WO2017044723A1

WO2017044723A1 - Capture device for detection of malignant cells in blood and methods thereof

Info

Publication number: WO2017044723A1
Application number: PCT/US2016/050916
Authority: WO
Inventors: Govindarajan Srimathveeravalli; Joan Massague; Larry Norton; Stephen Solomon; Daniel A. Heller; Yosef SHAMAY; Rune FREDERIKSEN
Original assignee: Memorial Sloan Kettering Cancer Center
Current assignee: Memorial Sloan Kettering Cancer Center
Priority date: 2015-09-09
Filing date: 2016-09-09
Publication date: 2017-03-16
Anticipated expiration: 2018-03-09

Abstract

Surgical removal of tumors and other interventions are known to cause the acute release of malignant cells into the patient's bloodstream. These cells can implant at distant sites to cause metastatic disease. Described herein are devices and methods for selectively isolating and removing circulating tumor cells from the bloodstream. The device is implanted into the patient's vein or artery prior to surgery and can be removed at a suitable time point in the post-surgical period. The device may reside in the patient's body for many weeks if needed. In certain embodiments, the devices use a combination of mechanical isolation and targeted adhesion to filter and capture circulating malignant cells.

Description

CAPTURE DEVICE FOR DETECTION OF MALIGNANT CELLS IN BLOOD AND

METHODS THEREOF

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No.

62/216,245, filed September 9, 2015, the content of which is hereby incorporated by reference herein in its entirety.

GOVERNMENT SUPPORT

[0002] This invention was made with government support under CA008748 awarded by the National Institutes of Health. The government has certain rights in the invention.

FIELD

[0003] This invention relates generally to systems, methods, and devices for isolating circulating tumor cells. In particular embodiments, the invention relates to an implanted capture device for detection of malignant cells in blood.

BACKGROUND

[0004] Circulating tumor cells (CTCs) are cells that sporadically release from a primary tumor and circulate in the bloodstream. Because CTCs travel in the bloodstream, they may spawn growth of additional tumors in different tissues, creating a condition known as metastasis. Therefore, CTCs can offer information regarding potential sources of tumor growth. CTCs are increasingly being examined (e.g., in place of biopsies) during chemotherapy, radiation therapy, surgery, and other cancer treatments to assess treatment effectiveness and the likelihood of cancer spread. Moreover, in some cases, surgical removal of tumors and other interventions are known to cause an acute release of malignant cells into the patient's bloodstream, further contributing to the likelihood of metastatic disease.

[0005] Thus, there is a need for a device that detects and captures CTCs in the bloodstream and prevents CTCs from causing metastatic disease.

SUMMARY

[0006] Described herein is a device and methods of use to selectively isolate and remove circulating tumor cells from the bloodstream. The device is implanted into an artery or vein (e.g., IVC) of a patient prior to surgery and can be removed at a suitable time point in the postsurgical period. The device can reside in the patient's body for many weeks if needed. In certain embodiments, the device uses a combination of mechanical isolation and targeted adhesion to filter and capture circulating malignant cells.

[0007] In one aspect, the invention is directed to a device for in vivo, passive isolation of malignant cells from blood of a subject, the device comprising: a biocompatible body having a cylindrical cross section sized and shaped for placement into a blood vessel, the biocompatible body comprising: a housing comprising a rigid or semi-rigid outer wall; an entry zone at a proximal end of the biocompatible body for entry of blood into the device from vasculature and an exit zone at a distal end of the biocompatible body for exit of blood components from the device back into the vasculature; one or more interior walls extending at least partially from the proximal end to the distal end of the biocompatible body, the one or more interior walls comprising one or more small fenestrations and one or more large fenestrations and a molecular adhesion component incorporated within and/or coated on the one or more interior walls. In certain embodiments, the interior walls are flexible. In certain embodiments, the interior walls are removable from the biocompatible body of the device.

[0008] In certain embodiments, the device is used for passive isolation of malignant cells from the peritoneal fluid of a subject (e.g., where the device is implanted and/or positioned in a body cavity in order to passivate tumor cells present in the fluid for detection and/or analysis).

[0009] In certain embodiments, the biocompatible body has a cylindrical cross section sized and shaped for placement into one or more members selected from the group consisting of an inferior vena cava, an aorta, an internal jugular vein, a subclavian vein, an axillary vein, a femoral vein, a cephalic vein, a basilica vein, a brachial vein, and a superior vena cava. In certain embodiments, the device has a form factor similar to a catheter.

[0010] In certain embodiments, the molecular adhesion component aids the passive isolation of malignant cells, wherein the passively isolated cells are circulating tumor cells.

[0011] In certain embodiments, the device is constructed for in vivo use.

[0012] In certain embodiments, the biocompatible body of the device is flexible. In certain embodiments, the biocompatible body of the device has a diameter from 1 mm to 5 cm.

[0013] In certain embodiments, the device has a diameter from 1 mm to 1.5 cm (e.g., for use in a vein). In certain embodiments, the device has a diameter from 1 mm to 1.0 cm.

[0014] In certain embodiments, the biocompatible body comprises at least one member selected from the group consisting of plastic, natural rubber, and synthetic rubber.

[0015] In certain embodiments, the one or more interior walls comprise at least one member selected from the group consisting of plastic, natural rubber, and synthetic rubber. In certain embodiments, the the rigid or semi-rigid outer wall comprises polycarbonate and/or metal. In certain embodiments, the rigid or semi-rigid outer wall comprises metal, and wherein the metal is stainless steel or nitinol.

[0016] In certain embodiments, each of the small fenestrations is no larger than 10 microns. In certain embodiments, each of the small fenestrations has a characteristic dimension (e.g., diameter, length, or width) no larger than 10 microns.

[0017] In certain embodiments, each of the large fenestrations has a characteristic dimension (e.g., diameter, length, width, etc.) in a range of 10 to 5000 microns (e.g., 10 to 100 microns, 20 to 100 microns, 20 to 1000 microns, 100 microns to 5 mm).

[0018] In certain embodiments, the device comprises a plurality of small fenestrations, wherein the small fenestrations are randomly distributed. In certain embodiments, the device comprises a plurality of large fenestrations, wherein the large fenestrations are randomly distributed. In certain embodiments, the device comprises a plurality of small fenestrations, wherein the one or more interior walls have a distribution of small fenestrations in a range from 1 to 100 thousand per square millimeter. In certain embodiments, the device comprises at least one mechanical element located on an inside surface of any of the one or more interior walls to locally slow flow.

[0019] In certain embodiments, the at least one mechanical element comprises grooves or traps. In certain embodiments, the at least one mechanical component comprises fins.

[0020] In certain embodiments, the molecular adhesion component comprises one or more members selected from the group consisting of P-selectin, E-selectin, folate receptor, fucoidan, VEGFR, EGFR, PSMA, VCAM, and EpCAM. In certain embodiments, the molecular adhesion component comprises P-selectin. In certain embodiments, the molecular adhesion component is coated on an inside surface of the one or more interior walls. [0021] In certain embodiments, the device comprises an anti-coagulant located on the inside of the rigid or semi-rigid outer wall. In certain embodiments, the device comprises a hydrophilic agent located on the inside of the rigid or semi-rigid outer wall.

[0022] In certain embodiments, the anti -coagulant and/or hydrophilic agent comprises heparin, dextran, HPMA, functionalized polycarbodiimides or polyethylene glycol.

[0023] In certain embodiments, the device comprises an antibacterial agent.

[0024] In another aspect, the invention is directed to a device for in vivo, passive isolation of malignant cells from blood of a subject the device comprising: a biocompatible body having a cylindrical cross section the biocompatible body comprising: a housing comprising a rigid or semi-rigid outer wall an entry zone at a proximal end of the biocompatible body for entry of blood into the device from vasculature and an exit zone at a distal end of the biocompatible body for exit of blood components from the device back into the vasculature; at least one mechanical component spanning at least a portion of an interior cross-section of the housing; and a molecular adhesion component within the housing to aid the passive isolation of malignant cells

[0025] In certain embodiments, the device has a form factor similar to a blood filter. In certain embodiments, the blood filter is an inferior vena cava filter (IVC), for example, as described in https://en.wikipedia.org/wiki/Inferior_vena_cava_filter. In certain embodiments, the IVC has a diameter from about 1 to 2.5 cm.

[0026] In certain embodiments, the passively isolated cells are circulating tumor cells.

[0027] In certain embodiments, the device is constructed for in vivo use. [0028] In certain embodiments, the rigid or semi-rigid outer wall comprises polycarbonate and/or metal. In certain embodiments, the rigid or semi-rigid outer wall comprises metal, a wherein the metal comprises stainless steel or nitinol.

[0029] In certain embodiments, the at least one mechanical component is located on an inside surface of the rigid or semi-rigid outer wall. In certain embodiments, the at least one mechanical component comprises one or more shaped filters. In certain embodiments, the one or more shaped filters comprise a metal skeleton. In certain embodiments, the one or more shaped filters are foldable. In certain embodiments, the one or more shaped filters are removable and/or replaceable (e.g., removable from the subject without necessitating removal of the housing). In certain embodiments, the one or more shaped filters are parabolic in shape. In certain embodiments, the one or more shaped filters are porous. In certain embodiments, the one or more shaped filters are located along the length of an inside surface.

[0030] In certain embodiments, the inside surface of the device is 1 to 5 cm in length.

[0031] In certain embodiments, the one or more shaped filters comprise multiple layers of spun material. In certain embodiments, the spun material comprises polytetrafluoroethylene and/or polycarbonate.

[0032] In certain embodiments, the molecular adhesion component comprises one or more members selected from the group consisting of P-selectin, E-selectin, folate receptor, fucoidan, VEGFR, EGFR, PSMA, VCAM, or EpCAM. In certain embodiments, the molecular adhesion component is coated on a surface of the one or more shaped filters.

[0033] In certain embodiments, the device comprises an anti-coagulant located on the inside surface of the rigid or semi-rigid outer wall. In certain embodiments, the device comprises a hydrophilic agent located on the inside surface of the rigid or semi-rigid outer wall. [0034] In certain embodiments, the anti -coagulant and/or hydrophilic agent comprises heparin, dextran, HPMA, functionalized polycarbodiimides or polyethylene glycol.

[0035] In certain embodiments, the device comprises an antibacterial agent.

[0036] In certain embodiments, the anti-coagulant and/or hydrophilic agent is coated on an outside surface of the rigid walls.

[0037] In certain embodiments, the device is located at a tip of a catheter. In certain embodiments, the catheter is 60 cm to 90 cm in length.

[0038] In certain embodiments, the device is stable in the subject from 30 minutes to 7 decades. In certain embodiments, the device is stable in the subject from 2 months to 10 years.

[0039] In certain embodiments, the device is retrievable.

[0040] In certain embodiments, the device further comprises a remote sensor. In certain embodiments, the remote sensor comprises near-infrared optical elements (e.g., wherein the remote sensor comprises carbon nanotubes). In certain embodiments, the remote sensor interacts via a radiofrequency.

[0041] In another aspect, the invention is directed to a method for detecting malignant cells in blood of a subject, the method comprising: inserting into the subject a device as described herein; allowing sufficient time to pass such that one or more malignant cells are passively immobilized on one or more interior walls and/or at least one mechanical element of the device; retrieving the immobilized one or more malignant cells from the subject; and detecting and/or analyzing the retrieved one or more malignant cells.

[0042] In certain embodiments, detecting the retrieved one or more malignant cells is performed in vivo. [0043] In certain embodiments, the method comprises inserting the device prior to a cancer treatment procedure.

[0044] In certain embodiments, the method comprises detecting the retrieved one or more malignant cells at a time selected from the group consisting of prior to, during, and after the cancer treatment procedure. In certain embodiments, the cancer treatment procedure is chemotherapy, radiation therapy, or surgery.

[0045] In another aspect, the invention is directed to a method for detecting malignant cells in blood of a subject, the method comprising: inserting into the subject any one of the devices described herein; allowing sufficient time to pass such that one or more malignant cells are passively immobilized on a component of the device; retrieving the immobilized one or more malignant cells from the subject; and detecting and/or analyzing the retrieved one or more malignant cells.

[0046] In certain embodiments, detecting the retrieved one or more malignant cells is performed in vivo.

[0047] In certain embodiments, the method comprises inserting the device prior to a cancer treatment procedure.

[0048] In certain embodiments, the method comprises detecting the retrieved one or more malignant cells at a time selected from the group consisting of prior to, during, and after the cancer treatment procedure. In certain embodiments, the cancer treatment procedure is chemotherapy, radiation therapy, or surgery.

[0049] In certain embodiments, the component comprises one or more filters. In certain embodiments, the one or more filters comprise a metal skeleton. In certain embodiments, the one or more filters are foldable. In certain embodiments, the one or more filters are located along the length of an inside surface.

[0050] In certain embodiments, the one or more filters are removable and/or replaceable.

[0051] In certain embodiments, the method comprises passively immobilizing the malignant cells on the one or more filters.

[0052] In certain embodiments, the method comprises retrieving the one or more immobilized malignant cells by removing one or more of the one or more filters. In certain embodiments, the one or more malignant cells are passively immobilized by the molecular adhesion component of any of the devices described herein.

[0053] In certain embodiments, the immobilized cells are circulating tumor cells that express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, or Wilm's tumor. [0054] In certain embodiments, the method further comprising: treating the subject with a cancer treatment procedure; removing the device or any component of any of the devices described herein after the cancer treatment procedure following a delay in time; and/or analyzing the malignant cells to determine their origin.

[0055] In certain embodiments, the cancer treatment procedure is either chemotherapy, radiation therapy, or surgery.

[0056] In certain embodiments, the delay in time is from 5 hours to 5 years.

[0057] In certain embodiments, any of the devices described herein is for use in in vivo diagnosis. In certain embodiments, the malignant cells are circulating tumor cells that express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer,

neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor,

retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, Wilm's tumor, or combinations thereof. [0058] Elements of embodiments involving one aspect of the invention (e.g., methods) can be applied in embodiments involving other aspects of the invention (e.g., devices), and vice versa.

DEFINITIONS

[0059] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0060] In this application, the use of "or" means "and/or" unless stated otherwise. As used in this application, the term "comprise" and variations of the term, such as "comprising" and "comprises," are not intended to exclude other additives, components, integers or steps. As used in this application, the terms "about" and "approximately" are used as equivalents. Any numerals used in this application with or without about/approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. In certain

embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%), 2%), 1%), or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0061] "Biocompatible": The term "biocompatible", as used herein is intended to describe materials that do not elicit a substantial detrimental response in vivo. In certain embodiments, the materials are "biocompatible" if they are not toxic to cells. In certain embodiments, materials are "biocompatible" if their addition to cells in vitro results in less than or equal to 20% cell death, and/or their administration in vivo does not induce inflammation or other such adverse effects. In certain embodiments, materials are biodegradable.

[0062] "Biodegradable" . As used herein, "biodegradable" materials are those that, when introduced into cells, are broken down by cellular machinery {e.g., enzymatic degradation) or by hydrolysis into components that cells can either reuse or dispose of without significant toxic effects on the cells. In certain embodiments, components generated by breakdown of a biodegradable material do not induce inflammation and/or other adverse effects in vivo. In some embodiments, biodegradable materials are enzymatically broken down. Alternatively or additionally, in some embodiments, biodegradable materials are broken down by hydrolysis. In some embodiments, biodegradable polymeric materials break down into their component polymers. In some embodiments, breakdown of biodegradable materials (including, for example, biodegradable polymeric materials) includes hydrolysis of ester bonds. In some embodiments, breakdown of materials (including, for example, biodegradable polymeric materials) includes cleavage of urethane linkages.

[0063] "Blood component": As used herein, "blood component" refers to any component of whole blood, including red blood cells, white blood cells, platelets, endothelial cells, mesothelial cells or epithelial cells. Blood components also include the components of plasma, such as proteins, lipids, nucleic acids, and carbohydrates, and any other cells that can be present in blood, due to pregnancy, organ transplant, infection, injury, or disease.

[0064] "Circulating tumor cell (CTC): As used herein, "circulating tumor cell (CTC)" refers to any cancer cell in the bloodstream of a subject. Typically CTCs have been exfoliated from a solid tumor. As such, CTCs are often epithelial cells shed from solid tumors found in very low concentrations in the circulation of patients with advanced cancers. CTCs can also be mesothelial from sarcomas or melanocytes from melanomas.

[0065] "Subject". As used herein, the term "subject" includes humans and mammals

(e.g., mice, rats, pigs, cats, dogs, and horses). In many embodiments, subjects are be mammals, particularly primates, especially humans. In some embodiments, subjects are livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. In some embodiments (e.g., particularly in research contexts) subject mammals will be, for example, rodents (e.g., mice, rats, hamsters), rabbits, primates, or swine such as inbred pigs and the like.

[0066] Drawings are presented herein for illustration purposes, not for limitation.

BRIEF DESCRIPTION OF DRAWINGS

[0067] The foregoing and other objects, aspects, features, and advantages of the present disclosure will become more apparent and better understood by referring to the following description taken in conduction with the accompanying drawings, in which:

[0068] FIG. 1 is a schematic of an exemplary configuration of a capture device, according to an illustrative embodiment of the invention; and

[0069] FIG. 2 is a schematic of an exemplary configuration of a capture device, according to an illustrative embodiment of the invention.

[0070] FIG. 3 are images showing the selective trapping of cancer cells expressing p- selectin using a fucoidan-passivated microfluidic chamber, according to an illustrative embodiment of the invention. [0071] FIG. 4 is a block flow diagram of a method of detecting malignant cells in the blood of a subject, according to an illustrative embodiment of the invention.

DETAILED DESCRIPTION

[0072] Throughout the description, where compositions are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0073] It should be understood that the order of steps or order for performing certain action is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0074] The mention herein of any publication, for example, in the Background section, is not an admission that the publication serves as prior art with respect to any of the claims presented herein. The Background section is presented for purposes of clarity and is not meant as a description of prior art with respect to any claim.

[0075] Described herein is a device and methods of use to selectively isolate and remove circulating tumor cells (CTCs) from the bloodstream. Isolated CTCs can be used to determine a source of disease and/or prevent metastasis. The device can be implanted into the patient's artery or vein prior to surgery and removed at a suitable time point in the post-surgical period, and the device can quantify the drop-off in captured and detected CTCs following surgery or other treatment. Moreover, in certain embodiments, the implanted device provides more blood flow-through than conventional ex vivo systems, which increases the likelihood of capturing CTCs. The device can reside in the patient's body for many weeks if needed. Moreover, the device uses a combination of mechanical isolation and targeted adhesion to filter and capture circulating malignant cells. The use of adhesion molecules can significantly increase the ability of the device to trap target cells as compared to a control (e.g., cells of non interest (e.g., blood cells)) as shown in FIG. 3 where the trapping of p-selectin expressing cancer cells is compared to non p-selectin expressing cells. The use of a fucoidan-passivated microfluidic chamber leads to a 3 -fold increase in trapping efficiency of the cancer cells as compared to the control cells as measured by the number of cells in frame (-300 vs. -100, respectively). In certain embodiments of the present disclosure, targeted adhesion is achieved by coating an interior surface of the device with a molecular adhesion molecule, wherein the component slows the movement of certain cells and/or certain types of cells through the device. In certain embodiments, the molecular adhesion molecule is chosen specifically for targeted interaction with an expressed moiety of the cells intended for capture. Such a device would allow cells that do not express the targeted moiety to pass freely through the device while those cells that do express the targeted moiety are more likely to be captured than in a similar device lacking such a molecular adhesion component.

[0076] The device can be used for any malignant tumor diagnosis where there may be a possibility of metastasis, including breast cancers, lung cancers, sarcomas, melanomas, pancreatic cancer, prostate cancer, ovarian cancer, kidney cancer, and other diagnoses. The device is designed for temporary insertion for a period of days to months. The device captures malignant cells circulating in the blood (circulating tumor cells) during this period. One method of use involves insertion before a cancer treatment procedure, including surgery. The device can be removed after treatment following a delay which may last from days to months. The device has features to allow easy placement, removal without disturbing trapped cells, and maintenance of asepsis while inside the patient. In certain embodiments, the device is utilized in a method in as outlined in FIG. 4, wherein the device is placed into a subject for sufficient time to allow for one or more malignant cells (e.g., circulating tumor cells) to be immobilized in the device prior to the retrieval of the cells from the device for subsequent detection. The cells may be removed independently of the device itself. For example, the device may be inserted into the patient and allowed to remain there over an extended period in order for circulating tumor cells to be captured by the device. In order for the CTCs to be retrieved for detection and/or analysis, the device may be accessed either by removal of the entire device from the patient or any part of the device containing some or all of the CTCs (e.g., a filter, interior compartment, or device lining). By removing only a portion of the device in order to collect CTCs, the device itself could remain in the patient for an extended period of time that may span the length of a cancer treatment procedure, allowing several samples to be taken at stages before, during, or after treatment in order to assess effectiveness of the cancer treatment procedure including whether the detectable cancer cells were no longer present in the patient. In certain embodiments, the device is intended only for diagnostic purposes and the entire device is removed after an appropriate sampling time has elapsed. An appropriate sampling time would be one long enough for one or more malignant cells (e.g., circulating tumor cells) to be captured by the device and may be on the order of one or more days. After removal, the cells can be extracted from the device for further detection and/or analysis.

[0077] Described herein are two exemplary configurations that can be used to selectively isolate and remove circulating tumor cells from the bloodstream. For example, configuration 1 is shown in FIG. 1, and configuration 2 is shown in FIG. 2. In certain embodiments, the device is 1 to 5 cm in diameter, allowing placement within the inferior vena cava (IVC) or the aorta. In configuration 1 (FIG. 1), the device can be placed at the tip of a catheter that is 60 to 90 cm long. Moreover, configuration 1 (FIG. 1) and configuration 2 (FIG. 2) have a cylindrical geometry, although other geometries are possible. In configuration 1, the device features fins ranging from sub-mm to a maximum of 5 mm in size. Furthermore, each configuration comprises pores that allow the release of blood cells (e.g., white blood cells and red blood cells) but block the passage of circulating tumor cells (CTCs). In certain embodiments, the filtration pores are smaller than 8 microns. The pore spacing can be random and provide a density from 0.1 million to 1 million pores/mm².

[0078] Both configurations of the device can be implantable for short time periods (e.g., from minutes to hours) before, during, and/or after surgical or interventional procedures or longer time periods (e.g., to years, or end of patient's life). Moreover, both versions of the device can be retrievable at the end of intended duration of use.

[0079] The device is designed such that it can be readily placed into major veins (e.g., the inferior vena cava). The device has at least two functional components to capture malignant cells: (1) a structural component comprising fenestrations (e.g., pores) and (2) a molecular adhesion component. The component comprising fenestrations isolates malignant cells from the bloodstream. The molecular component uses targeted adhesion molecules to sequester the malignant cells from the blood stream. Additionally, the device may have one or more mechanical features that further assist the isolation of malignant cells from the blood stream in addition to the structural component comprising fenestrations. Each portion is described in detail herein. [0080] In certain embodiments, the device offers one or more of the following: (i) redirection of blood flow from the IVC or another vein or artery, (ii) isolation of malignant cells, (iii) limitation of reduced red blood cells (RBCs) and white blood cells (WBCs), (iv) an increase in the dwell time of malignant cells on surfaces comprising adhesion molecules, (v) alteration of hemodynamics to increase chances of malignant cells making contact with adhesion molecules, (vi) allowance of long-term implantation, (vii) allowance of easy removal without release of malignant cells into the blood stream, and (viii) avoidance of thrombosis formation.

[0081] In certain embodiments, the device comprises a remote sensor (e.g., carbon nanotubes) that provides the ability to monitor and/or detect analytes in the surrounding environment (e.g., via a remote sensor), allowing malignant cell (e.g., CTC) detection to occur many times while the device remains in the patient for an extended period of time that may coincide with the administration of a cancer treatment procedure without necessitating direct access to the device or any component of the device. In some embodiments, this would allow the device to remain in the patient for an extended period of time (e.g., up to the end of life) while only undergoing a reduced number of invasive procedures as compared to a device which does not comprise a remote sensor.

[0082] The device can be realized in at least two forms, for example, one version (e.g., configuration 1) that resembles a vascular catheter and another version (e.g., configuration 2) that resembles a blood filter.

Configuration 1 (e.g., catheter-like)

[0083] The catheter-like device (FIG. 1) comprises a proximal portion with suitable design features (1) that allow diversion of blood flow from the vasculature through the device. Following the proximal portion, there is an elongated section (2) with fenestrations (3) on its walls that allows extravasation of RBCs and WBCs, but can restrict the exit of circulating tumor cells (CTCs) that are larger than other blood cells. In certain embodiments, the fenestrations are no larger than 8 microns on average.

[0084] In certain embodiments, the inner wall (4) of the elongated section is coated with adhesion molecules such as, but not limited to, P-selectin, E-selectin, folate receptor, fucoidan, VEGFR, EGFR, PSMA, VCAM, or EpCAM, in order to trap the circulating tumor cells by means of forming an association with them. The outer surface (5) of the elongated section can be coated with anti-coagulation and/or hydrophilic agents to limit thrombus formation. Example anti-coagulants and/or hydrophilic agents include heparin, polyethylene glycol, and/or other moieties. In certain embodiments, the inner portion of the elongated section comprises additional mechanical features (6) that can alter the hemodynamics to maximize the duration of time (e.g., dwell time) that cells are in contact with the inner surface. Additionally, the inner surface may include grooves or traps (7) that can promote mechanical retention of the tumor cells. At the end of the elongated section there exists a distal portion where larger fenestrations serve as an exit (8) for any remaining blood components without causing undue change in physiological pressure or otherwise injury to healthy cells. The larger fenestrations can be sub- millimeter to sub-centimeter in a size.

[0085] In certain embodiments, configuration 1 is constructed out of standard

biocompatible materials including plastic, natural, or synthetic rubbers. In certain embodiments, the device wall is constructed of rigid biocompatible material, including plastics (e.g., polycarbonate or metal (e.g., stainless steel or nitinol). Configuration 2 (e.g., vascular filter-like):

[0086] Configuration 2 of the device (FIG. 2) comprises the features disclosed in

Configuration 1 and additional elements to allow long-term implantation and safe retrieval. For example, in addition to materials described in configuration 1, the structure of the device of configuration 2 comprises a foldable super-elastic material (e.g., a nitinol or stainless steel). Moreover, the pores can be constructed of multiple layers of porous materials (e.g., spun PTFE or polycarbonate) for filtration of smaller blood cells.

[0087] In certain embodiments, the device is constructed with a sequence of shaped filters (1) that serve two purposes: to (i) redirect flow along surface of the filter and (ii) maximize surface contact with the filter. The shaped filters can span the entire lumen of the structure and range from 1 to 5 cm in size. In certain embodiments, the filters have an approximately parabolic shape. In some embodiments, the filters comprise a metal skeleton to allow folding and/or unfolding during placement and removal. In certain embodiments, the ability to fold and unfold the filter allows for the filter to be placed and removed from the device while the device remains inserted into the patient. The malignant cells (e.g., circulating tumor cells) can be retrieved from the filter outside of the device for detection and/or analysis. The shaped filters comprise both fenestrations (2) that allow smaller cells, such as WBCs and RBCs, to pass through while at the same time having surface features and/or adhesion molecules to promote the trapping of the larger CTCs. The filters can be staggered on the device to minimize thrombus formation and clogging, reduce undue changes in blood pressure due to the presence of the device, and improve capture efficiency. In some embodiments, an interior surface (3) of the device that is not a part of the filters is coated with hydrophilic and/or anti-coagulant agents to limit thrombus formation. Example anti-coagulants and/or hydrophilic agents include heparin, polyethylene glycol, and/or other moieties.

Claims

What is claimed is:

1. A device for in vivo, passive isolation of malignant cells from blood of a subject, the device comprising:

a biocompatible body having a cylindrical cross section sized and shaped for placement into a blood vessel, the biocompatible body comprising:

a housing comprising a rigid or semi-rigid outer wall;

an entry zone at a proximal end of the biocompatible body for entry of blood into the device from vasculature and an exit zone at a distal end of the biocompatible body for exit of blood components from the device back into the vasculature;

one or more interior walls extending at least partially from the proximal end to the distal end of the biocompatible body, the one or more interior walls comprising one or more small fenestrations and one or more large fenestrations

and a molecular adhesion component incorporated within and/or coated on the one or more interior walls.

2. The device of claim 1, wherein the biocompatible body has a cylindrical cross section sized and shaped for placement into one or more members selected from the group consisting of an inferior vena cava, an aorta, an internal jugular vein, a subclavian vein, an axillary vein, a femoral vein, a cephalic vein, a basilica vein, a brachial vein, and a superior vena cava.

3. The device of claim 1 or 2, wherein the device has a form factor similar to a catheter.

4. The device of any one of the preceding claims, wherein the molecular adhesion component aids the passive isolation of malignant cells, wherein the passively isolated cells are circulating tumor cells.

5. The device of any one of the preceding claims, wherein the device is constructed for in vivo use.

6. The device of any one of the preceding claims, wherein the biocompatible body of the device is flexible.

7. The device of any of one the preceding claims, wherein the biocompatible body of the device has a diameter from 1 mm to 5 cm.

8. The device of any one of the preceding claims, wherein the biocompatible body comprises at least one member selected from the group consisting of plastic, natural rubber, and synthetic rubber.

9. The device of any one of the preceding claims, wherein the one or more interior walls comprises at least one member selected from the group consisting of plastic, natural rubber, and synthetic rubber.

10. The device of any one of the preceding claims, wherein the one or more interior walls are removable.

11 The device of any one of the preceding claims, wherein the rigid or semi-rigid outer wall comprises polycarbonate and/or metal.

12. The device of any one of claims 1 - 8, wherein the rigid or semi-rigid outer wall comprises metal, and wherein the metal is stainless steel or nitinol.

13. The device of any one of the preceding claims, wherein each of the small fenestrations is no larger than 10 microns.

14. The device of any one of the preceding claims, wherein each of the large fenestrations has a characteristic dimension in a range of 10 to 5000 microns.

15. The device of any one of the preceding claims comprising a plurality of small fenestrations, wherein the small fenestrations are randomly distributed.

16. The device of any one of the preceding claims comprising a plurality of large fenestrations, wherein the large fenestrations are randomly distributed.

17. The device of any one of the preceding claims comprising a plurality of small fenestrations, wherein the one or more interior walls have a distribution of small fenestrations in a range from 1 to 100 thousand per square millimeter.

18. The device of any one of the preceding claims, wherein the device comprises at least one mechanical element located on an inside surface of any of the one or more interior walls to locally slow flow.

19. The device of claim 18, wherein the at least one mechanical element comprises grooves or traps.

20. The device of claim 18, wherein the at least one mechanical component comprises fins.

21. The device of any one of the preceding claims, wherein the molecular adhesion component comprises one or more members selected from the group consisting of P-selectin, E- selectin, folate receptor, fucoidan, VEGFR, EGFR, PSMA, VCAM, and EpCAM.

22. The device of claim 21, wherein the molecular adhesion component comprises P-selectin.

23. The device of claim 21, wherein the molecular adhesion component is coated on an inside surface of the one or more interior walls.

24. The device of any one of the preceding claims, wherein the device comprises an anticoagulant located on the inside of the rigid or semi-rigid outer wall.

25. The device of any one of the preceding claims, wherein the device comprises a hydrophilic agent located on the inside of the rigid or semi-rigid outer wall.

26. The device of any one of claims 24 to 25, wherein the anti-coagulant and/or hydrophilic agent comprises heparin, dextran, HPMA, functionalized polycarbodiimides or polyethylene glycol.

27. The device of any one of the preceding claims, wherein the device comprises an antibacterial agent.

28. A device for in vivo, passive isolation of malignant cells from blood of a subject the device comprising:

a biocompatible body having a cylindrical cross section the biocompatible body comprising:

a housing comprising a rigid or semi-rigid outer wall

at least one mechanical component spanning at least a portion of an interior cross- section of the housing;

and a molecular adhesion component within the housing to aid the passive isolation of malignant cells

29. The device of claim 28, wherein the device has a form factor similar to a blood filter.

30. The device of claim 28 or 29, wherein the passively isolated cells are circulating tumor cells.

31. The device of any one of claims 28 - 30, wherein the device is constructed for in vivo use.

32. The device of any one of claims 28 - 31, wherein the rigid or semi-rigid outer wall comprises polycarbonate and/or metal.

33. The device of any one of claims 28 - 31, wherein the rigid or semi-rigid outer wall comprises metal, a wherein the metal comprises stainless steel or nitinol.

34. The device of any one of claims 28 - 33, wherein the at least one mechanical component is located on an inside surface of the rigid or semi-rigid outer wall.

35. The device of any one of claims 28 - 34, wherein the at least one mechanical component comprises one or more shaped filters.

36. The device of claim 35, wherein the one or more shaped filters comprise a metal skeleton.

37. The device of claims 35 - 36, wherein the one or more shaped filters are foldable.

38. The device of claims 35 - 37, wherein the one or more shaped filters are removable and/or replaceable.

39. The device of any one of claims 35 - 38, wherein the one or more shaped filters are parabolic in shape.

40. The device of any one of claims 35 - 39, wherein the one or more shaped filters are porous.

41. The device of any one of claims 35 - 39, wherein the one or more shaped filters are located along the length of an inside surface.

42. The device of claim 41, wherein the inside surface of the device is 1 to 5 cm in length.

43. The device of any one of claims 35 - 42, wherein the one or more shaped filters comprise multiple layers of spun material.

44. The device of claim 43, wherein the spun material comprises polytetrafluoroethylene and/or polycarbonate.

45. The device of any one of claims 28 - 44, wherein the molecular adhesion component comprises one or more members selected from the group consisting of P-selectin, E-selectin, folate receptor, fucoidan, VEGFR, EGFR, PSMA, VCAM, or EpCAM.

46. The device of any one of claims 35 - 45, wherein the molecular adhesion component is coated on a surface of the one or more shaped filters.

47. The device of any one of claims 28 - 46, wherein the device comprises an anti-coagulant located on the inside surface of the rigid or semi-rigid outer wall.

48. The device of any one of claims 28 - 47, wherein the device comprises a hydrophilic agent located on the inside surface of the rigid or semi-rigid outer wall.

49. The device of any one of claims 47 or 48, wherein the anti-coagulant and/or hydrophilic agent comprises heparin, dextran, HPMA, functionalized polycarbodiimides or polyethylene glycol.

50. The device of any one of claims 28 - 49, wherein the device comprises an antibacterial agent.

51. The device of claims 46 - 50, wherein the anti-coagulant and/or hydrophilic agent is coated on an outside surface of the rigid walls.

52. The device of any one of the preceding claims, wherein the device is located at a tip of a catheter

53. The device of claim 52, wherein the catheter is 60 cm to 90 cm in length.

54. The device of any one of the preceding claims, wherein the device is stable in the subject from 30 minutes to 7 decades.

55. The device of any one of the preceding claims, wherein the device is stable in the subject from 2 months to 10 years.

56. The device of any one of the preceding claims, wherein the device is retrievable.

57. The device of any one of the preceding claims, further comprising a remote sensor

58. The device of claim 54, wherein the remote sensor comprises carbon nanotubes.

59. A method for detecting malignant cells in blood of a subject, the method comprising: inserting into the subject the device of claim 1;

allowing sufficient time to pass such that one or more malignant cells are passively immobilized on one or more interior walls and/or at least one mechanical element of the device; retrieving the immobilized one or more malignant cells from the subject; and

detecting and/or analyzing the retrieved one or more malignant cells.

60. The method of claim 59, wherein detecting the retrieved one or more malignant cells is performed in vivo.

61. The method of claim 59 or 60, wherein the method comprises inserting the device prior to a cancer treatment procedure.

62. The method of claim 61, wherein the method comprises detecting the retrieved one or more malignant cells at a time selected from the group consisting of prior to, during, and after the cancer treatment procedure.

63. The method of claim 61 or 62, wherein the cancer treatment procedure is chemotherapy, radiation therapy, or surgery.

64. A method for detecting malignant cells in blood of a subject, the method comprising: inserting into the subject the device of claim 28;

allowing sufficient time to pass such that one or more malignant cells are passively immobilized on a component of the device;

retrieving the immobilized one or more malignant cells from the subject; and

detecting and/or analyzing the retrieved one or more malignant cells.

65. The method of claim 64, wherein detecting the retrieved one or more malignant cells is performed in vivo.

66. The method of claim 64 or 65, wherein the method comprises inserting the device prior to a cancer treatment procedure.

67. The method of claim 66, wherein the method comprises detecting the retrieved one or more malignant cells at a time selected from the group consisting of prior to, during, and after the cancer treatment procedure.

68. The method of claim 66 or 67, wherein the cancer treatment procedure is chemotherapy, radiation therapy, or surgery.

69. The method of any one of claims 64 - 68, wherein the component comprises one or more filters.

70. The device of claim 69, wherein the one or more filters comprise a metal skeleton.

71. The method of any one of claims 69 or 70, wherein the one or more filters are foldable.

72. The method of any one of claims 69 - 71, wherein the one or more filters are located along the length of an inside surface.

73. The device of claims 69 - 72, wherein the one or more filters are removable and/or replaceable.

74. The method of claim 73, wherein the method comprises passively immobilizing the malignant cells on the one or more filters.

75. The method of claim 74, wherein the method comprises retrieving the one

immobilized malignant cells by removing one or more of the one or more filters.

76. The method of any one of claims 59 - 75, wherein the one or more malignant cells are passively immobilized by the molecular adhesion component of the device of any one of claims 1 - 58.

77. The method of any one of claims 59 - 76, wherein the immobilized cells are circulating tumor cells that express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, Wilm's tumor, or combinations thereof.

78. The method of any one of claims 59 to 77, further comprising:

treating the subject with a cancer treatment procedure;

removing the device or any component of the device of any one of claims 1 to 58 after the cancer treatment procedure following a delay in time; and/or

analyzing the malignant cells to determine their origin.

79. The method of claim 78, wherein the cancer treatment procedure is either chemotherapy, radiation therapy, or surgery.

80. The method of claim 78 or 79, wherein the delay in time is from 5 hours to 5 years.

81. The device of any one of claims 1 to 58 for use in in vivo diagnosis.

82. The device for use according to claim 81, wherein the malignant cells are circulating tumor cells that express at least one marker of prostate cancer, lung cancer, adenocarcinoma, adenoma, adrenal cancer, basal cell carcinoma, bone cancer, brain cancer, breast cancer, bronchi cancer, cervical dysplasia, colon cancer, epidermoid carcinoma, Ewing's sarcoma, gallbladder cancer, gallstone tumor, giant cell tumor, glioblastoma multiforma, head cancer, hyperplasia, hyperplastic corneal nerve tumor, in situ carcinoma, intestinal ganglioneuroma, islet cell tumor, Kaposi's sarcoma, kidney cancer, larynx cancer, leiomyoma tumor, liver cancer, malignant carcinoid, malignant hypercalcemia, malignant melanomas, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuromas, mycosis fungoide, neck cancer, neural tissue cancer, neuroblastoma, osteogenic sarcoma, osteosarcoma, ovarian tumor, pancreas cancer, parathyroid cancer, pheochromocytoma, primary brain tumor, rectum cancer, renal cell tumor, retinoblastoma, rhabdomyosarcoma, seminoma, skin cancer, small-cell lung tumor, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, thyroid cancer, topical skin lesion, veticulum cell sarcoma, Wilm's tumor, or combinations thereof.