Temperature-sensitive biomaterials for local perfusion therapy of solid tumors and methods of making
By using temperature-sensitive injectable hydrogels and utilizing aminopolysaccharide derivatives to regulate phase transition temperature and degradation rate, the problem of long-term sustained release and precise treatment of chemotherapy drugs at the tumor site has been solved, achieving protection of healthy tissues and improvement of treatment efficacy.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- QINGDAO ANYRULE BIOLOGICAL HEALTH TECHNOLOGY CO LTD
- Filing Date
- 2026-03-03
- Publication Date
- 2026-06-05
AI Technical Summary
Traditional chemotherapy drugs lack selectivity for tumor sites, leading to damage and adverse reactions to normal tissues when administered systemically. Existing carrier materials diffuse drugs into healthy tissues and lack the ability to precisely target and release them.
A temperature-sensitive injectable hydrogel was developed, using an aminopolysaccharide derivative as a carrier. The phase transition temperature is close to the physiological environment, and gelation is triggered by body temperature to achieve long-term sustained release and precise treatment of chemotherapy drugs. The phase transition temperature and degradation rate are regulated by the aminopolysaccharide derivative.
It achieves long-term sustained release of chemotherapy drugs at the tumor site, reduces toxicity to healthy tissues, reduces systemic toxic side effects, and has good biocompatibility and low immunogenicity.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a temperature-sensitive injectable hydrogel based on aminopolysaccharide derivatives and its application in local chemotherapy for solid tumors. Background Technology
[0003] Chemotherapy is the main clinical treatment for malignant tumors. However, traditional chemotherapy drugs are usually administered systemically, which lacks selectivity for tumor sites. This causes the drugs to damage normal tissues while killing cancer cells, resulting in serious adverse reactions and toxic side effects, and the therapeutic index is low.
[0004] To address these issues, local chemotherapy for tumors (such as intratumoral injection) has gained increasing attention. This method can significantly increase the drug's accumulation concentration at the target site and reduce the drug's diffusion concentration in normal tissues and blood, thereby enhancing drug efficacy and therapeutic index while reducing systemic toxicity.
[0005] In the field of drug delivery, liposomes or microspheres are commonly used as carriers in current technologies. However, these suffer from the problem of drug diffusion into healthy tissues and lack precise targeting and release capabilities. Thermosensitive hydrogels, as carriers that respond to temperature changes, are liquid at room temperature, facilitating injection. Once inside the body and reaching physiological temperatures, they undergo a phase transition to form a gel, enabling prolonged drug retention and sustained release at the injection site, demonstrating significant application potential. However, commonly used thermosensitive materials, such as PLGA-PEG-PLGA, have high phase transition temperatures (approximately 35°C), requiring external heating to trigger gelation, making it difficult to achieve in-situ phase transitions directly through body temperature. While PNIPAM can respond to body temperature, its degradation rate is uncontrollable, potentially leading to drug burst release or residue risks. Summary of the Invention
[0006] Given the shortcomings of existing technologies, it is of great significance to develop a carrier material with good biocompatibility and mechanical properties, which has a phase transition temperature close to the physiological environment (10-35℃), a controllable degradation rate, can be injected at low temperatures and form gels in situ, so as to achieve long-term sustained release of chemotherapy drugs and precise treatment.
[0007] To address the above problems, the present invention provides a temperature-sensitive injectable hydrogel formulation comprising a temperature-sensitive hydrogel, a chemotherapy drug, and physiological saline, wherein the phase transition temperature of the formulation is 10-35°C.
[0008] Furthermore, the content of the chemotherapy drug is 0.1-1.0 mg / ml, and the mass concentration of the temperature-sensitive hydrogel is 0.3%-2.0%.
[0009] Furthermore, the active ingredient of the temperature-sensitive hydrogel is an aminopolysaccharide derivative, which includes hydrophilic derivatization groups and acylation groups.
[0010] Furthermore, the hydrophilic derivatizing group includes carboxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, and the acylation group includes formyl, acetyl, or succinyl.
[0011] Furthermore, the molecular weight of the aminopolysaccharide derivative is 15,000-300,000 Da.
[0012] Preferably, the temperature-sensitive hydrogel is a hydroxypropyl aminopolysaccharide amidation.
[0013] Furthermore, the chemotherapy drugs include cisplatin, paclitaxel, gemcitabine, doxorubicin, etoposide, mitomycin, epirubicin, hydroxycamptothecin, cantharidin, elemol, turmeric oil / goose bile oil, bufotin, and Pseudomonas aeruginosa inhibitors.
[0014] The second aspect of the present invention provides a method for preparing the above-mentioned temperature-sensitive injectable hydrogel formulation, comprising: S1: preparing a temperature-sensitive hydrogel, S2: preparing a physiological saline solution of the temperature-sensitive hydrogel, and S3: mixing a chemotherapy drug with the physiological saline solution.
[0015] Preferably, the mass concentration of the physiological saline solution of the temperature-sensitive hydrogel is 0.3%-2.0%.
[0016] A third aspect of the present invention provides the use of the above-described temperature-sensitive injectable hydrogel formulation in the preparation of a medicament for local perfusion therapy of solid tumors.
[0017] Furthermore, the drug is used for local chemotherapy of various solid tumors, such as primary or metastatic cancers, sarcomas, or carcinosarcomas of the liver, breast, or bladder, and is particularly suitable for the treatment of tumors adjacent to vital organs or those that are inoperable.
[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) Low temperature injectability: The phase transition temperature of the temperature-sensitive injectable hydrogel preparation provided by the present invention is 10-35℃ and the phase transition time is 5-25 minutes. It can be triggered by body temperature to gel in situ without external heating, thus reducing the complexity of minimally invasive surgery. (2) Precise controlled release and sustained release: The gel degradation rate can be regulated by adjusting the molecular weight and degree of derivatization of aminopolysaccharide derivatives, so as to achieve the continuous release of chemotherapy drugs for at least 2 weeks; at the same time, the gel barrier restricts drug diffusion, and the degradation rate matches the drug release kinetics, reducing toxicity to healthy tissues. (3) Biocompatibility: Aminopolysaccharide derivatives have good biocompatibility and can be metabolized and absorbed by the human body, avoiding the need for secondary surgery to remove them; (4) Low immunogenicity: amidation blocks free amino groups, reduces positive charge, and avoids stress response that stimulates tumor tissue. Detailed Implementation
[0019] To make the technical problem to be solved, the technical solution, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.
[0020] Because local drug delivery to tumor sites is cumbersome, technically demanding, and unsuitable for frequent administration, the injected drug formulation must possess excellent sustained-release properties. To meet this requirement, this invention employs a novel aminopolysaccharide derivative thermosensitive gel as a drug carrier. The liquid drug-containing gel, which is fluid at relatively low temperatures, is injected into the tumor site, rapidly transforming into a non-flowing gel state at body temperature to slowly release the drug. This allows the drug to exert a long-term local therapeutic effect. Simultaneously, the gel barrier effect limits the drug diffusion rate, increases the duration of effective drug concentration at the tumor site, reduces systemic toxicity, and achieves better anti-tumor therapeutic effects.
[0021] This invention provides a temperature-sensitive injectable hydrogel formulation, which includes a temperature-sensitive hydrogel, a chemotherapy drug, and physiological saline.
[0022] The temperature-sensitive injectable hydrogel formulation comprises 0.1-1.0 mg / ml of chemotherapeutic drug and a physiological saline solution of temperature-sensitive hydrogel with a mass concentration of 0.3%-2.0%, wherein the phase transition temperature of the formulation is 10-35℃.
[0023] The temperature-sensitive hydrogel is an aminopolysaccharide derivative, which includes hydrophilic derivatization groups and acylation groups.
[0024] Furthermore, the hydrophilic derivatizing group includes carboxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, and the acylation group includes formyl, acetyl, or succinyl.
[0025] The molecular weight of the aminopolysaccharide derivative is 15,000-300,000 Da.
[0026] By adjusting the preparation process parameters, molecular weight, and degree of derivatization of aminopolysaccharide derivatives, the phase transition temperature can be controlled within the range of 10-35℃. At low temperatures (< phase transition temperature), it is in a liquid state for easy injection, and after being triggered by body temperature (≥ phase transition temperature), it forms a gel.
[0027] When the aminopolysaccharide derivative is N-acetyl-hydroxypropylglucosamine, it is prepared by the following method: Glucosamine is slowly added to an excess of 10-15% potassium hydroxide or sodium hydroxide solution and stirred until fully dissolved. The mixture is then frozen overnight, thawed, shaken, and stirred at room temperature for 1 hour. Propylene oxide (molar ratio of glucosamine to propylene oxide 1:3-1:10) is then slowly added at 4-10°C, and the reaction is stirred for 48-72 hours. The time and temperature are controlled to maintain the degree of hydroxypropyl substitution (DS) (number of hydroxypropyl groups on glucose residues of glucosamine: glucosamine) between 1 and 1.2. After the reaction, the pH is adjusted to neutral with dilute hydrochloric acid. The product is precipitated with an organic solvent, filtered, and washed several times with anhydrous ethanol to obtain hydroxypropylglucosamine. At 10°C, the obtained hydroxypropyl glucosamine is dissolved in anhydrous methanol (hydroxypropyl glucosamine methanol solution concentration 1-5%), stirred, and after complete dissolution, acetic anhydride is added. The recommended molar ratio of acetic anhydride to amino group of hydroxypropyl glucosamine is 2:1 to 3:1. The mixture is stirred until completely dissolved, and the reaction is carried out for 24-48 hours. The reaction is terminated by adding excess ice water, dialyzed at 4°C, and then freeze-dried under vacuum to obtain thermosensitive N-acetyl-hydroxypropyl glucosamine.
[0028] The thermosensitivity of aminopolysaccharide derivatives mainly stems from the addition of hydrophilic derivatizing groups (such as hydroxypropyl groups) during derivatization, and the molecular conformation formed under specific reaction conditions. When the aqueous solution temperature of thermosensitive aminopolysaccharide derivatives is below the phase transition temperature, the hydrophilic derivatizing groups will fully bind with water molecules based on thermodynamic effects, exhibiting water solubility. When the overall solution temperature is above the phase transition temperature, the hydrophilic derivatizing groups will undergo hydrophobic cross-linking, causing the solution to exhibit a gel-like state. Based on this principle, the degree of derivatization, derivatization uniformity, and molecular conformation of aminopolysaccharide derivatives can be adjusted by modifying conditions such as the pH value of the solution, reaction temperature, and time during the preparation process, thereby controlling the phase transition temperature. Furthermore, compared to small molecular weight (short molecular chain) aminopolysaccharide derivatives, large molecular weight (long molecular chain) derivatives are more prone to cross-linking and de-cross-linking in aqueous solutions under the same concentration and temperature changes, resulting in differences in phase transition temperatures.
[0029] Preferably, the temperature-sensitive hydrogel is N-acetyl-hydroxypropylglucosamine.
[0030] The N-acetyl-hydroxypropyl glucosamine polysaccharide is prepared via a specific route and then dissolved in physiological saline. The resulting solution of a certain concentration exhibits temperature sensitivity, possessing a phase transition temperature of 10-35°C. When the overall solution temperature is below 10-35°C, it is a fluid liquid; when the solution temperature is above 10-35°C, it is a non-fluid gel. This solution offers the following advantages: a. It has the characteristic of bidirectional solid-liquid transformation; b. The N-acetyl-hydroxypropyl glucosamine polysaccharide contained in this solution has a large number of free amino groups in the molecule blocked by formyl, acetyl, succinyl and other groups, thereby reducing the number of positive charges carried in the molecule, avoiding the stress response that stimulates tumor tissue, and at the same time ensuring the stability of the molecular structure and function of chemotherapy drugs.
[0031] The chemotherapy drugs mentioned are any chemical drugs that can be used to treat solid tumors, including cisplatin, paclitaxel, gemcitabine, doxorubicin, etoposide, mitomycin, epirubicin, hydroxycamptothecin, cantharidin, elemol, turmeric oil / goose bile oil, bufotin, and Pseudomonas aeruginosa inhibitors.
[0032] A second aspect of the present invention provides a method for preparing a temperature-sensitive injectable hydrogel formulation, comprising: preparing a temperature-sensitive hydrogel, preparing a physiological saline solution of the temperature-sensitive hydrogel, and mixing a chemotherapy drug with the physiological saline solution.
[0033] The physiological saline solution of the temperature-sensitive hydrogel has a mass concentration of 0.3%-2.0%.
[0034] The concentration of the chemotherapy drug is 0.1-1.0 mg / ml.
[0035] A third aspect of the present invention provides the use of a temperature-sensitive injectable hydrogel formulation in the preparation of a medicament for local perfusion therapy of solid tumors.
[0036] The injectable agent is suitable for local chemotherapy of various solid tumors, such as primary or metastatic cancers, sarcomas, or carcinosarcomas of the liver, breast, or bladder, and is especially suitable for the treatment of tumors adjacent to vital organs or those that cannot be surgically removed.
[0037] The following description is based on specific embodiments: Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available, and techniques not described in detail were performed according to standard methods well known to those skilled in the art.
[0038] Example 1: Preparation of N-acetyl-hydroxypropyl glucosamine polysaccharide
[0039] Glucosamine was slowly added to an excess of 10% potassium hydroxide solution and stirred until fully dissolved. The mixture was then frozen overnight. After thawing, it was shaken and stirred at room temperature for 1 hour. Then, propylene oxide (molar ratio of glucosamine to propylene oxide 1:10) was slowly added at 4°C, and the mixture was stirred for 48 hours. The time and temperature were controlled to ensure that the degree of hydroxypropyl substitution (DS) (number of hydroxypropyl groups on glucose residues of glucosamine: glucosamine) was 1. After the reaction was completed, the pH was adjusted to neutral with dilute hydrochloric acid. The product was precipitated with an organic solvent, filtered, and washed several times with anhydrous ethanol to obtain hydroxypropyl glucosamine.
[0040] At 10℃, the obtained hydroxypropyl glucosamine was dissolved in anhydrous methanol (1% concentration of hydroxypropyl glucosamine methanol solution), stirred, and after complete dissolution, acetic anhydride was added. The molar ratio of acetic anhydride to amino group of hydroxypropyl glucosamine was 2:1. The mixture was stirred until completely dissolved, and the reaction was carried out for 24 hours. The reaction was terminated by adding excess ice water, dialyzed at 4℃, and then freeze-dried under vacuum to obtain thermosensitive N-acetyl-hydroxypropyl glucosamine.
[0041] Under the same conditions, after adding propylene oxide, setting the stirring reaction to 72 hours and controlling the time and temperature, the degree of hydroxypropyl substitution (DS) of the thermosensitive compound can be 1.2.
[0042] Example 2 Preparation of N-formyl-carboxymethyl glucosamine polysaccharide
[0043] Glucosamine was slowly added to an excess of 15% sodium hydroxide solution and stirred until fully dissolved. The mixture was then frozen overnight. After thawing, it was shaken and stirred at room temperature for 1 hour. Then, sodium chloroacetate (molar ratio of glucosamine to sodium chloroacetate 1:3) was slowly added at 10°C and stirred for 48 hours. The time and temperature were controlled to ensure that the degree of carboxymethyl substitution (DS) (number of carboxymethyl groups on glucose residues of glucosamine: glucosamine) was 1. After the reaction was completed, the pH was adjusted to neutral with dilute hydrochloric acid. The product was precipitated with an organic solvent, filtered, and washed several times with anhydrous ethanol to obtain carboxymethyl glucosamine.
[0044] At 10℃, the obtained carboxymethyl glucosamine was dissolved in anhydrous methanol (5% concentration of carboxymethyl glucosamine methanol solution), stirred, and after complete dissolution, formic anhydride was added, with a formic anhydride to carboxymethyl glucosamine amino molar ratio of 3:1. The mixture was stirred until completely dissolved, and the reaction was allowed to proceed for 48 hours. The reaction was terminated by adding excess ice water, dialyzed at 4℃, and then freeze-dried under vacuum to obtain thermosensitive N-formyl-carboxymethyl glucosamine.
[0045] Example 3 Preparation of a temperature-sensitive injectable hydrogel formulation
[0046] At 4°C, the N-acetyl-hydroxypropyl glucosamine polysaccharide with a degree of hydroxypropyl substitution of 1 prepared in Example 1 was fully dissolved in a physiological saline solution to prepare a physiological saline solution with a mass concentration of 0.6%; paclitaxel was dissolved in the above physiological saline solution to prepare an injectable hydrogel formulation of 0.5 mg / ml.
[0047] Example 4: Preparation of a temperature-sensitive injectable hydrogel formulation
[0048] At 4°C, the N-formyl-carboxymethyl glucosamine polysaccharide prepared in Example 2 was fully dissolved in a physiological saline solution to prepare a physiological saline solution with a mass concentration of 0.6%; gemcitabine was dissolved in the above physiological saline solution to prepare an injectable hydrogel formulation with a concentration of 1.0 mg / ml.
[0049] Example 5: Determination of phase transition temperature and gel strength
[0050] 1. Phase transition temperature test experiment
[0051] Thermosensitive N-acetyl-hydroxypropyl glucosamine polysaccharides with substitution degrees of 1 and 1.2 prepared in Example 1 were used to prepare saline solutions with concentrations of 0.4%, 0.6%, 0.8%, 1.0%, and 1.2% at 4°C. After being dispensed into vials, the solutions were placed in a water bath with an initial temperature of 10°C. The solutions were removed every 5 minutes, inverted, and observed for any phase transition (weakened fluidity). The temperature was increased by 1°C every 10 minutes. The phase transition temperatures of the thermosensitive N-acetyl-hydroxypropyl glucosamine saline solutions with different substitution degrees and concentrations were observed. The results are shown in Tables 1 and 2, where "-" indicates no phase transition and "+" indicates a phase transition.
[0052] Table 1. Phase transition temperature test of thermosensitive N-acetyl-hydroxypropylglucosamine saline solutions with different concentrations and a degree of substitution of 1.
[0053] Table 2. Phase transition temperature test of different concentrations of thermosensitive N-acetyl-hydroxypropylglucosamine saline solutions with a degree of substitution of 1.2.
[0054] 2. Gel strength test
[0055] Thermosensitive N-acetyl-hydroxypropyl glucosamine polysaccharides with substitution degrees of 1 and 1.2 prepared in Example 1 were used to prepare physiological saline solutions with concentrations of 0.6%, 0.8%, 1.0%, and 1.2% at 4°C. After being dispensed into vials, the solutions were placed at 36°C (simulating human body temperature) until a complete phase transition (completely non-flowing when inverted). The gel strength (Bloom g mean) was then tested using the puncture test method. The results are shown in Table 3.
[0056] Table 3. Gel strength test of thermosensitive N-acetyl-hydroxypropyl glucosamine with substitution degrees of 1 and 1.2.
[0057] 3. Injectability test
[0058] It is known that 5ml 22g syringe needles are often used to inject liquid preparations into muscle tissue and cavities. The upper limit requirement for the viscosity of the injection solution is 1000-2000 millipascal-seconds (mPa·s), and the injection time is generally no more than 5 minutes.
[0059] Thermosensitive N-acetyl-hydroxypropyl glucosamine polysaccharides with degrees of substitution of 1 and 1.2 prepared in Example 1 were used to prepare physiological saline solutions with concentrations of 0.6%, 0.8%, 1.0%, and 1.2% at 4°C. The time required for the solution viscosity to exceed 1000 mPa·s was measured using rotational viscometry at 36°C. The results are shown in Table 4.
[0060] Table 4. Injectability test of thermosensitive N-acetyl-hydroxypropyl glucosamine polysaccharides with substitution degrees of 1 and 1.2
[0061] Example 6: Evaluation of therapeutic effect in animal models
[0062] Immunodeficient mice were purchased and subcutaneously injected with bladder cancer cells into their upper limbs. After culturing for 4 weeks until the tumor size reached 1.5cm x 1cm, the hydrogel formulation prepared in Example 3 was tested. The tumor-bearing mice were randomly divided into 4 groups of 5 mice each. Specific grouping and experimental protocols are shown in Table 5.
[0063] Table 5 Experimental Scheme
[0064] All groups were treated with percutaneous tumor center injections. Prior to injection, all injectable fluids were stored at 4°C to prevent the thermosensitive gel from reaching its phase transition temperature and solidifying into a gel state, thus affecting the injection efficacy. After injection, tumor size changes were monitored daily, and samples were taken on days 0, 3, 6, 9, 12, and 15 to measure the concentration of chemotherapy drugs in the blood. All test results are shown in Tables 6-9.
[0065] Table 6. Tumor growth inhibition (cm)
[0066] Table 7. Drug concentration in blood (ppb)
[0067] Table 8. Drug concentration (ppb) in tissue adjacent to the tumor sample taken on day 15.
[0068] Table 9. Drug concentrations (ppb) in target organ tissues sampled on day 15.
[0069] The results above show that the temperature-sensitive injectable hydrogel formulation prepared in this application has a strong inhibitory effect on tumors. On day 15, the tumor size was significantly smaller than that on day 0 (0.79 x 0.32), and also significantly lower than that of the group using paclitaxel alone (1.16 x 0.79) (Table 6). Simultaneously, due to the gel barrier effect of the temperature-sensitive gel, the diffusion of chemotherapy drugs was limited. On day 15, the drug concentrations detected in the blood and adjacent tissues were lower than those in the paclitaxel group, indicating that the injectable formulation of this application has lower toxicity to surrounding tissues (Tables 7-8). As shown in Table 9, the drug concentrations of the temperature-sensitive injectable hydrogel formulation prepared in this application in various target organ tissues were also significantly lower than those in the paclitaxel group. This is because the temperature-sensitive injectable hydrogel formulation of this application can slowly degrade and continuously release the drug (paclitaxel), allowing it to act in the tumor tissue for as long as possible. It is then continuously and at low concentrations excreted from the body through metabolism along with the killed tumor cells. This reduces the drug concentration in the target organ (safety evaluation organ), thereby reducing damage to these organs.
[0070] Experiments have shown that the hydrogel prepared in Example 4 also has similar therapeutic effects.
[0071] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A temperature-sensitive injectable hydrogel formulation, the formulation comprising a temperature-sensitive hydrogel, a chemotherapy drug, and physiological saline, wherein the phase transition temperature of the formulation is 10-35°C.
2. The formulation according to claim 1, characterized in that, The content of the chemotherapy drug is 0.1-1.0 mg / ml, and the mass concentration of the temperature-sensitive hydrogel is 0.3%-2.0%.
3. The formulation according to claim 1, characterized in that, The active ingredient of the temperature-sensitive hydrogel is an aminopolysaccharide derivative, which includes hydrophilic derivatization groups and acylation groups.
4. The formulation according to claim 3, characterized in that, The hydrophilic derivatizing group includes carboxymethyl, hydroxyethyl, hydroxypropyl, or hydroxybutyl, and the acylation group includes formyl, acetyl, or succinyl.
5. The formulation as described in claim 3, characterized in that, The molecular weight of the aminopolysaccharide derivative is 15,000-300,000 Da.
6. The formulation according to claim 3, characterized in that, The temperature-sensitive hydrogel is a hydroxypropyl aminopolysaccharide amidation.
7. The formulation according to claim 1, characterized in that, The chemotherapy drugs include one or more of the following: cisplatin, paclitaxel, gemcitabine, doxorubicin, etoposide, mitomycin, epirubicin, hydroxycamptothecin, cantharidin, elemol, turmeric oil / goose bile oil, bufotin, and Pseudomonas aeruginosa inhibitors.
8. A method for preparing a formulation according to any one of claims 1-7, the method comprising: S1: Preparation of temperature-sensitive hydrogels S2: Prepare physiological saline solution for temperature-sensitive hydrogels. S3: Mix chemotherapy drugs with the physiological saline solution.
9. Use of the formulation according to any one of claims 1-7 in the preparation of a medicament for local perfusion therapy of solid tumors.
10. The use as described in claim 9, characterized in that, The drug is suitable for local chemotherapy of solid tumors, including primary or metastatic cancers, sarcomas, or carcinosarcomas of the liver, breast, or bladder.