This disclosure relates generally to assessing non-labeled therapeutic agents as theranostic agents and more particularly to methods, systems and media for assessing the non-labeled therapeutic agents.
1. Field of Invention
The field of the currently claimed embodiments of this invention relates to systems and methods of using non-labeled antimetabolites and analogs thereof as theranostic agents.
2. Discussion of Related Art
Imaging drug delivery is of great clinical importance. Achieving effective anticancer drug therapy requires not only the effectiveness of an anticancer drug to act against a particular type of cancer cells, but also the delivery of the drug so as to exceed a threshold effective level of drug activity in the full anatomic extent of the cancer cell population. For instance, the heterogeneity in cancer architecture, especially in the vasculature anatomy and the related tissue barrier functions, also determines the success of the administered drug3,4, which are often unpredictable in an individual patient. It is essential to develop tools to assess whether drugs are delivered to the tumor at an adequate concentration in each individual patient and subsequently adjust the treatment plan accordingly, a so-called “personalized medicine” strategy5, in which non-invasive imaging modalities are believed to play a central role. Currently there is an extensive investment in the development of molecular imaging techniques that can stratify patients to select appropriate patients for treatment and to provide early proof of response6. As a result, for these drugs to advance to the clinic, the Food and Drug Administration (FDA) has provided its vision of the future in the form of the Critical Path Initiative, where molecular imaging will play a pivotal role in hastening drug development in early clinical trials and will also provide data critical for subsequent approval.
However, most currently available molecular imaging modalities rely heavily on the use of imaging tags, e.g., radioactive compounds for PET/SPECT and metallic compounds for MRI. In MRI, metallic agents are widely used to track the delivery of drug carriers such as Mn2+-based7 and Gd3+-based8 T1 agents and iron-based T2* agents9. Several challenges arise from the use of extra imaging tags. First, MRI detection relies on the signal of imaging agents, which do not necessarily reflect correct information (e.g. concentration and location) of the drug unless they are conjugated together. Second, the incorporation of extra imaging tags into the drug or drug delivery systems could potentially change the physico-chemical properties and affect the delivery. Moreover, there are various regulatory, financial, and practical barriers that prevent the imaging agents that have been developed pre-clinically from being translated quickly to the clinic to play an important role in accelerating clinical trials of new therapeutics. All these led us to explore a totally new “label-free” approach.
While some label-free imaging techniques have been developed directly based on the inherent signal of drugs, for example, the inherent fluorescence signal of doxorubicin10 or the inherent fluorine NMR signal of 5-fluorouracil (5-FU)11, an approach suitable for a broad array of drugs is still lacking Therefore, there remains a need for improved systems and methods using label-free imaging techniques.
A method of planning, guiding and/or monitoring a therapeutic procedure can include: receiving a non-labeled therapeutic agent by a subject, the non-labeled therapeutic agent comprising at least one type of water-exchangeable proton that is exchangeable with protons in surrounding water molecules so as to enhance detection by a chemical exchange saturation transfer (CEST) process; acquiring a plurality of CEST magnetic resonance images of the non-labeled therapeutic agent within a region of interest of the subject for a corresponding plurality of times; and assessing at least one of a therapeutic plan or therapeutic effect of the non-labeled therapeutic agent in tissue of the subject based on the plurality of magnetic resonance images.
A non-transitory, computer-readable storage medium for planning, guiding and/or monitoring a therapeutic procedure can include computer-executable instructions that, when executed by a computer, cause the computer to perform: acquiring a plurality of chemical exchange saturation transfer (CEST) magnetic resonance images of a non-labeled therapeutic agent that has been received by a subject, wherein the acquiring step acquires the plurality of magnetic resonance images within a region of interest of the subject for a corresponding plurality of times, the non-labeled therapeutic agent comprising at least one type of water-exchangeable proton that is exchangeable with protons in surrounding water molecules so as to enhance detection by a CEST process; and assessing at least one of a therapeutic plan or therapeutic effect of the non-labeled therapeutic agent in tissue of the subject based on the plurality of magnetic resonance images.
A system for planning, guiding and/or monitoring a therapeutic procedure can include: a data processing system; and a display system configured to communicate with the data processing system, where the data processing system comprises non-transitory, computer-executable instructions that, when executed by the data processing system, causes the data processing system to perform: acquiring a plurality of chemical exchange saturation transfer (CEST) magnetic resonance images of a non-labeled therapeutic agent that has been received by a subject, wherein the acquiring step acquires the plurality of magnetic resonance images within a region of interest of the subject for a corresponding plurality of times, the non-labeled therapeutic agent comprising at least one type of water-exchangeable proton that is exchangeable with protons in surrounding water molecules so as to enhance detection by a CEST process; and assessing at least one of a therapeutic plan or therapeutic effect of the non-labeled therapeutic agent in tissue of the subject based on the plurality of magnetic resonance images.
These and other features and advantages will be apparent from a reading of the following detailed description and a review of the associated drawings. It is to be understood that both the foregoing general description and the following detailed description are explanatory only and are not restrictive of aspects as claimed.
Some embodiments of the current invention are discussed in detail below. In describing embodiments, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. A person skilled in the relevant art will recognize that other equivalent components can be employed and other methods developed without departing from the broad concepts of the current invention. All references cited anywhere in this specification, including the Background and Detailed Description sections, are incorporated by reference as if each had been individually incorporated.
The phrase “non-labeled therapeutic agent” refers to a solution, a dispersion, a powder, a tablet or any other administrable form of composition that comprises molecules that are not radioactive, not paramagnetic, and do not contain non-abundant magnetically enriched isotopes. It can be, or can include, a drug in any administrable form, including, but not limited to, drugs in delivery vehicles, such as nanoparticles. It can include anti-cancer drugs, a drug analog and/or a drug modulator.
The term “computer” is intended to have a broad meaning that may be used in computing devices such as, e.g., but not limited to, standalone or client or server devices. The computer may be, e.g., (but not limited to) a personal computer (PC) system running an operating system such as, e.g., (but not limited to) MICROSOFT® WINDOWS® NT/98/2000/XP/Vista/Windows 7/8/etc. available from MICROSOFT® Corporation of Redmond, Wash., U.S.A. or an Apple computer executing MAC® OS from Apple® of Cupertino, Calif., U.S.A. However, the invention is not limited to these platforms. Instead, the invention may be implemented on any appropriate computer system running any appropriate operating system. In one illustrative embodiment, the present invention may be implemented on a computer system operating as discussed herein. The computer system may include, e.g., but is not limited to, a main memory, random access memory (RAM), and a secondary memory, etc. Main memory, random access memory (RAM), and a secondary memory, etc., may be a computer-readable medium that may be configured to store instructions configured to implement one or more embodiments and may comprise a random-access memory (RAM) that may include RAM devices, such as Dynamic RAM (DRAM) devices, flash memory devices, Static RAM (SRAM) devices, etc.
The secondary memory may include, for example, (but is not limited to) a hard disk drive and/or a removable storage drive, representing a floppy diskette drive, a magnetic tape drive, an optical disk drive, a compact disk drive CD-ROM, flash memory, etc. The removable storage drive may, e.g., but is not limited to, read from and/or write to a removable storage unit in a well-known manner. The removable storage unit, also called a program storage device or a computer program product, may represent, e.g., but is not limited to, a floppy disk, magnetic tape, optical disk, compact disk, etc. which may be read from and written to the removable storage drive. As will be appreciated, the removable storage unit may include a computer usable storage medium having stored therein computer software and/or data.
In alternative illustrative embodiments, the secondary memory may include other similar devices for allowing computer programs or other instructions to be loaded into the computer system. Such devices may include, for example, a removable storage unit and an interface. Examples of such may include a program cartridge and cartridge interface (such as, e.g., but not limited to, those found in video game devices), a removable memory chip (such as, e.g., but not limited to, an erasable programmable read only memory (EPROM), or programmable read only memory (PROM) and associated socket, and other removable storage units and interfaces, which may allow software and data to be transferred from the removable storage unit to the computer system.
The computer may also include an input device may include any mechanism or combination of mechanisms that may permit information to be input into the computer system from, e.g., a user. The input device may include logic configured to receive information for the computer system from, e.g. a user. Examples of the input device may include, e.g., but not limited to, a mouse, pen-based pointing device, or other pointing device such as a digitizer, a touch sensitive display device, and/or a keyboard or other data entry device (none of which are labeled). Other input devices may include, e.g., but not limited to, a biometric input device, a video source, an audio source, a microphone, a web cam, a video camera, and/or other camera. The input device may communicate with a processor either wired or wirelessly.
The computer may also include output devices which may include any mechanism or combination of mechanisms that may output information from a computer system. An output device may include logic configured to output information from the computer system. Embodiments of output device may include, e.g., but not limited to, display, and display interface, including displays, printers, speakers, cathode ray tubes (CRTs), plasma displays, light-emitting diode (LED) displays, liquid crystal displays (LCDs), printers, vacuum florescent displays (VFDs), surface-conduction electron-emitter displays (SEDs), field emission displays (FEDs), etc. The computer may include input/output (I/O) devices such as, e.g., (but not limited to) communications interface, cable and communications path, etc. These devices may include, e.g., but are not limited to, a network interface card, and/or modems. The output device may communicate with processor either wired or wirelessly. A communications interface may allow software and data to be transferred between the computer system and external devices.
The term “data processor” is intended to have a broad meaning that includes one or more processors, such as, e.g., but not limited to, that are connected to a communication infrastructure (e.g., but not limited to, a communications bus, cross-over bar, interconnect, or network, etc.). The term data processor may include any type of processor, microprocessor and/or processing logic that may interpret and execute instructions (e.g., for example, a field programmable gate array (FPGA)). The data processor may comprise a single device (e.g., for example, a single core) and/or a group of devices (e.g., multi-core). The data processor may include logic configured to execute computer-executable instructions configured to implement one or more embodiments. The instructions may reside in main memory or secondary memory. The data processor may also include multiple independent cores, such as a dual-core processor or a multi-core processor. The data processors may also include one or more graphics processing units (GPU) which may be in the form of a dedicated graphics card, an integrated graphics solution, and/or a hybrid graphics solution. Various illustrative software embodiments may be described in terms of this illustrative computer system. After reading this description, it will become apparent to a person skilled in the relevant art(s) how to implement the invention using other computer systems and/or architectures.
The term “data storage device” is intended to have a broad meaning that includes removable storage drive, a hard disk installed in hard disk drive, flash memories, removable discs, non-removable discs, etc. In addition, it should be noted that various electromagnetic radiation, such as wireless communication, electrical communication carried over an electrically conductive wire (e.g., but not limited to twisted pair, CAT5, etc.) or an optical medium (e.g., but not limited to, optical fiber) and the like may be encoded to carry computer-executable instructions and/or computer data that embodiments of the invention on e.g., a communication network. These computer program products may provide software to the computer system. It should be noted that a computer-readable medium that comprises computer-executable instructions for execution in a processor may be configured to store various embodiments of the present invention.
Some embodiments of the current invention are directed to the use of the MRI signal carried on the drug molecules for non-invasively detecting and quantifying the administered drugs using chemical exchange saturation transfer (CEST) MRI. Our approach allows transforming of currently available drugs, drug analogs and drug delivery systems, including those already in the clinic and those still under pre-clinical development, to be theranostic agents, without any radioactive-, paramagnetic- or super-paramagnetic-based labeling. This approach can allow the MRI monitoring of the drug delivery, assessment of the drug resistance, predicting of drug penetration to tumor stroma, and stratification of patients in clinical trials and clinical practices. This technology may be used as, but is not limited to, a clinical imaging package for stratifying patient before and/or during chemotherapy to select patients with the appropriate treatment plan.
Some embodiments are directed to the use of the MRI signal carried on the molecules of antimetabolites for non-invasively detecting and quantifying the administered anticancer drugs using chemical exchange saturation transfer (CEST) MRI. An approach can allow transforming of three categories of currently available metabolites (purine-, pyrimidine- and folate-based) and their analogs, as well as drug delivery systems containing these agents (including those already in the clinic and those still under pre-clinical development) to be theranostic agents, without any radioactive-, paramagnetic- or super-paramagnetic-based labeling. This approach can allow the MRI monitoring of the drug delivery, assessment of the drug resistance, predicting of drug penetration to tumor stroma, and stratification of patients in clinical trials and clinical practices. This technology can be used as, but is not limited to, a clinical imaging package for stratifying patient before and/or during chemotherapy to select patients with the appropriate treatment plan.
Papers related to background and conventional methodologies are provided below. MRI pulse sequences that can be used for the data acquisition, as the chemical exchange saturation transfer (CEST) technologies have been patented before (see below B1-B3). Some embodiments of the current invention are directed to the new clinical indication of drugs and drug analogs as theranostic agents, and the MRI detection together with extents for processing and displaying the data.
B1: Balaban; Robert S. (Bethesda, Md.), Ward; Kathleen M. (Arlington, Va.), Aletras; Anthony H. (Rockville, Md.); U.S. Pat. No. 6,963,769; PCT/US00/10878, published Nov. 8, 2005.
B2: van Zijl, Peter (Ellicott City, Md.), Jones, Craig (Ilderton, Canada), U.S. Pat. No. 7,683,617; PCT/US2006/028314, Mar. 23, 2010.
B3: van Zijl, Peter (Ellicott City); Kim, Mina and Gillen, Joseph. Frequency Referencing Method for Chemical Exchange Saturation Transfer (CEST) MRI; JHU disclosure C10151, 2007.
A specific MRI technology that can be used according to some embodiments to accomplish a goal is called Chemical Exchange Saturation Transfer (CEST)12. According to an embodiment, a method of planning, guiding and/or monitoring a therapeutic procedure is disclosed. While various embodiments of this method are disclosed as a method throughout this section, it is to be understood that a non-transitory, computer readable medium or a data processing system can include instructions that when executed by at least one computer or data processing system cause a computer or data processing system to perform analogous steps to the method embodiment. One embodiment can include receiving a non-labeled therapeutic agent by a subject. The term “receive” is intended to be broadly defined to encompass dispersing, administering, dispensing, applying, delivering, distributing, infusing and/or supplying the therapeutic agent into the subject. The non-labeled therapeutic agent can include at least one type of water-exchangeable proton that is exchangeable with protons in surrounding water molecules so as to enhance detection by a chemical exchange saturation transfer (CEST) process. The non-labeled therapeutic agent can be at least one of a drug, a drug analog, or a drug modulator. The non-labeled therapeutic agent can be an anticancer drug. The non-labeled therapeutic agent can be a drug delivery system. In this embodiment, the drug delivery system can be a nanoparticle drug delivery system. Thus, a subject can receive a non-labeled therapeutic agent.
As illustrated in
One embodiment can include acquiring a plurality of CEST magnetic resonance images of the non-labeled therapeutic agent within a region of interest of the subject for a corresponding plurality of times. In an embodiment, computer readable media can include instructions that, when executed, cause a computer to perform acquiring a plurality of CEST magnetic resonance images of a non-labeled therapeutic agent that has been received by a subject. In this embodiment, the acquiring step can acquire the plurality of magnetic resonance images within a region of interest of the subject for a corresponding plurality of times. The non-labeled therapeutic agent can include at least one type of water-exchangeable proton that is exchangeable with protons in surrounding water molecules so as to enhance detection by a CEST process.
As is shown in
Elements (a)-(d) of
Our approach is distinctive from most conventional molecular imaging techniques because it is “label-free” and directly exploits the signal originating from the drugs themselves. Unlike techniques that rely on the use of imaging agents, our approach can directly detect the effective dose of the administered drugs in each sub-region of tumors, providing direct information of the spatial distribution and temporal dynamic of the drugs, enabling personalized chemotherapy. More importantly, if drugs are detected without extra labeling, we will be able to directly transform currently available drugs into “imageable drugs” and the clinical translation of them will have minimal if any barriers. Consequently, our approach can promote a shift of the clinical evaluation of drug effectiveness from delayed endpoints (often months) to early time points (hours and days).
One embodiment can also include assessing at least one of a therapeutic plan or therapeutic effect of the non-labeled therapeutic agent in tissue of the subject based on the plurality of magnetic resonance images. For example, in one embodiment, the CEST magnetic resonance images can indicate a spatial distribution of the non-labeled therapeutic agent in the tissue. And the at least one of a therapeutic plan or therapeutic effect can be based on an assessment of the spatial distribution of the non-labeled therapeutic agent in the tissue. Further, the CEST magnetic resonance images can indicate an effective concentration of the non-labeled therapeutic agent in the tissue. And the at least one of a therapeutic plan or therapeutic effect can be based on an assessment of the effective concentration.
If drugs are directly MRI-visible, the cost (i.e., time and money) of clinical trials can be significantly reduced because the use of additional imaging agents can be, if not completely eliminated, minimized. The efficacy of an anticancer drug could be elevated only among patients who have shown effective tumor uptake of the drug, so-called stratification. And if a drug fails, it will be easy to know whether it is due to the insufficient toxicity of the drug against cancer cells, or due to the ineffectiveness of delivery. As such, the success rate of phase I trials (safety studies) can be increased because the evaluation will be carried out only on cancer patients who show effective drug accumulation and penetration. For the same reason, the success rates of phase II/III trials will also be increased and the duration will be decreased.
In addition to providing information directly about drug delivery, drugCEST can also be used according to some embodiments of the current invention to predict drug resistance by assessing the activity of certain enzymes directly related to drug resistance. Thus, one embodiment can further include acquiring a plurality of CEST magnetic resonance images of enzymes linked to the non-labeled therapeutic agent. This embodiment can further in include assessing activity of the enzymes based on the plurality of magnetic resonance images. This embodiment can further include predicting resistance to the non-labeled therapeutic agent based on the activity of the enzymes. For example, two enzymes, cytidine deaminase (CDA) and deoxycytidine kinase (dCk), have been reported to be highly related to the drug resistance of cancer cells to gemcitabine13. CDA catalyzes the removal of the amino group (deamination) from gemcitabine, and thus, deactivates the drugs14. Conversely, dCk is essential for the action of gemcitabine by phosphorylating the drug from the prodrug form into its active form15. We have established a CEST MRI technique platform in previous studies for assessing the activity of enzyme such as cytosine deaminase16, protein kinase17 and thymidine kinase18, the entire contents of which are incorporated herein by reference. It therefore is possible to use CEST MRI to detect CDA by observing the subsequent decrease in drugCEST, and to detect dCk by assessing the enhanced retention of drugCEST in tumor (the phosphorylation may not change the amino CEST signal as evidenced by our previous studies and the CEST signal of the phosphorylated form of fludarabine listed in Table 1). Consequently, drugCEST MRI can also be used to detect the enzyme activity that is highly related to drug resistance simply by using the drug (e.g., gemcitabine) as the imaging probe, which is also of important clinical significance.
Directly visualizing and quantifying drugs with MRI can also accelerate the pre-clinical development and clinical use of new strategies aiming at improving the targeted drug delivery. For example, it has been of vast research interest to develop nano-sized drug carriers to improve the therapeutic index and to reduce the systemic toxicity of small chemotherapeutic agents. However, while there are more than ten nanoparticulate anticancer therapeutics on the market19-21, the overall improvement in the survival rate remains modest22-26. It is now accepted that the enhanced permeability and retention (EPR) effect, which has been believed to be the key mechanism for passive targeting of tumor by macromolecular drug carriers, is often overrated27. This formidable hurdle, however, can be at least partially overcome by using drugCEST MRI technology to pre-screen patients to determine which individuals might benefit from nanoparticulate therapeutics. In addition, there is an ongoing interest in optimizing the surface physical properties of nanoparticles, developing active targeting, or adding moieties on the surface of nanoparticles for cell internalization or stimulus response. The proposed drugCEST technology can directly monitor drug delivery and subsequent release, providing information for the rationale evolution/optimization of the nanoparticles. Unlike the radioactive labeling methods (18F or 14C), drugCEST MRI can be performed repetitively in an extended time window. Compared to the approaches based on additional labeling, information provided by drugCEST MRI is directly from the drugs and thus more accurate.
Recently, there is a growing interest to develop interventions that can significantly improve the therapeutic index either by selectively increasing the tumor vascular permeability or by normalizing the extracellular matrix to reduce the interstitial fluid pressure (IFP)20. For instance, evidence from a number of recent studies28,29,30 revealed that co-injection of the pro-inflammatory cytokine Tumor Necrosis Factor-α (TNF-α) can greatly improve the tumor-selective accumulation of liposomal drugs by augmenting the enhanced permeability and retention (EPR) effect. Unlike the approaches based on macromolecular agents, drugCEST is able to provide direct and dynamic information about the penetration of drugs as the consequence of a treatment that targets to improve the therapeutic index. In addition, drugCEST MRI is also able to measure pH, which can indirectly reveal the location of the administered drugs as pH correlates well with the pathology of tumors. For example, when drugs remain in capillaries, they are surrounded by blood with a narrow pH range of 7.35 to 7.45 and, in contrast, if they penetrate to the poorly perfused regions of tumor, they will likely have a pH range of 6.0-6.5. In the previous studies, we have established a concentration-independent approach for accurately determining pH simply by calculating the ratio of CEST signals from two different types of exchangeable protons on the same molecule31-33, the entire contents of which are incorporated herein by reference. As many drugs have multiple types of exchangeable protons, it is, therefore, possible to use drugCEST—in addition to assessing drug concentration—to measure the pH where drugs are located.
Collectively, the successful establishment of a highly MRI-based technology to directly and noninvasively image drugs according to some embodiments of the current invention may immensely benefit the clinical treatment of cancer and the preclinical development of new drugs and nanoparticulate therapeutics. Some potential roles of drugCEST MRI according to some embodiments of the current invention are illustrated in
Some aspects of the current invention are directed to the following:
We have discovered that 5-fluorocytosine 5-FC, an antifungal drug and also a prodrug (compounds that can be converted to effective drugs) for cancer gene therapy, has a strong CEST signal, allowing us to detect the presence and metabolism of the drug without the use of imaging agent9. To the best of our knowledge, this is the first demonstration of label-free detecting of a drug directly by its CEST contrast. Other drugs, including prodrugs and drug modulators, as well as the drug carriers, are intended to be included within the general scope of this invention. Many of them have exchangeable protons such as OH, NH and NH2 (
In principle, drugCEST can be directly applicable to drugs that are being used at a relatively high dose in patients. For instance, in the regime of high-dose Cytarabine (araC) therapy for leukemia, it was reported that no noticeable cerebellar toxicity was found among patients who received repetitive infusions of araC (single dose, 3 g/m2 over three hours) for up to eight doses (total dose, 24 to 30 g/m2)47. As a reference, a single dose of 3 g/m2 corresponds to 80 mg/kg and 1000 mg/kg in humans and in mice respectively, using a body weight of 60 and 0.02 kg and a body surface area of 1.6 and 0.007 m2 respectively48. Another widely used anticancer drug gemcitabine has a clinically suggested dose of 1000 mg/m2 for treating of a variety of cancer types (equivalent mouse dose=333 mg/kg). In fact, it was reported that a single dose of 800 mg/kg (i.p.) could result in an accumulation of gemcitabine up to several mM in experimental murine hepatomas, allowing the detection the drug using 19F MR spectroscopic imaging (MRSI)49. As aforementioned, the CEST MRI generates a huge amplification of the NMR signal of a small agent, and thus, in principle, possesses a higher detectability than 1H spectroscopic and 19F MR spectroscopic methods. Based on the literature and our preliminary in vitro result (
Elements (a)-(c) of
We also examined the possibility the use of nontoxic drug analogs as predictive markers for the corresponding drugs in the case that drugs cannot accumulate in the tumor at a sufficient concentration. Most anti-metabolic drugs are derived from natural metabolites. These non-toxic drug analogs have similar chemical structures with the corresponding drugs, and thus similar CEST signals, and, very often, similar pharmacokinetics and pharmacodynamics. Therefore we can use non-toxic drug analogs as the predictive markers of the delivery and metabolism of the corresponding drugs. As such, the chemotherapy can be “rehearsed” using non-toxic drug analog. Patients can be stratified and only those whose tumors are accessible by the drugs can be selected to receive the actual treatment. The advantage of using drug analogs is the possibility to use high dose administration without introducing severe adverse effects, as is the case with the drugs. Our results (Table 2) have shown the drugCEST of the representative drug analog in each category. This alternative can warrant the detectability of drugCEST even drugs cannot be directly used.
Some embodiments of the current invention can also be used to reveal the location of delivered drugs by remote sensing of pH. That is, one embodiment can include determining a pH of the region of interest based on a CEST signal of the CEST magnetic resonance images of the non-labeled therapeutic agent. The CEST signal can indicate penetration of the therapeutic agent in the region of interest. As is well-documented, pH affects the exchange rate dramatically, and consequently influences the CEST effect substantially26,27. If a CEST agent possesses two or more types of exchangeable protons, and if their pH dependencies are different, pH can be estimated by the ratio of their CEST signals28-30. Luckily, many drugs have multiple types of exchangeable protons, thus allowing us to measure the pH of where drugs are located. Because pH correlates well to the physiology and pathology of tumor (Element (a) of
Element (a) of
2. In Vivo Animal Studies
According to an embodiment of the current invention, when drugs fail to generate detectable drugCEST due to low concentration, we can also use nanocarriers such as liposomes to push the detection limit. As we and others have demonstrated38,51-53, encapsulating CEST agents into liposomes could markedly improve the detection limit from mM(per molecule) to nM (per particle)38, and has enabled applications in experimental animal models54. Some examples (
Element (a) of
Element (a) of
Element (a) of
41. Li, W., Zhang, Z., Nicolai, J., Yang, G. Y., Omary, R. A. & Larson, A. C. Magnetization transfer mri in pancreatic cancer xenograft models. Magn. Reson. Med. 68, 1291-1297 (2012).
The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art how to make and use the invention. In describing embodiments of the invention, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. The above-described embodiments of the invention may be modified or varied, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.
This application claims priority to U.S. Provisional Patent Application No. 61/949,044, filed Mar. 6, 2014, which is hereby incorporated herein by reference in its entirety.
This invention was made with Government support of Grant No. R21EB015609 awarded by the Department of Health and Human Services, The National Institutes of Health (NIH). The U.S. Government has certain rights in this invention.
Filing Document | Filing Date | Country | Kind |
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PCT/US15/19291 | 3/6/2015 | WO | 00 |
Number | Date | Country | |
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61949044 | Mar 2014 | US |