event is completed within approximately 5°C. The method according to claim 1.

4. The method according to claim 1, wherein the placement of the cryoablation gel composition includes injecting the cryoablation gel composition into the tissue.

5. The method according to claim 1, wherein the cryoablation gel composition has a viscosity value of about 500 cP to about 7000 cP.

6. The method according to claim 5, wherein the injected cryoablation gel composition remains at the target site.

7. The method according to claim 2, wherein the cryoablation gel composition further comprises a drug.

8. The method according to claim 7, wherein the drug comprises a cytotoxic or immunomodulatory antitumor agent.

9. The method according to claim 8, wherein the cytotoxic antitumor agent directly targets FcRn-overexpressing tumor cells by utilizing the cytotoxic antitumor agent-mediated action of albumin.

10. The method according to claim 9, wherein the antitumor agent comprises at least one of TLR-9 or a STING agonist.

11. The method according to claim 10, wherein at least one of the TLR-9 or STING agonists utilizes immunological surveillance APC cells comprising at least one of dendritic cells, lymphocytes (B and T cells), NK cells, or macrophages.

12. polymers and A heat transfer accelerator containing ionic components and imaging components A cryoablation gel composition containing the following:

13. The composition according to claim 12, wherein the heat transfer accelerator further comprises a carrier containing albumin.

14. The composition according to claim 13, further comprising a drug configured to associate with the carrier, wherein the drug is configured to elute after the drug and the carrier are exposed to cryoablation.

15. The composition according to claim 14, wherein the drug dissolves to directly alleviate a disease or to act as a modulator of the patient's immune response, while minimizing side effects.

16. The composition according to claim 12, wherein the polymer comprises one or more naturally occurring biopolymers, artificial biopolymers, or genetically modified biopolymers.

17. The polymer contains an ionic functional group, The aforementioned ionic functional group is amino(-NR ３ ＋ ), carboxylate (-CO ２ － ), phosphate (P(O)O ３ － ), sulfonium (R ３ S ＋ ) or containing one or more other ionic groups The composition according to claim 16.

18. The composition according to claim 12, wherein the ionic component comprises at least one of alkali metal ions, alkaline earth metal ions, or transition metal ions.

19. The composition according to claim 13, wherein the albumin comprises human serum albumin (HSA).

20. The composition according to claim 19, wherein the HSA acts as a drug delivery vehicle.

21. The composition according to claim 20, wherein the HSA drug delivery vehicle delivers the drug via one or more non-covalent, covalent, or gene fusion means.

22. The composition according to claim 21, wherein the drug comprises one or more of albiglutide, semaglutide, abraxane, or levemir.

23. The composition according to claim 12, further comprising the heat transfer promoter as an antitumor agent.

24. The composition according to claim 23, wherein the antitumor drug comprises at least one of a STING agonist, a TLR9 agonist, or a cytotoxic agent.

25. The present invention further comprises a drug configured to associate with the cryoablation gel composition, wherein the drug is configured to dissolve after the drug and the cryoablation gel composition have been exposed to cryoablation. The aforementioned drug associates with the cryoablation gel composition by affinity or by covalent bonding. The composition according to claim 12.

26. A complex therapeutic composition that is activated at extremely low temperatures, Treatment drugs, A heat transfer accelerator, To promote ablation treatment, The aforementioned therapeutic agent is impregnated, The therapeutic agent is eluted after exposure to extremely low temperatures from an extremely low temperature source. A heat transfer accelerator configured in such a way Includes, The aforementioned combined therapeutic composition is activated at a cryogenic temperature by exposure to energy from the cryogenic source. composition.

27. The composition according to claim 26, wherein the therapeutic agent associates with the heat transfer enhancer by at least one of protein bonds or covalent bonds.

28. After the heat transfer accelerator is exposed to the cryoprobe, The heat transfer accelerator is configured to coagulate and bind to the ablated tissue. The heat transfer accelerator is configured to begin dissolving a portion of the therapeutic agent. The composition according to claim 26.

29. The aforementioned heat transfer accelerator, A carrier containing albumin, An ionic component containing at least one type of chaotrope, Imaging components and The composition according to claim 26, comprising:

30. The albumin includes human serum albumin or bovine serum albumin. The chaotrope comprises at least one of the following: calcium chloride, cesium chloride, lithium chloride, potassium chloride, rubidium chloride, sodium chloride, sodium citrate, trisodium citrate, sodium tryptophanate, citric acid, octanoic acid, or a combination thereof. The imaging component includes at least one of NaCl, CsCl, iohexol, or albumin. The composition according to claim 29.

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