Methods for localizing cancerous tissue using fluorescent molecular imaging agents for diagnosis or therapy - Patents.com

Abstract

A method is provided that includes navigating an instrument into a patient to which a molecular imaging agent has been administered intravenously via a minimally invasive route (e.g., an intraluminal procedure) to position the instrument in a region of tissue abnormality, and visualizing tissue in the region under near-infrared (NIR) light via the instrument, where the molecular imaging agent, upon administration, causes abnormal tissue in the region to fluoresce under the NIR light, allowing the fluorescing abnormal tissue to be localized within the region. The method may further include diagnosing and / or treating the fluorescing abnormal tissue.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 306,019, filed February 2, 2022, which is incorporated herein by reference. [Background technology]

[0002] Lung cancer is the leading cause of cancer deaths and the second most commonly diagnosed cancer in the United States and worldwide. Lung cancer diagnoses are expected to increase as the US Preventative Services Task Force revised its lung cancer screening guidelines in early 2021, thereby nearly doubling the number of people recommended to undergo regular screening for lung cancer. Today, most lung cancers are found at later stages when treatment options are limited, but advances in lung cancer technology and clinical practice have increased awareness of the disease and are expected to facilitate a stage shift in lung cancer. Because lung cancer is surgically treatable if detected early, stage shifting is expected to have a dramatic and positive impact on lung cancer outcomes and also increase the number of surgically eligible patients.

[0003] Historically, lung biopsies and resections have been performed using open thoracotomy, but these procedures are becoming less common. Minimally invasive approaches to both biopsy and resection are becoming the standard of care across all surgical disciplines, with minimally invasive surgery (MIS) reducing the risk of complications and trauma to the patient's body, thereby shortening recovery time. When performing these MIS procedures, including video-assisted thoracoscopic surgery (VATS), robotic surgery, or robot-assisted thoracoscopic surgery (RATS), the surgeon may not be able to rely on palpation to help identify neoplastic lung tissue, as the holes used in these minimally invasive procedures may not be large enough for the surgeon to easily get their hands or fingers into the patient's body. Instead, the surgeon may need to rely more heavily on information gathered from preoperative scans while attempting to find the tumor using a small camera placed in the thoracic cavity or bronchial passages.

[0004] Lung imaging, such as chest CT (Computed Tomography) and X-rays, can identify lung nodules and are used, along with other patient information, to determine appropriate follow-up steps. For nodules that require treatment, physicians utilize several techniques to confirm whether the nodules are malignant or benign. When diagnosing lung cancer, physicians identify potentially cancerous tumors by traditional screening and imaging techniques, such as CT, Positron Emission Tomography (PET) / CT, Cone Beam CT, Magnetic Resonance Imaging (MRI), X-ray, Fluoroscopy, and Ultrasound, among others. Although these non-invasive imaging techniques have improved significantly in recent years, they are still not completely effective in identifying and locating all potential lesions, nodules, tumors, or masses, whether benign or malignant. Furthermore, at best, these scans can only identify whether a patient has a nodule or tumor, but cannot provide information on whether the tumor is cancerous. A biopsy is required to confirm that a tumor is cancerous. Although the lesions may be benign, it remains important to obtain a definitive diagnosis through both biopsy of the lesion and staging of the lymph nodes. Lung cancer treatment is more successful when it is detected and treated early, so prompt and accurate evaluation of lesions requiring follow-up is important.

[0005] As used herein, the term "lesion" is used as a shorthand to refer broadly to any lesion, nodule, tumor, or mass, either benign or malignant, that a physician may wish to localize, unless a specific one of these is explicitly indicated. Thus, the terms "lesion," "nodule," and "tumor" may be used interchangeably, unless the context conveys that a particular term is intended.

[0006] Biopsies are usually performed endoscopically or transthoracically by an interventional pulmonologist, thoracic surgeon, or interventional radiologist. Surgical wedge resections are also performed by thoracic surgeons when lung cancer is highly likely and / or when a lesion is highly suspicious for cancer, but a definitive diagnosis could not be reached by other methods. Lung cancer nodal staging is typically performed by interventional pulmonologists using linear endobronchial ultrasound (EBUS), but may also be performed by thoracic surgeons performing surgical mediastinoscopy. EBUS has been widely adopted for staging and holds a top position in clinical guidelines, but there is growing evidence that many patients are misstaged due to clinician error, lack of adequate tissue, or simply too long a time between procedure and surgery.

[0007] Despite many advances in biopsy and staging techniques, from blood biomarker testing and pathology techniques, the average time from abnormality detection or first symptoms to treatment for lung cancer ranges from 3 to 6 months in the United States and worldwide. Challenges in continuity of patient care remain a top priority area in many hospitals, but making a diagnosis with confidence remains challenging for clinicians. Advanced bronchoscopy systems such as the Medtronic superDimension™ System and ILLUMISITE™ Platform, Olympus Veran SPiN System™, Bodyvision Lung Vision, Intuitive Ion™, Johnson and Johnson Auris Monarch™ Platform, Noah Medical Galaxy System™, and Bronchus Archimedes™ Systems all seek to improve biopsy by allowing minimally invasive access to all parts of the lung for tissue collection.

[0008] Although these systems provide great advances, biopsy remains challenging. Localization of nodules using these approaches or in combination with potential techniques such as fluoroscopy, cone-beam computed tomography (CBCT), radial endobronchial ultrasound (REBUS) and / or confocal laser endoscopy is difficult. Many techniques use pre-procedure CT and virtual lesion positioning, making real-time confirmation and localization difficult. Working channels can also be small, which may cause the biopsy tool to only take a small portion of tissue making traditional pathology requirements and approaches difficult.

[0009] Furthermore, even when a nodule is reliably found, only a portion of the nodule may be malignant. As a result, physicians use multiple techniques and biopsy tools to obtain as much tissue as possible from around the area of ​​interest to maximize the chances of obtaining a definitive answer. Some physicians bring a cytotechnologist into the operating room to further evaluate the tissue for adequacy through rapid on-site cytology (ROSE). Others are investing in digital pathology systems used at the bedside with the goal of improving diagnostic yields and reducing surgical time. Although diagnostic yields from advanced bronchoscopy continue to improve, a critical need in identifying, localizing, and confirming diagnoses within the procedure remains unmet.

[0010] Diagnosis and staging of lung cancer involves confirming that the patient has cancer and, if surgically eligible as determined by the stage of the disease and patient condition, following surgical resection. Pre-operative scans can provide surgeons with the relative location of nodules within the lungs, but these images do not translate well to what the surgeon will see during the actual procedure. For example, pre-operative scans are performed while the patient's lungs are fully inflated, whereas at surgery the lungs are deflated. As a result, even the most experienced surgeons can have difficulty spotting suspicious tumors during these procedures, caused by the relatively small size (less than 2 cm) of many operable lung nodules, the continuous movement and flexibility of lung tissue, and the variability in the appearance of tumors and healthy lung tissue.

[0011] These procedures therefore present a unique set of challenges to the surgeon, especially when operating on tumors that are particularly small or difficult to find. As a result, surgeons may convert to or begin with more complex and aggressive open procedures to ensure that they can find and remove the entire tumor. These procedures are significantly more expensive and often increase recovery time. However, these drawbacks are far preferable to a "futile" or unsuccessful surgery in which the surgeon is unable to find or completely remove the tumor.

[0012] Especially for early-stage disease, many surgeons prefer tissue-sparing resections to preserve lung function and allow possible repeat resections in patients with synchronous or metachronous disease. Lung-sparing surgery is also the mainstay of treatment for multifocal lung cancer, especially in patients with limited pulmonary reserve. Failure to localize pulmonary nodules during VATS is the most common reason for conversion to full thoracotomy. The inability to identify nodules for resection increases significantly when nodules are smaller than 10 mm or located more than 5 mm away from the pleural surface. Furthermore, during robotic-assisted surgery, no incision is made to allow direct palpation. Various preoperative localization techniques have been developed to aid in intraoperative nodule identification during VATS and robotic-assisted surgery. These localization techniques are intended to mark nodules for guidance in resection and provide some evidence of tumor margins after resection.

[0013] Some surgeons will opt for a complex preoperative marking procedure if they think the tumor is difficult to find or if the tumor is not necessarily confined to a predictable area of ​​the lung. This preoperative marking procedure consists of placing fiducial markers (such as small metal coils or similar objects) near the site of the tumor, either bronchoscopically by an interventional pulmonologist or percutaneously by an interventional radiologist, or by applying radioactive dyes ( 99m3Tc). Another approach is the placement of a transthoracic hook wire by an interventional radiologist. In some cases, the surgeon may perform the entire preoperative marking and surgical procedure. Of these methods, percutaneous injection appears to provide more accurate results but requires a hybrid operating room equipped with a CT scanner or another interventional radiology procedure prior to surgery.

[0014] In yet another alternative procedure, the surgeon can map the preoperative scan to the chest anatomy and bronchoscopically mark the vicinity of the tumor with indocyanine green (ICG), methylene blue, or omnipaque. This procedure can be performed with advanced bronchoscopic systems such as the Medtronic superDimension™ System and ILLUMISITE™ Platform, Olympus Veran SPiN System™, Bodyvision Lung Vision, Intuitive Ion™, Johnson and Johnson Auris Monarch™ Platform, Noah Medical Galaxy System™, Bronchus Archimedes™, or with conventional or low-profile bronchoscopes. These procedures can provide the surgeon with strong visual guidance, but there is also a risk that any dye will not be placed precisely on the nodule or that the dye will spread throughout the patient's tissues, compromising the purpose of the procedure.

[0015] To improve the accuracy of dye placement, surgeons may also utilize fixed or mobile CBCT imaging systems, such as those manufactured by Philips, Siemens, GE, and Ziehm, which attempt to provide real-time navigation guidance by taking CT images to track the head of the endoscope with respect to the location of the nodule. These systems are particularly disadvantageous because of the repeated radiation exposure of the patient, physician, and procedure staff, in addition to the fact that CBCT systems are very expensive and require special hybrid operating rooms to perform the procedure. Furthermore, the use of CBCT often significantly extends procedure times, resulting in longer anesthesia times and higher procedure costs. For example, most of these systems require staff to leave the procedure room during the CBCT spin, which can create workflow and procedural issues. Whether CBCT is performed in the same setting as the resection or separately, CBCT may increase the accuracy of preoperative markings at the expense of adding complexity, time, and cost to the procedure.

[0016] In most preoperative marking procedures, the patient requires a transfer between the interventional radiology or endoscopy suite and the operating room. In other cases, these can be done in a single procedure if the operating room has the appropriate staff and technology. In either case, the timing and coordination of preoperative marking is complex and requires additional planning, equipment, procedure staff, and time. When performing preoperative marking, the surgeon can later convert to a conventional thoracotomy if the surgeon is still unable to locate the tumor and perform an MIS resection.

[0017] While surgery is the gold standard for early operable patients, there has been great development in endoluminal therapies aimed at addressing the unmet clinical needs of those who cannot undergo surgery. Intraluminal therapies include energy (microwave, radiofrequency, cryotherapy, steam, pulsed electric field, and photodynamic therapy) and drugs (chemotherapy, viral, or immunotherapy) delivered to treat lesions locally. Local therapies can be delivered endoscopically, for example, by an interventional pulmonologist or thoracic surgeon through a bronchoscope or an expanded working channel, or percutaneously by an interventional radiologist. All advanced bronchoscopy systems are expected to broadly enable the delivery of local therapies by pulmonologists and thoracic surgeons in the future. Interventional radiologists may provide some of these non-surgical therapies, but many do not want to risk the complications associated with transthoracic pulmonary treatment and associated airway management.

[0018] Furthermore, some surgeons, such as those at local community hospitals, do not have the necessary technical or skilled personnel to perform these advanced marking procedures. Thus, these surgeons perform more aggressive resections or convert to thoracotomy if they are unable to identify the location or borders of the tumor. Because aggressive resections are not ideal as they may result in the removal of excessive amounts of healthy tissue, conversion to thoracotomy is generally preferred, but such thoracotomy procedures can still cause trauma and increase the patient's hospital stay and recovery time.

[0019] Thus, many challenges and unmet clinical needs remain in lesion localization, diagnosis, and treatment. Thus, there is a significant need for more reliable, real-time intraoperative visualization techniques to better assist surgeons and pulmonologists in localizing and differentiating neoplastic and healthy lung tissue when performing these procedures. Summary of the Invention

[0020] The present disclosure provides improved methods for localizing, diagnosing, and treating cancer, including but not limited to using minimally invasive surgical procedures.

[0021] In one aspect, a method is provided that includes navigating an instrument into a patient to which a molecular imaging agent has been administered intravenously via a minimally invasive route (e.g., an intraluminal procedure) to position the instrument in a region of tissue abnormality, and visualizing tissue within the region under near infrared (NIR) light via the instrument, where the molecular imaging agent, upon administration, causes abnormal tissue within the region to fluoresce under the NIR light, allowing the fluorescing abnormal tissue to be localized within the region. The method may further include diagnosing and / or treating the fluorescing abnormal tissue.

[0022] In another aspect, a method is provided that includes navigating an instrument in a patient to which VGT-309 (a specific molecular imaging agent defined below) has been administered intravenously via an intraluminal route to position the instrument in a target area, visualizing the target area under near-infrared (NIR) light via the instrument, and locating any cancerous tissue within the target area in real time by fluorescence of the cancerous tissue caused by VGT-309 under the NIR light.

[0023] These methods are particularly advantageous in the localization, diagnosis, and treatment of various cancers and solid tumors, For example, the methods can be used to endoscopically localize, diagnose, and treat lung cancer, as well as colorectal, gastric, and esophageal cancer. [Brief description of the drawings]

[0024] The detailed description is set forth with reference to the accompanying drawings. Use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may or may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0025] [Figure 1A] 1 shows a lesion (abnormal tissue) located outside the small airways of a patient (prior art). [Figure 1B] 1 shows a lesion (abnormal tissue) located outside the small airways of a patient (prior art). [Figure 1C] FIG. 1B illustrates the location of the lesion in FIG. 1A from an intra-airway perspective, showing that it cannot be visualized through the airway wall (prior art). [Figure 2A] 1 shows a lesion located outside the patient's peripheral airways that "lights up" following administration of a molecular imaging agent, according to one embodiment of the present disclosure. [Figure 2B] FIG. 2B is a close-up of the lesion of FIG. 2A according to one embodiment of the present disclosure. [Figure 2C] 2B illustrates visualization of the lesion of FIG. 2A from within the airway, according to one embodiment of the present disclosure. [Figure 2D] 1 shows visualization from within the airway of a lesion outside the small airways of a patient in which only a portion of the lesion "lights up" following administration of a molecular imaging agent, according to one embodiment of the present disclosure. [Figure 3A] 1 illustrates a method of biopsying a lesion (abnormal tissue) located outside a patient's peripheral airways following administration of a molecular imaging agent to illuminate the lesion, according to one embodiment of the present disclosure. [Figure 3B] 3B illustrates the method of FIG. 3A as viewed from within the airway, according to one embodiment of the present disclosure. [Figure 3C] 1 shows a method of visualization and biopsy of a lesion located outside a patient's peripheral airways, viewed from within the airways, where only a portion of the lesion "lights up" after administration of a molecular imaging agent to the patient, according to one embodiment of the present disclosure. [Figure 4A] FIG. 1 illustrates a method for visualizing and treating a lesion located outside a patient's peripheral airways following administration of a molecular imaging agent, in which the lesion is "lighted up" to guide a treatment instrument into / through the lesion, according to one embodiment of the present disclosure. [Figure 4B] 4B illustrates the method of FIG. 4A as viewed from within the airway, according to one embodiment of the present disclosure. [Figure 4C]Located outside a patient's peripheral airways and viewed from within the airways, a method of visualizing and treating a lesion is shown in which only a portion of the lesion "lights up" following administration of a molecular imaging agent to the patient, where a treatment instrument is directed to or passes through the "lighted up" portion of the lesion, according to one embodiment of the present disclosure. [Figure 5A] FIG. 1 is a diagram of tissue abnormalities commonly resulting from colorectal cancer. [Figure 5B] FIG. 1 is a diagram of tissue abnormalities commonly resulting from colorectal cancer. [Figure 5C] FIG. 1 is a diagram of tissue abnormalities commonly resulting from colorectal cancer. [Figure 5D] FIG. 1 is a diagram of tissue abnormalities commonly resulting from colorectal cancer.

[0026] As used throughout the figures, shading represents tissue that fluoresces when viewed under near-infrared (NIR) light after a molecular imaging agent has been administered to a patient as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Methods are described for using fluorescent molecular imaging agents, particularly near-infrared (NIR) fluorescent imaging agents, to localize tissue abnormalities in a patient in real time, particularly during medical procedures such as minimally invasive procedures, e.g., endoscopic procedures, for diagnosis and / or treatment, including, but not limited to, biopsy, resection or ablation of the localized tumor, or drug delivery to the localized tumor.

[0028] In some particular embodiments, the localization method includes (i) navigating an instrument through an intraluminal or other minimally invasive route into a patient to which a molecular imaging agent, such as VGT-309 (defined below), has been administered intravenously, to position the instrument in a target area, e.g., an area where a tissue abnormality is believed to be located, (ii) visualizing the target area under near-infrared (NIR) light through the instrument, and (iii) locating the abnormal tissue within the target area in real time by fluorescence of the abnormal tissue caused by the molecular imaging agent under the NIR light. The method typically further includes diagnosing and / or treating the localized tissue, which may involve further positioning a portion of the instrument within (or, if sufficient, near) the illuminated portion to undergo a biopsy or deliver a therapy. Advantageously, the fluorescing tissue provides a fixed visual reference point (like a North Star) for instrument guidance, particularly in endoluminal procedures where the distal tip of the instrument is advanced / steered based at least in part on the tissue landscape as seen from the distal tip of the instrument (as opposed to a virtual reference point used by navigation software, for example).

[0029] Instruments used in this method include conventional scopes (e.g., endoscopes, bronchoscopes, thoracoscopes, laparoscopes, etc.) containing cameras and light sources, as well as catheters, biopsy needles, and other conventional tools for tissue sampling or diagnosis, and delivery of therapeutic agents and tools for ablation or localized treatment by any means known in the art.

[0030] NIR light is generally understood in the art to have a wavelength in the range of 700-900 nm. As used herein, references to "visualizing" tissue "under near-infrared (NIR) light" and causing tissue to "fluoresce under NIR light" refer to the process of directing NIR light (e.g., having a wavelength in the range of 770-810 nm) at the tissue and receiving / sensing the NIR radiation (e.g., having a wavelength in the range of 790-850 nm) produced in response. The received emissions are manipulated as known in the art to allow the physician to view the tissue's fluorescence through a scope deployed near the tissue. Advantages of using NIR light include (i) having effective tissue penetration (e.g., at least 5-10 mm), (ii) limited interference by biological tissues due to blood absorbing below 650 nm and water / lipids absorbing above 900 nm, and (iii) not producing significant autofluorescence. In a preferred embodiment of the described method, NIR light wavelengths are selected for optimal imaging using ICG or an ICG-containing molecular imaging agent.

[0031] These methods may be used to localize nodes as a standalone or combined modality in traditional biopsy and therapy performed via an endoluminal approach. These methods may be used to identify and localize hot spots of lesions, i.e., parts of a lesion that are cancerous, since not all lesions are cancerous in all cases. These methods may be used to identify lymph nodes, for example, prior to endobronchial ultrasound bronchoscopy, to confirm in conjunction with another diagnostic procedure. These methods may be used to evaluate or assess lymph nodes without tissue sampling. These methods may be used to facilitate biopsy, staging, and proper localized treatment of cancerous tissue within a single procedure. These localization methods may be used to facilitate rapid and accurate catheter placement at the lesion for localized therapy delivery and to enhance understanding of ablation treatment zones / node destruction. In various embodiments, these localization methods may replace or augment traditional approaches to confirm the presence of cancer cells, including, but not limited to, white light, fluoroscopy, CBCT, radial scanning endobronchial ultrasound (rEBUS).

[0032] One advantage of the methods of the present invention is that physicians can have greater confidence in the biopsy results because they have greater certainty that they are obtaining tissue from a fluorescing portion of the nodule. Physicians can share this additional evidence with patients and tumor boards to create greater confidence in the diagnostic results, which may shorten treatment times and / or reduce unnecessary additional procedures.

[0033] The diagnostic methods described herein may reduce the need for surgeons to rely on traditional rapid diagnostic methods such as frozen section pathology or rapid on-site cytology (ROSE).

[0034] As used herein, the term "patient" generally refers to a human, although the methods described herein can be applied to other mammals, for example, in preclinical animal models or veterinary applications.

[0035] The molecular imaging agent is one that covalently binds to a target molecule (such as a cathepsin, a type of protease) that is present at increased levels in solid tumors, tumor-associated macrophages (TAMs), and the tumor microenvironment. In certain embodiments, the molecular imaging agent includes indocyanine green (ICG) as a NIR dye and can be used with a variety of conventional, commercially available imaging systems. In some embodiments, the molecular imaging agent is a covalently activatable protease-targeted imaging molecule, such as those described in U.S. Pat. No. 10,100,037 to Bogyo et al., which is incorporated herein by reference. In some embodiments, the molecular imaging agent includes ICG as a fluorophore, such as those described in U.S. Pat. No. 10,869,936 to Bogyo et al., which is incorporated herein by reference.

[0036] In a preferred embodiment of the methods described herein, the molecular imaging agent is referred to herein as "VGT-309", which comprises: [ka] VGT-309 is an agonist, antagonist, or agonist for the treatment of tumors, including pharma- ceutically acceptable salts or formulation variants thereof.VGT-309 advantageously binds covalently to its targets and remains at the target site in a wide variety of tumor types.

[0037] In a preferred embodiment of the methods described herein, the molecular imaging agent is the sodium salt form of VGT-309.

[0038] In certain embodiments, these methods improve the efficacy of diagnostic procedures and surgical tumor resection and removal. Although the present disclosure describes applications in the localization, diagnosis, and treatment of lung cancer, those skilled in the art will recognize that these teachings can be applied to the diagnosis and treatment of other forms of cancer. For example, the disclosures herein can be applied to other cancers, particularly colorectal cancer, gastric cancer, and esophageal cancer.

[0039] In particular, VGT-309 targets cathepsins that are more abundant in solid tumors than in normal tissues. VGT-309 can be used in a variety of cancers, including brain, breast, colorectal, esophageal, gastric, liver, lung, melanoma, ovarian, pancreatic, prostate, and thyroid, where solid tumors have been shown to have cathepsins present at increased levels compared to normal tissues. Thus, the method can be applied to localize abnormal tissues in various locations in a patient's body.

[0040] In certain embodiments, VGT-309 may be administered to a human patient at a dosage of 0.01 mg / kg to 0.7 mg / kg, e.g., 0.016 mg / kg to 0.64 mg / kg. In some preferred embodiments, the dosage is 0.3 to 0.4 mg / kg, e.g., 0.32 mg / kg, administered 2 to 36 hours prior to a medical procedure involving NIR imaging of the patient's tissue as described herein. In some embodiments, the dosage is 0.16 mg / kg, 12 to 36 hours prior to the procedure. In some embodiments, the dosage is 0.32 mg / kg, 2 to 6 hours, or 12 to 36 hours prior to the procedure. In some embodiments, the dosage may be 0.32 to 0.52 mg / kg, e.g., 0.5 mg / kg, 2 to 48 hours prior to the procedure. In some other embodiments, the dosage may be up to 0.64 mg / kg, e.g., 2 to 48 hours prior to the procedure.

[0041] localization In recent years, there has been a shift to minimally invasive surgical procedures, which, unlike open chest surgery, are performed through several small holes, thus limiting the surgeon's view and / or touch. As used herein, "surgeon" refers to a physician who can perform any of the procedures described herein, such as a cardiothoracic surgeon, an oncological surgeon, or an interventional pulmonologist. During these procedures, surgeons are often concerned with their ability to find and localize known lesions, ensure adequate resection margins, and identify primary lesions, synchronous and metachronous lesions, and metastatic tumor spread that are not identified by preoperative scans.

[0042] There has also been a move to less invasive advanced bronchoscopic procedures for biopsy, which is limited by physician skill, system inaccuracies, lack of real-time visualization and localization of nodules, instrumentation and biopsy tool capabilities, and pathology. Surgeons performing these procedures are challenged by a lack of ability to localize known lesions, biopsy these lesions, and confidently confirm whether they are benign or malignant.

[0043] For example, physicians have limited information available to guide them during a biopsy. Some techniques use multiple CT or MRI scans and software to create a three-dimensional (3D) model 100, examples of which are shown in Figures 1A-1B. A physician can use such a model 100 to guide an endoscope down a tortuous airway 104 toward the general area where the physician believes the lesion 102 is located. While these models may provide the physician with enough information to navigate the biopsy tool to the general location of the lesion 102, the physician may struggle to precisely locate the lesion 102, especially since the physician performing the bronchoscopy may not be able to see the lesion (using visible light) when looking from within the airway 104, as the lesion 102 is often not located exactly on the outside or within the wall of the airway 104, as shown in Figure 1C. For example, the physician may be able to see the general outline of a tissue abnormality, but there is no way for the physician to be certain that this is even a lesion 102, let alone the specific lesion 102 the physician is trying to find.

[0044] However, the disclosed method utilizes a molecular imaging agent to "light up" abnormal tissue (nodule, mass, tumor) or a portion thereof (e.g., a heterogeneous lesion), allowing the physician to localize and align an instrument (e.g., a biopsy needle) and view it in real time and apply the instrument to the abnormal tissue. Abnormal tissue that lights up is more likely to be malignant (cancerous), while abnormal tissue that lights up may be benign. In either case, the lighting and localization of abnormal tissue is a beneficial outcome for the surgeon, as it may help the surgeon avoid conversion to an open surgery.

[0045] Molecular imaging agents have the potential to significantly improve patient outcomes when used during biopsy and surgical removal procedures, which are often MIS procedures. Surgeons rely solely on white light visualization or virtual navigation with various external imaging modalities to locate and identify tumors during these procedures. This can often be challenging given the limited field of view in the tight spaces of the body and the complexity of combining multiple modalities within a single procedure. Preoperative marking can assist surgeons in nodule localization and margin assessment, but is limited by inaccurate advanced bronchoscopy systems, dye spread throughout the lungs when dye is utilized, and operational, skill, and scheduling challenges in various hospital environments. Also, even during open thoracotomy, where palpation may be used to identify nodules, surgeons may struggle to find and identify these nodules if they are small or obscured by pulmonary anatomy. Thus, there is a significant need in the art for fluorescent molecules that target tumor cells or the surrounding extracellular matrix to help surgeons locate nodules identified on preoperative scans during both biopsy and procedures.

[0046] There are several molecular imaging agents currently in various stages of development and testing, of which VGT-309 is particularly advantageous. VGT-309 targets and covalently binds to cathepsin targets, which are more abundant in solid tumors and tumor margins than in normal tissues. When this binding occurs, the quencher is cleaved from the molecule and VGT-309 becomes "active," at which point the tumor fluoresces under near-infrared (NIR) light. Furthermore, based on preclinical studies, the covalent binding creates a wide therapeutic window, such that VGT-309 can fluoresce cancerous tissue anywhere from 2 hours to 4 days after VGT-309 is administered. (Animal model studies also suggest that it may be possible for VGT-309 to continue to emit a signal in tissues up to 7 days after administration.) This extended therapeutic window may be particularly beneficial in cases where biopsies and resection procedures cannot be scheduled in a short time window, but only a single administration of VGT-309 is required.

[0047] While this disclosure highlights how VGT-309 can make MIS procedures more efficient and effective, VGT-309 can also add value to standard open surgical procedures as VGT-309 can help surgeons quickly find primary tumors and define tumor borders when deciding where to cut, and can find additional small primary and metastatic tumors that could not be seen by the surgeon using preoperative scans or during the procedure using only their eyes and hands.

[0048] Another advantage of the VGT-309, particularly with respect to the pulmonary surgery market, is that laparoscopic and robotic near-infrared (NIR) fluorescence imaging systems are already readily available in hospitals. Some of these NIR imaging systems include those developed by Intuitive Surgical, Olympus, Medtronic, Johnson & Johnson, Bracco, and Stryker. Flexible manual bronchoscopy systems (such as those made by Olympus, Fujinon, Pentax, and Storz, as well as advanced systems such as the Medtronic superDimension™ System and ILLUMISITE™ Platform, Olympus Veran SPiN System™, Bodyvision Lung Vision and Bronchus Archimedes™ System) and flexible robotic bronchoscopy devices (such as Intuitive Ion™, Johnson and Johnson Auris Monarch™ Platform, and Noah Medical Galaxy System™) are used to perform lung biopsies and, in the future, provide localized therapy, but do not yet have NIR capabilities; as the use of molecular imaging agents develops for lung surgery, the advanced bronchoscopy market will follow and NIR capabilities may be added to these systems.

[0049] In use, VGT-309 may be administered intravenously prior to surgery or non-surgical local treatment to improve the surgeon's ability to visualize any tumors during the MIS procedure. Incorporating VGT-309 and NIR into the MIS procedure has been demonstrated to improve the surgeon's visualization of the tumor. Similar to the 3D model shown in Figures 1A-1B, Figures 2A-2B show a 3D imaging model 200 of an airway 204 highlighting an irradiated tumor 202. Under white light, the tissue on the outside or inside of the luminal wall of the airway 204 may appear abnormal, but it is not clear where the tumor is, if there is any at all. Thus, in this case, the surgeon may take aggressive measures to identify and / or remove any abnormal tissue 202, which may involve an overly aggressive resection or thoracotomy. Both treatment courses are more aggressive and improve the chances that all cancer will be successfully removed, but there is still a risk that not all cancerous tissue will be identifiable.

[0050] In contrast, when using NIR to visualize lung tissue after giving the patient VGT-309, the cancerous tissue 202 fluoresces, allowing the surgeon to clearly and rather easily identify which tissue is cancerous. As shown in FIG. 2C, the imaging device can be configured to display an image of the airway 204 on a screen with the NIR fluorescence shown in a visible color, e.g., green, to help the surgeon see which tissue 202 is fluorescing. Thus, instead of resecting all the tissue in the area or only a portion of the tissue, the surgeon can more accurately identify and remove only the cancerous tissue 202. In this way, the surgeon can be more confident that he is resecting the tumor 202 with clean margins so that no cancerous tissue 202 is left behind.

[0051] Also, a portion 203 of the lesion 202 may be more fluorescent than the rest of the lesion 202. In some cases, the hyperfluorescent portion 203 may represent a higher concentration of cathepsin, which would indicate to the surgeon that the hyperfluorescent portion 203 is a tumor "hot spot" (i.e., highly cancerous tissue). In other cases, as shown in FIG. 2D, only a portion 203 of the lesion may be fluorescent, which would indicate that only the fluorescent portion 203 of the lesion 202 is potentially cancerous. In either case, the surgeon can more precisely target the portions 203 of the lesion 202 that are cancerous or more likely to be cancerous.

[0052] Thus, VGT-309 can provide surgeons with important information during the diagnostic and treatment process that would otherwise be inaccessible, and thus may be particularly useful in the localization, diagnosis, and treatment of lung cancer. If a lung nodule or abnormality is identified on a patient's scan, the patient's next step is likely to be a biopsy to confirm whether the nodule is cancerous. And by administering VGT-309 prior to the biopsy, the pulmonologist and / or surgeon can significantly increase the likelihood that the biopsy results will be accurate, thereby decreasing the chances that the patient will be misdiagnosed or will need to undergo additional or more invasive procedures to confirm the diagnosis.

[0053] The localization methods described herein may be used with essentially any minimally invasive tool / device, conventional or developed in the future, for accessing internal tissue target sites. For example, these tools / devices may include advanced endoluminal approaches, such as catheter-based robotics.

[0054] diagnosis Turning to the details of the diagnostic process, VGT-309 can be used in conjunction with traditional pathology to provide pulmonologists with high confidence in their diagnosis. Preoperative scans often help locate tumors, but these scans cannot provide information on whether the tumor is cancerous or not. In the context of lung cancer in particular, proper diagnosis and staging is important, which almost completely defines the remaining course of treatment. Patients with localized tumors, or early-stage cancer, require a less invasive course of treatment than patients with metastatic spread at a later stage of the cancer, but it is nevertheless important to identify and treat the cancer early so that patients have the best chance of survival.

[0055] When performing a biopsy, surgeons are guided by the limited information provided from the patient's preoperative scans. Typically, these scans, at best, allow the surgeon to determine the general area of ​​the nodule, but surgeons are still faced with the difficult task of pinpointing the exact location of the nodule, often using virtual navigation in combination with a secondary imaging system such as fluoroscopy, REBUS, CBCT, or confocal laser endomicroscopy. Systems that use white light cameras are of minimal utility in the peripheral parts of the lung where the airways are very small and the lesions are typically outside the direct airways.

[0056] As previously discussed with respect to Figures 1A-1C, surgeons generally have limited resources available to guide them during lung biopsy. Although preoperative scans can be effective in generating a 3D model to guide the endoscope within the patient's airway to the general location of the lesion, surgeons may still struggle to accurately locate and biopsy the lesion from within the airway. However, if the pulmonologist is using VGT-309 and NIR, they have additional guidance when locating and biopsying the tumor. Fluorescence under NIR clearly distinguishes malignant nodules from healthy tissue and gives the pulmonologist a precise guide after successfully navigating the biopsy needle to the general location of the tumor identified on the preoperative scan.

[0057] 3A-3C illustrate the concept of the VGT-309 to illuminate a cancerous lesion 302 so that, when an endoscope with NIR imaging capabilities is used, the surgeon can determine where to biopsy tissue that is most likely to give an accurate assessment of whether cancer is present. Using the VGT-309, the surgeon can localize the lesion 302 in the lung near the airway 304 in real time, align a biopsy tool or other instrument with the lesion 302, and precisely target and sample the lesion 302. That is, the VGT-309 provides a direct guide for the surgeon performing the bronchoscopy procedure so that the biopsy instrument can be properly positioned to obtain the most accurate diagnosis possible. For example, the lesion may be irradiated to various degrees, i.e., some areas of the lesion may be irradiated more vigorously than other areas. In these cases, the surgeon may target the portion 303 of the lesion 302 that is more vigorously irradiated because that portion 303 of the lesion 302 is most likely to be cancerous compared to the rest of the lesion. Existing technology does not provide such a capability.

[0058] As shown in FIG. 3C, it is also possible that a patient has a nodule that is only partially non-cancerous, which may lead to a situation in which the patient is given an incorrect diagnosis because the surgeon was not able to identify or biopsy the specific cancerous portion of the nodule. VGT-309 and NIR may be particularly advantageous in these cases where only a portion 303 of the nodule 302 is cancerous, at least in that the surgeon can adequately visualize the cancerous portion of the nodule to guide the biopsy. For example, if VGT-309 is administered to the patient and then a robotic endoscope with NIR capabilities is used, the surgeon can see the illuminated area 303 of the nodule 302. That is, only the cancerous portion 303 of the nodule 302 fluoresces under NIR. Compared to the overall size of the nodule 302, the cancerous portion 303 may be relatively small, and thus, in the absence of VGT-309 and NIR, the surgeon would likely collect a biopsy from the non-cancerous portion of the nodule. That is, VGT-309 allows the biopsy to be precisely targeted to the irradiated cancerous region 303 of the nodule 302.

[0059] In some cases, the surgeon may initially misposition the biopsy tool, so that it does not reach the cancerous portion of the nodule where it fluoresces. In procedures where VGT-309 and NIR are not used, the surgeon may proceed to take a biopsy from this non-cancerous portion, since conventional tools cannot assess which parts of the nodule are cancerous and which are benign, potentially giving the patient an incorrect diagnosis. However, when the cancerous portion of the nodule fluoresces, the surgeon has the opportunity to correct the path of the biopsy tool to ensure that the biopsy is taken from the correct part of the nodule so that the diagnosis is as accurate as possible.

[0060] This has the added benefit of increasing the physician's confidence in the ultimate pathology from the procedure, thus reducing the need for additional procedures. Without VGT-309 and NIR imaging, patients may be inaccurately diagnosed or may need to undergo multiple, additional, and / or more invasive procedures.

[0061] VGT-309 may also aid in bronchoscopic lymph node evaluation. For example, it may eliminate the need for tissue biopsy as a standalone diagnostic agent to illuminate cancerous lymph nodes. The ability to illuminate such lymph nodes could completely open up the ability to biopsy, stage, and treat in a single procedure. Traditional lymph node biopsy and staging requires histopathology and takes several days to complete. VGT-309 could enable staging in a single diagnostic and therapeutic procedure, where the patient can receive potentially curative surgery or non-surgical endoluminal therapy during a single anesthesia event.

[0062] Physicians may also use VGT-309 as an independent diagnostic agent during surgery or non-surgical endoluminal treatments, so that intraoperative pathology reads (otherwise known as frozen sections) are no longer necessary. This allows pulmonologists and / or surgeons to determine in real time what is or is not cancerous, without waiting for pathology results. VGT-309 may also eliminate the need for traditional preoperative marking techniques that some surgeons use to identify nodules during resection procedures.

[0063] In some other embodiments, VGT-309 may be used in combination with other technologies, such as those being developed by Mauna Kea Technologies, to further optimize the diagnostic process. For example, Mauna Kea has developed a series of in vivo cellular imaging technologies that include a catheter fitted with a NIR confocal microscope. This microscope may be guided and inserted into the nodule to perform a biopsy, and can detect low levels of VGT-309 fluorescence within the cells themselves. The information gathered by fluorescent cellular imaging may be combined with information already provided by the Mauna Kea imaging platform, eliminating the need to perform a biopsy altogether.

[0064] After a biopsy confirms that a patient's nodules are cancerous, the next step in treatment is often surgical removal. As previously mentioned, these procedures are often performed using laparoscopic, endoscopic, or robotic techniques that use a scalpel or heat, ultrasound, or laser cutters. Administering VGT-309 prior to surgery allows surgeons to better find, identify, and remove the tumor while simultaneously examining the surrounding tissue to ensure the cancer has not spread to other parts of the patient's lungs.

[0065] Treatment method VGT-309 and NIR can be used in non-surgical tumor destruction treatments such as ablation therapy, drug delivery, pulsed electric field (PEF), or photodynamic therapy (PDT). As with other procedures described herein, ablation therapy and other non-surgical local therapies are advantageous compared to surgical resection because they are minimally invasive but generally maximize the preservation of healthy tissue. These non-surgical approaches will also expand the patient population that can receive treatment because they are typically safe for inoperable patient populations when delivered endoscopically, and because they can be used alone or in combination with other therapeutic modalities.

[0066] 4A-4C illustrate the concept of VGT-309 illuminating a cancerous lesion 402 adjacent to an airway 404 so that, when an endoscope with NIR imaging capabilities is used, the surgeon can precisely deliver a localized therapy to the lesion 402 via a treatment device. Surgeons must be very precise when performing ablation and other localized therapy procedures because the proximity of the treatment device (e.g., an ablation catheter) to the tumor 402 (FIGS. 4A-4B), or the cancerous portion 403 of the lesion 402 (FIG. 4C), is critical in determining the efficacy of the procedure. Unlike biopsies, endoluminal ablations and other localized therapies require the delivery device to completely traverse the lesion 402 to maximize the efficacy of the treatment and improve treatment margins. Because of the need for such precision when performing these ablation procedures, the incorporation of VGT-309 and NIR would be particularly advantageous.

[0067] Similar to biopsy procedures, an ablation catheter may be navigated bronchoscopically to the general area of ​​the tumor 402, but the same complications arise in identifying the exact location of the tumor 402. These procedures are clinically challenging and often require access to fixed CBCT systems, which are not yet as widely available as those for performing other MIS procedures. These instrumentation systems under development do not include NIR capabilities, but the incorporation of NIR would not significantly change the design or function of these systems.

[0068] Alternative use artificial intelligence Additionally, data collected during bronchoscopies and surgeries performed with VGT-309 and NIR may be used to train artificial intelligence (AI) algorithms that can be used to improve the effectiveness of future surgeries. Specifically, AI algorithms trained using images and videos of surgeries performed with VGT-309 may improve how these biopsies and / or resection procedures are performed, particularly as they relate to identifying and localizing cancerous tumors.

[0069] Non-lung cancer VGT-309 may also be particularly useful in the diagnosis and treatment of colorectal cancer, although it is worth noting that colorectal cancer manifests differently than lung cancer. Unlike lung cancer, which manifests as a tumor, colorectal cancer can be found in a variety of morphologies, as shown in Figures 5A-5D. These may include polyps (Figure 5A) and / or lesions, including elevated lesions (Figure 5B), flat lesions (Figure 5C), and depressed lesions (Figure 5D).

[0070] Molecular imaging agents including VGT-309 and NIR can be incorporated into conventional colonoscopy procedures to better help surgeons identify cancerous polyps and / or lesions. Lesions, especially when flat or depressed, are difficult for surgeons to identify if the endoscope is guided by white light alone. Protruding polyps are more likely to be identified with white light alone, while flat or depressed lesions are more likely to blend with the normal tissue of the colon. Since some of these lesions may be difficult to identify, there is a risk that surgeons will not identify any or all of the lesions and / or polyps present in the patient's colon, and as a result, the patient may be left with undiagnosed and / or untreated cancer. However, surgeons who use VGT-309 and NIR during routine colonoscopy are more likely to identify otherwise difficult to find polyps and / or lesions, and therefore, can more accurately diagnose colorectal cancer in patients, if necessary.

[0071] Furthermore, because the standard of care for treating colorectal cancer is significantly different from the standard of care for treating lung cancer, VGT-309 and NIR are more likely to be applied during the diagnostic process than during resection and removal. When treating lung cancer, surgeons are very concerned about preserving as much healthy tissue during the resection process. Colorectal cancer treatment is much more aggressive. Surgeons are less concerned about preserving healthy tissue when treating colorectal cancer, so they remove polyps and / or lesions with large margins. However, VGT-309 and NIR may be used to ensure that there are no residual traces of cancer in the patient's colon or nearby peritoneum, even with aggressive resections.

[0072] In addition to resecting localized tumors with clear margins, surgeons are also concerned with ensuring that the tissues surrounding the lungs, especially the lymph nodes, are not invaded by the cancer. During these procedures, surgeons spend a significant amount of time taking lymph node biopsies and sending those biopsies for frozen section pathology. Each frozen section can take anywhere from 15 to 30 minutes while the patient is under anesthesia. This prolonged procedure can increase the patient's risk of surgical complications while also increasing the overall cost of the surgery. However, surgeons also want to be sure that the patient is properly diagnosed and staged. If the surgeon does not identify lymph node spread, the patient may not receive proper treatment, which could negatively impact their prognosis.

[0073] When a tumor is found and then removed, the surgeon also aims to obtain a clear margin around the tumor, which is usually considered to be a cancer-free area of ​​2 cm in all directions around the tumor. If the tumor margins are well defined, achieving a clear margin is not particularly difficult. However, tumors, especially around the edges, may not be well defined or may have small cancerous projections that invade the surrounding normal tissue, making it particularly difficult to achieve a clear margin.

[0074] For example, when viewing a tumor under white light, it may appear that the surgeon has localized the tumor, even though cancerous tissue remains in the patient's airway surrounding the resected tumor. Without VGT-309, the surgeon may have left this cancerous tissue behind, or may have resected the area too aggressively to ensure adequate margins. However, with VGT-309, the surgeon is able to visualize the remaining cancerous tissue and remove the entire tumor with clear margins, as verified by pathology, while sparing as much healthy tissue as possible.

[0075] Therefore, VGT-309 and NIR can help surgeons identify lymph nodes that may be affected, as lymph nodes that contain cancer are fluorescent under NIR.

[0076] Using existing surgical techniques, surgeons often struggle to find and remove small tumors, which are often considered tumors less than 2 cm in size. This tumor may be clearly identifiable on a patient's preoperative scan, but it can be difficult for surgeons to identify during an MIS procedure. For example, when looking at the surface of the lung under regular white light, surgeons have difficulty finding the tumor. If the procedure were performed without VGT-309 and NIR, the surgeon may be prompted to aggressively resect tissue in this area or convert to an open procedure.

[0077] The methods described herein with respect to the use of VGT-309 may also be carried out with other fluorescent molecular imaging agents that covalently bind to target molecules present in greater amounts in solid tumors than in normal tissues, effective in causing cancerous tissue to fluoresce under NIR light and facilitating localization of cancerous tissue.

[0078] While the present disclosure has been described with reference to certain exemplary applications, it will be understood by those skilled in the art that the present disclosure is not limited to such disclosed embodiments. Rather, the disclosed application may be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein, but which are compatible with the spirit and scope of the present disclosure. EXAMPLES

[0079] The present invention can be further understood with reference to the following non-limiting examples.

[0080] Example 1. Tumor localization with VGT-309 and NIR imaging The patient was administered 0.32 mg / kg of VGT-309 approximately 21 hours prior to surgery. Surgeons used NIR imaging to improve visualization and clearly demonstrate the location and extent of the tumor.

[0081] Example 2. Localization of an uncertain tumor with VGT-309 and NIR imaging and resection of a localized tumor with clear margins The patient appeared to have a localized tumor, as identified on pre-operative scans, but the surgeon identified lymph node spread during resection with VGT-309. The patient's pre-operative PET scans showed a large, easily identifiable tumor. These scans had no evidence of spread to other areas of the lungs or lymph nodes. The patient was administered 0.16 mg / kg VGT-309 approximately 21 hours prior to surgery. To more easily locate the primary tumor during surgery, the tissue was visualized under NIR. The surgeon also visually inspected and biopsied proximal lymph nodes, none of which suggested the tumor had spread. However, during the procedure, the surgeon observed unexpected fluorescence in a more distant lymph node. The surgeon was therefore able to perform a biopsy, thereby confirming that the cancer had spread, and as a result, restaged the patient in real time and performed a radical lymphadenectomy. At the end of the procedure, the surgeon removed all traces of the cancer.

[0082] Example 3. Identification of metastatic spread The patient experienced tumor regrowth following radiation treatment of the primary tumor, but the patient's scans showed no metastatic spread. Here, the patient was administered 0.32mg / kg of VGT-309 approximately 18.5 hours prior to surgery, allowing the surgeon to rapidly identify and remove the previously identified tumor. In addition to removing the primary tumor, the patient was administered VGT-309 prior to surgery, allowing the surgeon to also identify additional tumors using NIR. When visualized under normal white light, the patient's lung tissue showed some signs of abnormality, but abnormality does not necessarily indicate cancerous tissue. However, with NIR, this abnormal lung tissue was confirmed to be, in fact, cancerous.

[0083] Example 4. Increase in clinically significant events during tumor removal The use of VGT-309 and NIR has been shown to substantially increase the likelihood of clinically significant events (CSE) during the removal procedure. To be clear, CSE in this context is good in that it is being used as a primary endpoint in clinical trials to show that an imaging agent has the ability to change decision-making for the better during surgery. CSE is one way of measuring whether an imaging agent such as VGT-309 adds clinical benefit to the diagnostic and treatment process. In this context, CSE generally falls into one of three categories: (1) localizing hard-to-find tumors, (2) identifying positive resection margins, and (3) identifying additional primary and metastatic lesions not previously detected using existing techniques. In trials, VGT-309 has been shown to increase CSE compared to other comparable imaging agents in development. In a Phase II trial of VGT-309 in Australia, one-third of patients experienced CSE, which is better than results from a Phase II trial of a comparable imaging agent, where approximately one-quarter of patients experienced CSE. Thus, VGT-309 increased the frequency of CSE, indicating that VGT-309 is effective in helping surgeons (1) identify and localize primary tumors, (2) resect tumors with clear margins, and (3) identify additional unknown primary and metastatic lesions.

[0084] Some embodiments of the present disclosure may be described in consideration of one or more of the following.

[0085] Embodiment 1. A method comprising navigating an instrument in a patient to which a molecular imaging agent has been administered intravenously via a minimally invasive route to position the instrument in an area of ​​tissue abnormality, visualizing tissue in the area under near infrared (NIR) light via the instrument, wherein the molecular imaging agent, upon administration, causes the abnormal tissue in the area to fluoresce under the NIR light, enabling the fluorescing abnormal tissue to be localized within the area, and optionally then diagnosing and / or treating the localized fluorescing abnormal tissue.

[0086] Embodiment 2. The method of embodiment 1, wherein navigating via a minimally invasive pathway is an intraluminal procedure.

[0087] Embodiment 3. The method of embodiment 1 or 2, wherein areas of tissue abnormality are identified from one or more pre-operative scans.

[0088] Embodiment 4. The method of any one of embodiments 1-3, wherein the instrument comprises a biopsy needle or other biopsy tool, and diagnosing and / or treating comprises collecting one or more biopsy samples from the localized fluorescing abnormal tissue.

[0089] Embodiment 5. The method of any one of embodiments 1 to 4, wherein diagnosing and / or treating comprises ablation or destruction of localized fluorescing abnormal tissue (e.g., cancerous tissue).

[0090] Embodiment 6. The method of embodiment 5, wherein destruction of the localized fluorescing abnormal tissue comprises (i) ablation (e.g., by heat, microwave, RF (radio frequency) energy, laser, ultrasound, or histotripsy) of the localized fluorescing abnormal tissue, and / or (ii) local administration of a drug (e.g., a chemotherapeutic agent, an antibody, an immuno-oncology agent, an oncolytic virus, a cellular therapy).

[0091] Embodiment 7. The method of any one of embodiments 1-6, wherein the tissue abnormality comprises a tumor with poorly defined margins.

[0092] Embodiment 8. The method of any one of embodiments 1-7, wherein the localized fluorescing abnormal tissue is within the patient's lungs.

[0093] Embodiment 9. The method of embodiment 8, wherein the localized fluorescing abnormal tissue comprises an extrabronchial nodule.

[0094] Embodiment 10. The method of embodiment 8 or 9, wherein the instrument comprises a flexible bronchoscope and navigating comprises guiding the flexible bronchoscope through the patient's airways.

[0095] Embodiment 11. The method of any one of embodiments 1-7, wherein the localized fluorescing abnormal tissue is in the colon of the patient.

[0096] Embodiment 12. The method of embodiment 11, wherein the localized fluorescing abnormal tissue comprises a flat lesion or a depressed lesion.

[0097] Embodiment 13. The method of embodiment 11 or 12, wherein the instrument comprises an endoscope and navigating comprises guiding the endoscope through the patient's colon.

[0098] Embodiment 14. The method of any one of embodiments 1 to 13, wherein a NIR-enabled confocal microscope is inserted into the tissue to fluoresce and directly visualize living cells and their organization within the tissue abnormality.

[0099] Embodiment 15. The method according to any one of embodiments 1 to 14, which is performed without a preoperative marking procedure.

[0100] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the molecular imaging agent is administered 2 hours to 7 days, or 2 hours to 4 days, prior to navigating.

[0101] Embodiment 17. The method of embodiment 16, wherein the molecular imaging agent is administered 12 to 36 hours prior to navigating.

[0102] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the molecular imaging agent is administered to the patient at a dose of 0.01 mg / kg to 0.7 mg / kg.

[0103] Embodiment 19. The method of embodiment 18, wherein the dose is 0.015 mg / kg to 0.65 mg / kg, for example, 0.15 mg / kg to 0.65 mg / kg.

[0104] Embodiment 20. The method of embodiment 18, wherein the dose is 0.1 mg / kg to 0.6 mg / kg, for example, 0.3 mg / kg to 0.5 mg / kg.

[0105] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the molecular imaging agent is configured to covalently bind to a target molecule that is upregulated in a solid tumor or is present in a solid tumor in greater amounts than in normal tissue.

[0106] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the molecular imaging agent is configured to bind to a cathepsin.

[0107] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the molecular imaging agent comprises VGT-309.

[0108] Embodiment 24. The method of any one of embodiments 1 to 23, wherein the localized fluorescing abnormal tissue is malignant or cancerous.

[0109] Embodiment 25. A method comprising: navigating an instrument in a patient to which VGT-309 is being administered intravenously via an intraluminal route to position the instrument in a target area; visualizing the target area under near-infrared (NIR) light via the instrument; and locating any abnormal tissue within the target area in real time by fluorescence of the abnormal tissue caused by VGT-309 under the NIR light.

[0110] Embodiment 26. The method of embodiment 25, wherein VGT-309 is administered 2 hours to 4 days prior to navigation.

[0111] Embodiment 27. The method of embodiment 26, wherein VGT-309 is administered 12 to 36 hours prior to navigating.

[0112] Embodiment 28. The method of any one of embodiments 25 to 28, wherein VGT-309 is administered to the patient at a dose of 0.01 mg / kg to 0.7 mg / kg, for example, 0.1 mg / kg to 0.7 mg / kg, 0.2 mg / kg to 0.6 mg / kg, or 0.3 mg / kg to 0.5 mg / kg.

[0113] Embodiment 29. A method of performing a biopsy comprising identifying a tissue abnormality on a pre-operative scan of a patient, intravenously administering a molecular imaging agent to the patient, navigating a biopsy needle to a location of the tissue abnormality, visualizing the tissue under near-infrared (NIR) light, where the molecular imaging agent causes the abnormal tissue at the location to fluoresce under the NIR light, and collecting one or more biopsy samples from the fluorescing tissue, wherein the biopsy needle is navigated to the location via a minimally invasive pathway, and the fluorescent tissue guides (i) navigation of the biopsy needle and / or (ii) collection of the one or more biopsy samples.

[0114] Embodiment 30. A method of removing or destroying a tumor in a patient, the method comprising: intravenously administering a molecular imaging agent to the patient; navigating a surgical instrument to the location of the tumor as indicated by a pre-operative scan and / or biopsy; visualizing tissue at the location under near-infrared (NIR) light, where the molecular imaging agent is effective to cause cancerous tissue within the tumor at the location to fluoresce under the NIR light; and then ablating or destroying the fluorescing tissue of the tumor using a surgical instrument, wherein the surgical instrument is navigated to the location via a minimally invasive pathway, and the fluorescent tissue guides (i) the navigation of the surgical instrument, and / or (ii) the ablation or destruction.

[0115] Embodiment 31. The method of embodiment 29 or 30, wherein the molecular imaging agent is administered 2 hours to 4 days prior to navigation.

[0116] Embodiment 32. The method of embodiment 31, wherein the molecular imaging agent is administered 12 to 36 hours prior to navigating.

[0117] Embodiment 33. The method of any one of embodiments 29 to 32, wherein the molecular imaging agent is administered to the patient at a dose of 0.01 mg / kg to 0.7 mg / kg, for example, 0.1 mg / kg to 0.7 mg / kg, 0.2 mg / kg to 0.6 mg / kg, or 0.3 mg / kg to 0.5 mg / kg.

[0118] Embodiment 34. The method of any one of embodiments 29 to 33, wherein the molecular imaging agent is configured to covalently bind to a target molecule that is upregulated in a solid tumor or is present in a solid tumor in greater amounts than in normal tissue.

[0119] Embodiment 35. The method of any one of embodiments 29 to 34, wherein the molecular imaging agent is configured to bind to a cathepsin.

[0120] Embodiment 36. The method of any one of embodiments 29 to 35, wherein the molecular imaging agent comprises VGT-309 (e.g., a pharma- ceutically acceptable salt of VGT-309).

Claims

1. 1. A method comprising: visualizing tissue of the patient in the area of ​​the tissue abnormality under near-infrared (NIR) light via an instrument, wherein the instrument is navigated via a minimally invasive route into the patient to whom a molecular imaging agent has been intravenously administered and positioned in the area of ​​the tissue abnormality; wherein the administered molecular imaging agent causes abnormal tissue within the region to fluoresce under the NIR light, allowing the fluorescing abnormal tissue to be localized within the region.

2. The method of claim 1 , further comprising determining a diagnosis and / or treatment for the fluorescing abnormal tissue.

3. The method of claim 1 , wherein the instrument is navigated through the minimally invasive pathway by an endoluminal procedure.

4. the instrument includes a biopsy needle or other biopsy tool; the determined diagnosis and / or treatment: collecting one or more biopsy samples from said fluorescing abnormal tissue; or wherein the determined diagnosis and / or treatment comprises removal or destruction of the fluorescing abnormal tissue, the destruction of the fluorescing abnormal tissue preferably being (i) ablation, and / or (ii) local administration of a drug to the fluorescent abnormal tissue; The method of claim 2.

5. The method of claim 1 , wherein the tissue abnormality comprises a tumor with a poorly defined margin.

6. The method of claim 1 , wherein the fluorescent abnormal tissue is in the patient's lungs.

7. the fluorescing abnormal tissue comprises an extrabronchial nodule; and / or the instrument includes a flexible bronchoscope, and the instrument is navigated within the patient by guiding the flexible bronchoscope through the patient's airways; The method of claim 6.

8. The method of claim 1 , wherein the fluorescent abnormal tissue is in the patient's colon.

9. the fluorescing abnormal tissue comprises a flat or depressed lesion; and / or the instrument includes an endoscope, and the instrument is navigated within the patient by guiding the endoscope through the patient's colon; The method of claim 8.

10. 10. The method of claim 1, wherein living cells and their organization within the tissue abnormality are directly visualized by a NIR-enabled confocal microscope inserted within the fluorescing tissue of the patient.

11. 10. The method of claim 1, wherein the molecular imaging agent is administered 2 hours to 4 days, or 12 hours to 36 hours, before the device is navigated into the patient.

12. 10. The method of claim 1, wherein the molecular imaging agent is administered to the patient at a dose of 0.01 mg / kg to 0.7 mg / kg, or at a dose of 0.015 mg / kg to 0.65 mg / kg, or at a dose of 0.1 mg / kg to 0.4 mg / kg.

13. the molecular imaging agent is configured to covalently bind to a target molecule that is present in greater amounts in solid tumors than in normal tissue; and / or the molecular imaging agent is configured to bind to a cathepsin; The method of claim 1.

14. The method of any one of claims 1 to 13, wherein the molecular imaging agent comprises VGT-309 or a pharmaceutically acceptable salt thereof.

15. 1. A molecular imaging agent for use in in vivo fluorescence imaging to localize a tissue abnormality in a patient, said molecular imaging agent comprising VGT-309 or a pharmaceutically acceptable salt thereof, said fluorescence imaging to localize said tissue abnormality comprising: administering the molecular imaging agent intravenously to the patient; navigating an instrument through a minimally invasive route into a patient to which the molecular imaging agent has been intravenously administered, and positioning the instrument at a target area; visualizing the target area under near-infrared (NIR) light through the instrument; and locating any abnormal or cancerous tissue within the target area in real time by fluorescence emission of the abnormal or cancerous tissue caused by the molecular imaging agent under the NIR light. Molecular imaging agents for use.

16. The molecular imaging agent for use according to claim 15, wherein the minimally invasive route is an intraluminal route.

17. The molecular imaging agent for use according to claim 15 or 16, wherein the molecular imaging agent is administered 2 hours to 4 days before the navigating, or 12 hours to 36 hours before the navigating.

18. 17. The molecular imaging agent for use according to claim 15 or 16, wherein said molecular imaging agent is administered to said patient at a dose of 0.01 mg / kg to 0.7 mg / kg.

19. 17. The molecular imaging agent for use according to claim 15 or 16, wherein following real-time identification of the location of any abnormal or cancerous tissue within the target area by fluorescence of the abnormal or cancerous tissue caused by the molecular imaging agent under the NIR light, (i) one or more biopsy samples are collected from the fluorescent tissue using the instrument, and / or (ii) the fluorescent tissue is excised or destroyed using the instrument.

20. The molecular imaging agent is used to increase the frequency of clinically significant events during tumor removal, the clinically significant events being one of the following: (i) localization of hard-to-find tumors, (2) identification of positive resection margins, and (3) identification of additional primary and metastatic lesions not previously detected using existing techniques.

17. A molecular imaging agent for use according to claim 15 or 16.

Images