57 results about "Sonodynamic therapy" patented technology

The invention discloses an ultrasonic controllable multifunctional microneedle patch as well as a preparation method and application thereof, and belongs to the technical field of biological materials. The preparation method comprises the following steps: preparing crystalline CoW-LDH nanosheets from Co (NO3) 2.6 H2O, Na2WO4. 2H2O and NaOH, dispersing the crystalline CoW-LDH nanosheets in PBS (Phosphate Buffer Solution), centrifuging and collecting the crystalline CoW-LDH nanosheets, and re-dispersing the crystalline CoW-LDH nanosheets in ultrapure water to obtain amorphous CoW-LDH nanosheets; adding PEG (Polyethylene Glycol), ultrasonically dispersing, stirring at room temperature, centrifuging, collecting and centrifugally washing with ultrapure water to obtain a PEG modified amorphous CoW-LDH nanosheet; and adding microalgae and an amorphous CoW-LDH nanosheet modified by PEG (Polyethylene Glycol) to prepare the ultrasonic controllable multifunctional microneedle patch. The multifunctional microneedle patch disclosed by the invention is high in biological safety, can realize ultrasonic controllability, has a sonodynamic treatment effect and an oxygen supply effect, remarkably inhibits melanoma recurrence and remarkably promotes wound healing, and has a wide application prospect.

The invention discloses an aptamer-modified lipid nano delivery platform as well as a preparation method and application thereof, and belongs to the field of biomedicine. The platform is prepared by taking DPPC, DOTAP and cholesterol as basic lipid components, Ce6 as a sound-sensitive agent and Flt3L as an immune agonist, controlling the particle size through gradient extrusion, and coupling cholesterol with an EpCAM aptamer for surface modification. The method has the core advantages that active targeting enrichment of tumors is realized by virtue of the aptamer, tumor cell immunogen cell death (ICD) is induced in combination with a sonodynamic therapy (SDT), and damage-related molecular patterns (DAMPs) are released; meanwhile, Flt3L is released in a tumor microenvironment, collection and activation of type 1 classical dendritic cells (cDC1) are specifically promoted, an'endogenous cDC1 vaccine 'is constructed, and CD8 + T cell mediated anti-tumor immune response is enhanced. Experiments prove that the platform can significantly improve the cDC1 infiltration level of a tumor site, effectively inhibit the progress of prostate cancer (PCa), and provide a new normal form for immune'cold tumor 'treatment.

The application belongs to the technical field of medicine, and particularly relates to a La2(WO4)3 / CuWO4 composite sonosensitizer, a preparation method thereof and application thereof in sonodynamic therapy. The La2(WO4)3 / CuWO4 composite sonosensitizer contains 5-40% of La2(WO4)3 in terms of mass percentage. The application takes U251 glioma cells as a model target, and explores the application of the La2(WO4)3 / CuWO4 composite sonosensitizer in sonodynamic therapy of tumors. The results show that the La2(WO4)3 / CuWO4 composite sonosensitizer has a good sonodynamic therapy effect on U251 glioma cell lines after 1MHz US irradiation for 1min.

The present disclosure relates generally to methods of utilizing sonosensitizers in the presence of thiamine or a derivative thereof for the purpose of cross-linking animal tissue, producing singlet oxygen within or at the site of animal tissue, or treating a condition in a subject, wherein the condition is an aneurysm, cancer, and / or a scleral condition.

The application discloses a kind of sustainable oxygen production sonodynamic therapy nanoparticles, including core-shell structure, the core of core-shell structure is located in shell inside, the core of core-shell structure is manganese oxide nanoparticle, the shell of core-shell structure is the high molecular polymer of carrying sound sensitizer, manganese dioxide nanoparticle is manganese dioxide nanoparticle, sound sensitizer is one of porphyrin and its derivatives, high molecular polymer is polylactic acid glycolic acid copolymer, this kind of sustainable oxygen production sonodynamic therapy nanoparticles by using high molecular polymer simultaneously carrying manganese dioxide nanoparticle and sound sensitizer to enhance SDT effect, high molecular polymer has good biocompatibility and drug controlled release performance, not only can reduce the toxicity of manganese dioxide to normal tissue, can also make it continuously controllable with tumor site excess H2O2 Reaction generates oxygen, reverses tumor hypoxic microenvironment while providing sufficient oxygen for SDT, under the action of ultrasound, generate a large amount of ROS to inhibit tumor.

The present invention relates to an enhanced sonodynamic therapeutic agent using a liposome having the ability to transfer oxygen, and more particularly, to lipid nanoparticles having the ability to transfer oxygen in which perfluorocarbon (PFC) and indocyanine green (ICG) are loaded inside liposomes to increase the efficiency of sonodynamic therapy.

The invention provides a sound-sensitive-agent-loaded targeted adipose tissue extracellular vesicle for assisting sonodynamic treatment of obesity as well as a preparation method and application of the sound-sensitive-agent-loaded targeted adipose tissue extracellular vesicle, and particularly belongs to the technical field of obesity drug preparation. The invention provides an application of an extracellular vesicle of a targeted adipose tissue loaded with a sound-sensitive agent in preparation of a medicine for assisting sonodynamic treatment of obesity. The sound sensitive agent is hematoporphyrin monomethyl ether; the extracellular vesicle of the targeted adipose tissue is an extracellular vesicle of which the surface expresses targeted adipose tissue sequence peptide ATS, and the amino acid sequence of the ATS is as shown in SEQ ID NO. 1. The extracellular vesicle loaded with the haematoporphyrin monomethyl ether surface expression targeting adipose tissue sequence peptide ATS can accurately induce adipose tissue browning, finally safe and effective fat reduction is achieved, and the effect of treating obesity is achieved.

The invention discloses a tumor treatment synergistic interaction system and method based on the acoustic cavitation effect of a phase-change nano-droplet. The system comprises the phase-change nano-droplet entrapped with a chemotherapeutic drug and a sound-sensitive agent and a cavitation effect intelligent monitoring and adjusting system. The method is characterized in that cavitation noise signals of a tumor target area are collected in real time through a cavitation monitoring system integrated in an ultrasonic probe, the inertial cavitation dosage is rapidly calculated through a signal processing system and compared with a preset threshold value, then a feedback instruction is generated to dynamically regulate and control ultrasonic irradiation parameters, and intelligent closed-loop control is formed. According to the method, the cavitation effect can be accurately maintained in an ideal treatment window, targeted release and deep penetration of the medicine and activation of the sound-sensitive agent are synchronously achieved through cavitation mechanical energy, and time-space synchronous synergistic interaction of chemotherapy and sonodynamic therapy is achieved.

The invention relates to the technical field of research and development of tumor photodynamic therapy photosensitizers, photothermal therapy photothermal reagents and sonodynamic therapy sonosensitizers, and provides a preparation method and application of a binuclear metal complex of a polythiophene bridging ligand. The invention relates to a ruthenium complex TBLRu3a-TBLRu6a and a ruthenium complex TBLRu3b-TBLRu6b of a polythiophene bridged tri-bidentate ligand, a ruthenium complex TTLRu1-TTLRu12 of a polythiophene bridged bis-tridentate ligand, and an osmium complex TTLOs1-TTLOs6 of a polythiophene bridged bis-tridentate ligand, which are respectively designed and invented by the invention. The invention further relates to a preparation method of the ruthenium complex TBLRu3a-TBLRu6a and the ruthenium complex TBLRu3b-TBLRu6b of the polythiophene bridged tri-bidentate ligand and a preparation method of the ruthenium complex TTLRu1-TTLRu12 of the polythiophene bridged bis-tridentate ligand. The polythiophene bridged metal complex has extremely high stability and excellent two-photon absorption characteristic, has excellent biotoxicity and photothermal conversion capability under the action of infrared exciting light, and can induce A549R cell apoptosis. The polythiophene bridged metal complex provided by the invention is a potential novel two-photon absorption photodynamic therapy photosensitizer, a photothermal therapy photothermal reagent and a sonodynamic therapy sonosensitizer, and has a wide application prospect in photodynamic therapy, photothermal therapy and sonodynamic therapy of tumors.

The invention discloses efficient tumor sonodynamic therapy nanoparticles based on carbon-doped nano-zinc oxide as well as a preparation method and application of the efficient tumor sonodynamic therapy nanoparticles. Belongs to the field of biomedicine. On the basis of MOF-5, carbon-doped hollow-hole-shaped nano-particles C-ZnO are formed after calcination in a nitrogen atmosphere, then chloroplatinic acid hexahydrate and sodium borohydride are added into a C-ZnO nano-particle solution, so that Pt nano-particles are loaded on the surface of C-ZnO, in addition, AB is loaded in a CZP hollow structure, HA-AA modification is carried out on the surface of the CZP hollow structure, and the CZP hollow structure loaded with the AB is obtained. Therefore, the effects of hydrogen treatment, consumption of excessive glutathione in a biological microenvironment and targeting are achieved, and the effect of treating cancers is achieved from multiple aspects. The nano particles are uniform in size, the average particle size is about 200 nm, good biocompatibility is achieved, and the material prepared through the method has excellent ROS generation capacity, so that the material has excellent sonodynamic therapy potential and has wide application prospects in the field of tumor therapy.

This invention discloses a FA-ICG-NBs nanobubble, its preparation method, and its application in the preparation of tumor-targeted therapeutic agents. The FA-ICG-NBs nanobubble employs a composite phospholipid shell, with folic acid (FA) covalently bonded to the surface and indocyanine green (ICG) loaded onto it, encapsulating a mixture of oxygen and sulfur hexafluoride. The preparation method includes: preparing a lipid solution for forming the composite phospholipid shell; mixing the lipid solution with the oxygen and sulfur hexafluoride mixture, and then performing a reciprocating shearing gas-liquid interface self-assembly to obtain the FA-ICG-NBs nanobubble. The FA-ICG-NBs nanobubble prepared by this invention utilizes dual-wavelength photoacoustic imaging for non-invasive assessment of tumor blood oxygenation and hypoxia improvement, combined with ICG fluorescence timing for screening the optimal therapeutic window, and synergistic oxygen-enhanced sonodynamic therapy. It exhibits good biocompatibility, structural stability, and integrates targeted enrichment, blood oxygenation assessment, hypoxia monitoring, timing regulation, and enhanced therapeutic effects.

This invention provides a multifunctional biomaterial, its preparation method, and its application, relating to the field of biomaterials technology. The multifunctional biomaterial is characterized by comprising: a biocompatible polymer matrix; and a sonosensitive agent complex dispersed in the biocompatible polymer matrix. The sonosensitive agent complex comprises a metal-insulator phase change material and an MXene two-dimensional material, wherein the metal-insulator phase change material and the two-dimensional material form a heterostructure. The metal-insulator phase change material undergoes a phase transition under thermal stimulation to alter the band structure and built-in electric field of the heterostructure. The multifunctional biomaterial according to embodiments of this invention can achieve a significant synergistic improvement in carrier generation efficiency, separation efficiency, and migration efficiency, solving the problem of a fixed upper limit for carrier concentration in traditional static heterostructures, achieving a secondary amplification of ROS generation, and improving the efficiency of sonodynamic therapy.

The present application relates to the technical field of nanobiomedicine, and particularly relates to a porphyrin oxygen-carrying polymer sonosensitizer, a preparation method and application thereof; the porphyrin oxygen-carrying polymer sonosensitizer takes porphyrin as a main body structure and takes polyheptafluorobutyramide as a polymer side chain. The polyheptafluorobutyramide contained in the porphyrin oxygen-carrying polymer sonosensitizer can carry oxygen, and under the activation of ultrasound, the perfluoroalkyl-modified polymer can release oxygen explosively, the perfluoroalkyl-modified polymer triggered by visible light increases oxygen supply to relieve tumor hypoxia, reverses a low-oxygen microenvironment, enhances the generation of reactive oxygen species in the SDT process, further improves the accumulation efficiency at a tumor site, improves the effect of SDT in treating tumors, and becomes an effective method for enhancing the chemical sonodynamic therapy of hypoxic tumors.

This invention provides an activatable semiconductor polymer, its preparation method, and its applications. The activatable semiconductor polymer of this invention can efficiently accumulate at tumor sites. Due to the presence of electron-withdrawing groups on its side chains, the polymer's fluorescence is quenched. Upon response to tumor markers—biothiols, reactive oxygen species, and cathepsin B—the polymer's fluorescence recovers, enabling precise imaging and sonodynamic therapy at the tumor site. Simultaneously, the activatable semiconductor polymer of this invention can label immune cells (such as dendritic cells and macrophages) and track their metastasis from the tumor to the draining lymph nodes.

The invention discloses a preparation method and application of IBFO (at) high-entropy alloy heterojunction piezoelectric hydrogel (IBHA-SAPS), and the preparation method comprises the following steps: preparing high-entropy alloy (HEA) powder through sol-gel and calcination, compounding the HEA powder with bismuth-doped bismuth ferrite (IBFO) to construct an IBFO (at) HEA heterojunction (IBHA), and finally carrying out cross-linking molding with a sodium alginate-phenylboronic acid polymer. Under ultrasonic stimulation, the piezoelectric effect of the hydrogel can synergistically enhance the sonodynamic performance and the nano-enzyme activity, and in an acidic microenvironment, efficient antibiosis and biological membrane removal can be achieved through high-intensity ultrasound; in a neutral physiological microenvironment, low-intensity ultrasound can trigger the composite material to remove active oxygen so as to relieve oxidative stress and generate an electric signal to promote osteoblast differentiation, and the composite material has good biocompatibility, injectability and intelligent responsiveness and has wide application prospects in the fields of sonodynamic therapy, tissue engineering scaffolds, infectious bone defect repair and the like.

The invention discloses a degradable microneedle patch co-loaded with a sound sensitive agent and an STING agonist as well as a preparation method and application of the degradable microneedle patch. The invention provides a microneedle raw material composition. The microneedle raw material composition comprises a sound-sensitive agent and an STING agonist, the mass ratio of the sound sensitive agent to the STING agonist is (0.2-1): 1. Furthermore, the invention provides a microneedle patch which comprises a back weighing layer and a needle body array arranged on the back weighing layer, and a microneedle raw material composition is loaded in an aqueous solution of a degradable polymer of the needle body array. According to the invention, co-delivery of the sound-sensitive agent and the STING agonist is utilized, penetration of the drug to the deep part of the tumor tissue can be enhanced through a sonodynamic therapy, more accurate drug release is realized, a stronger immune effect is caused, in-situ tumors are eliminated, growth of far-end tumors is inhibited, and the immunotherapy effect of the drug is synergistically improved.

The invention discloses a preparation method and application of a titanium-based nano material for enhancing osteosarcoma sonodynamic therapy. The preparation method comprises the following steps: 1, preparing a titanium dioxide nano material; 2, calcining after drying to obtain oxygen vacancy modified titanium dioxide; 3, preparing palladium modified titanium dioxide rich in oxygen vacancies; and 4, dispersing the palladium-modified titanium dioxide rich in oxygen vacancies into a folic acid-polyethylene glycol-sulfydryl solution, violently stirring, and then centrifuging and washing to obtain the titanium-based nano material. Titanium dioxide with sound-sensitive performance is used as a carrier, oxygen vacancies are introduced to modify the surface of the carrier, the sonodynamic performance of the material is remarkably enhanced, the palladium element is further loaded to improve the generation efficiency of active oxygen, folic acid is used for surface modification, so that the biocompatibility and tumor targeting ability of the material are improved, and the preparation method is simple and easy to implement. Functional integration of tumor targeted delivery and sonodynamic treatment is achieved, and the comprehensive treatment effect on osteosarcoma is remarkably enhanced.

This invention discloses a bismuth-copper bimetallic coordination nanomaterial, its preparation method, and its applications, belonging to the technical field of biofunctional materials. The prepared bismuth-copper bimetallic coordination nanomaterial can efficiently generate reactive oxygen species (ROS) under ultrasonic stimulation, initiating the sonodynamic therapy (SDT) process; the Cu in this material... 2+ The weakly acidic environment of the tumor microenvironment can also trigger a Fenton-like reaction, generating cytotoxic hydroxyl radicals (•OH) and oxygen in situ, thus initiating the chemokinetic therapy (CDT) process. Through the synergistic effect of sonodynamic therapy (SDT) and chemokinetic therapy (CDT), they jointly inhibit cancer cell proliferation and promote T cell generation.

The invention relates to methods of sonodynamic therapy comprising the co-administration of a microbubble-chemotherapeutic agent complex together with a microbubble-sonosensitiser complex. It further relates to pharmaceutical compositions comprising these complexes and their use in methods of sonodynamic therapy and / or sonodynamic diagnosis. Such methods find particular use in the treatment of cancer, e.g. pancreatic cancer.

The present invention relates to a phage or a composition that comprises it, wherein said phage expresses at least one specific recognition element and is furthermore conjugated with at least 300 molecules of a sonosensitiser. The invention further relates to the use of said phage in a sonodynamic therapy.

The invention relates to an ultrasonic response defect titanium oxide coating as well as a preparation method and application thereof. The ultrasonic response defect titanium oxide coating is an anoxic copper-doped titanium oxide coating positioned on the surface of the medical titanium substrate; wherein the oxygen-deficient copper-doped titanium oxide coating comprises a porous titanium oxide coating, copper ions and / or copper elementary substances uniformly distributed in the porous titanium oxide coating, and oxygen vacancies uniformly distributed in the porous titanium oxide coating. The titanium-based implant is subjected to surface modification, and transition metal ions and structural defects (such as Ti < 3 + > and oxygen vacancies) are introduced into the titanium oxide coating, so that the energy band structure of TiO2 can be adjusted, the sonodynamic treatment efficiency is improved, and the surface modified medical titanium metal material capable of resisting bacteria and promoting osteogenesis is obtained; the synchronous resistance to early-stage bacterial infection and the effective promotion of later-stage osseointegration are expected to be realized.

Ultrasound transducer element arrays using acoustic ensonification drive patterns via a patient interface for sonosensitizer activation in sonodynamic therapy. Acoustic field generation varying phase, frequencies, and / or amplitude via controlled delivery of low intensity planar acoustic waves. Method includes generating a first and a second signal to generate respective acoustic ensonification drive patterns with phase, frequency, and amplitude and generating at least one relative phase, frequency or amplitude difference to generate a third incoherent acoustic ensonification pattern to activate a sonosensitizer.

The application belongs to the technical field of antitumor drugs, and particularly relates to a nanofiber hydrogel for synergistic antitumor sonodynamic / chemodynamic therapy, a preparation method and application thereof, synthesis of Nap-Pept, preparation of Nap-Pept / Fe 3+ / Cur nanogel, under ultrasonic conditions, synergistic sonodynamic therapy of a traditional Chinese medicine sonosensitizer Cur and Fe 3+ mediated chemodynamic therapy, triggering immunogenic death of cancer cells by increasing ROS levels of B16F10 cells and then damaging mitochondrial function. Nap-Pept / Fe 3+ / Cur@US promotes expression of the immune-related factor calnexin, release of high mobility group protein 1 and maturation of dendritic cells to kill tumor cells, thereby exerting an antitumor effect. In vivo and in vitro studies show that the anticancer effect of the combined sonodynamic and chemodynamic therapy is superior to that of single therapy, achieving the purpose of precise and efficient anti-melanoma.

The invention provides preparation of a biodegradable sound-sensitive agent and application of the biodegradable sound-sensitive agent in acoustic immunotherapy, and in order to overcome the defects of a current Cu2O-based nano material in acoustic immunotherapy application, an in-situ phosphorization strategy of a Cu2O nanocube is reported for the first time so as to adjust the degradation behavior of the Cu2O nanocube. Compared with Cu2O nanocubes, the obtained Cu3P nanocubes can only be degraded in tumor cells and cannot be degraded in normal cells, so that the Cu3P nanocubes are endowed with TME response degradation characteristics.

The invention discloses an intelligent artificial bionic DC cell nanoparticle nDC-M and a preparation method, application and a detection method thereof. The nano-particle is of a core-shell structure, the inner core is a hypoxia response type nano-micelle of a sound-sensitive agent SP8 and IL-2 for activating T cells to be mature, the outer layer is coated with a mature DC cell membrane, and the nano-particle has the immune recognition characteristic and the treatment function. In a tumor hypoxic microenvironment, the micelle specifically releases SP8 and IL-2; sP8 generates ROS through ultrasonic excitation, tumor cell immunogenicity death is induced, and antigens are released; iL-2 activates proliferation and functions of tumor infiltration lymphocytes; the outer DC cell membrane and the antigen capture functional group enhance the collection and activation of immune cells through surface antigen presentation, and amplify the anti-tumor immune response. By combining sonodynamic therapy and immunoregulation, tumor growth is inhibited, metastatic load is reduced, good biocompatibility and safety are achieved, and a novel bionic delivery system is provided for metastatic tumor immune combined therapy.

The invention belongs to the technical field of biological medicines, and relates to a sound-sensitive agent engineered oncolytic adenovirus as well as a preparation method and application thereof. In particular to a sonosensitizer engineered oncolytic adenovirus with oncolytic and sonodynamic dual effects as well as a preparation method and application of the sonosensitizer engineered oncolytic adenovirus. The sonosensitizer engineered oncolytic adenovirus is prepared by covalently linking an oncolytic adenovirus and a nano sonosensitizer (THD). The sonosensitizer engineered oncolytic adenovirus disclosed by the invention can be combined with sonodynamic therapy to be used for preparing an anti-tumor treatment product. The sound-sensitive agent engineered oncolytic adenovirus disclosed by the invention not only can specifically recognize a transferrin receptor highly expressed on the surface of a tumor cell so as to transduce the transferrin receptor into the tumor cell, but also can generate effective active oxygen under ultrasonic irradiation and promote generation of progeny viruses, so that the splitting efficiency of the oncolytic adenovirus on the tumor cell is obviously improved; the growth of in-situ melanoma can be obviously inhibited.

The application discloses an iridium complex sound sensitizer, a preparation method and application thereof, and belongs to the technical field of anti-tumor sound sensitizer drugs. The iridium complex sound sensitizer has two structures, which are named as Ir-1 and Ir-2 respectively, and the preparation methods of the iridium complex sound sensitizer with the two structures are provided. The preparation method is simple, raw materials are easy to obtain, and purification is convenient and easy to operate. Moreover, the prepared iridium complex sound sensitizer has excellent optical physical properties, exhibits good therapeutic effect in mouse breast tumors, effectively inhibits the growth of tumors, and has excellent sonodynamic therapy effect.

The application relates to a preparation method of a hybrid nanogel for strengthening tumor sonodynamic therapy, which adopts a hydrophilic polymer derivative to self-assemble and encapsulate an oxygen-deficient response drug in a manganese dioxide inorganic salt solution; the hydrophilic polymer derivative is obtained by modifying benzene boronic acid and a sonodynamic agent on a hydrophilic polymer material through a one-step method; the hydrophilic polymer material is selected from any one of starch, dextrin, hyaluronic acid, chitosan, dextran, gelatin or silk fibroin. The hydrophilic polymer derivative is constructed through one-step modification, and is self-assembled with manganese dioxide nano to form a hybrid nanogel, so that efficient sonodynamic therapy effect and inhibition of energy metabolism at a tumor site are realized; the oxygen-deficient response drug encapsulated by the nanogel can be specifically activated at an oxygen-deficient part of the tumor, so that a synergistic tumor sonodynamic therapy effect is realized.

The invention belongs to the technical field of biological medicines, and provides a sound-sensitive agent and lysosome targeted degradation polypeptide coupled drug-loaded nano preparation as well as a preparation method and application of the sound-sensitive agent and lysosome targeted degradation polypeptide coupled drug-loaded nano preparation. In the invention, the sonosensitizer contains an N-oxide structure, and energy circulation is changed due to intramolecular movement limitation during aggregation of molecules, so that enhanced fluorescence and ROS are generated, and the sonosensitizer is more suitable for sonodynamic therapy. The sonosensitizer can generate a large amount of active oxygen under the stimulation of ultrasonic waves, ROS is generated through targeted mitochondria, tumor ICD is efficiently activated, and the sonosensitizer is used for achieving PCa sound-immunotherapy.

This invention relates to ficolin-2, a serum biomarker for assessing carotid atherosclerotic plaques, and its applications, belonging to the field of biomedical technology. To address the urgent need for readily available and repeatable circulating biomarkers that reflect the unstable state of atherosclerotic plaques, particularly their hemorrhagic characteristics, this invention provides the application of ficolin-2 as a serum biomarker in the preparation of products for assessing the stability of atherosclerotic plaques and the prognosis of sonodynamic therapy for atherosclerosis. This invention is the first to use serum ficolin-2 protein as an efficacy monitoring indicator for SDT treatment of hemorrhagic carotid plaques, monitoring the level of complement activation-related inflammation within the plaque, enabling dynamic management of patient treatment, filling the gap in the quantification of efficacy in hemorrhagic plaque treatment, and providing a key tool for the clinical translation of emerging therapies such as sonodynamic therapy.