A composition of microscopic devices utilizable in a medical diagnostic or therapeutic procedure. Each microscopic device includes a nanostructure provided with a ligand for effectively coupling the nanostructure to a predetermined chemical or molecular site. A medical method in part comprises inserting the medical devices into a patient, attaching the nanostructures via the respective ligands to instances of a predetermined type of target structure inside the patient, and thereafter activating the nanostructures to perform a preselected medical diagnostic or therapeutic function.

Description of the Invention

BACKGROUND OF THE INVENTION

Generally, this invention relates to a composition containing nanostructures such as nanotubes. This invention may be used in a medical method, therapeutically and/or diagnostically.

Despite the ever accelerating advances in medical technology, there are many disease states which present medical techniques are unable to adequately treat. For example, there is no effective treatment of nerve tissue damage. Extant therapies for other illnesses are only partially effective in most people. Such illnesses or afflictions include gout, excess weight, bone injuries, aging, and cancer. In addition, while other disease states or systemic malfunctions are treatable by current methods, the treatments frequently have disadvantages or undesirable side effects. For example, in the treatment of cardiac arrhythmias, pacemakers are implanted in the patients, thus requiring open surgery with the attendant risks, costs, and traumas. Drugs used in the treatment of AIDS have serious side effects such as toxicity and rapid rise of resistant viral strains.

SUMMARY OF THE INVENTION

The present invention is directed in part to a generally applicable medical methodology which may be used in the treatment of many kinds of injuries and diseases, whether of an infectious nature, a genetic nature, systemic, localized. The present invention is also useful in the acquisition of information for the performance of medical diagnoses.

The present invention is more generally directed to a composition of matter including nanostructures. The nanostructures are functionalized in the sense of being provided with coupling ligands for enabling the targeting of the nanostructures to predefined sites.

In brief, the present invention is specifically directed to the insertion or implantation or targeting into patients of microscopic or submicroscopic devices at predetermined target sites. The microscopic devices are manufactured items each at least partially inorganic in composition. The insertion or implantation may be effectuated through open surgery, minimally invasive techniques, injection into the vasculature, or in some cases, through ingestion by the patient.

It is contemplated that the medical devices are in an inactive state prior to insertion in the patient and during transport through the patient to a target site in the patient. This transport may be accomplished through the natural functions of the body, for instance, through the individual patient's vascular system, endocrine system, digestive tract, and/or lymphatic system, etc. Alternatively or additionally, there may be a more direct conveyance of the medical devices to their respective target sites. For instance, the devices may be deployed in the patient through a catheterization process (e.g., vascular), an endoscopic or laparoscopic procedure, hypodermic injection, etc.

The present invention contemplates that the microscopic or submicroscopic medical devices become effectively attached to cellular or molecular target structures at the respective target sites. These target structures may take the form of protein segments embedded, for instance, in cellular or viral membranes. The targets may be viral antigens expressed in infected cells of a host organism. In any case, the proteins are markers for the particular kind of target cell, while effective attachment is preferably effectuated via ligands in the form of antibodies or cognate proteins (polypeptides). These ligands are provided as connector elements on the microscopic devices during the manufacturing process.

Pursuant to the present invention, the microscopic medical devices take the form of nanostructures, that is, fabricated elements having a nanometer to micrometer size. A medical device such as a battery may comprise a single nanostructure. Alternatively, a microscopic medical device may comprise several nanostructures which are separately inserted into the patient and which self-assemble to form a more complex device inside the patient, for instance, at a target site. Self-assembly is effectuated by providing members of a connecting pair of nanostructures with respective cooperating or interlocking ligands. The nanostructures thus seek each other out and self-attach in the same manner as one or more nanostructures attach to a target molecule at a target cellular site.

Accordingly, a medical method in accordance with the present invention utilizes an implantable microscopic medical device including a nanostructure provided with a ligand. The method in part comprises inserting the medical device into a patient, effectively attaching the targeting nanostructure via the ligand to an instance of a predetermined type of target structure inside the patient, and thereafter utilizing the nanostructure to perform a preselected medical diagnostic or therapeutic function.

Typically, the target structure is a cellular structure such as a membrane protein or an instance of messenger RNA. However, the target structure may be an extracellular substance such as urea deposits or intravascular plaque. In some instances, the mere attachment of the nanostructure to the target structure will be sufficient to destroy the target structure. Where the target structure (e.g., protein) is embedded in a larger structure (e.g., cell membrane), that larger structure may be ruptured or destroyed as well. In other instances, the utilizing of the attached nanostructure entails an activation of the nanostructure. The activation may be implemented by a change in shape or dimension of the nanostructure and the introduction of energy into the reshaped nanostructure by induction. Alternatively or additionally, the activating of the nanostructure may be implemented by an attachment of the nanostructure to other nanostructures. For instance, the change in the shape or dimension of the nanostructure may be accomplished in whole or in part by a connecting of the nanostructure to other nanostructures. Or the attachment may result in an electrical device which may be operated to perform a predetermined function.

Where the target structure is messenger RNA, the nanostructure is utilized to destroy the mRNA. This destruction may be effectuated by mere attachment of the nanostructure via the ligand or may be effectuated in part by the heating of the nanostructure. The destruction of mRNA is beneficial, for example, where the mRNA is implicated in the replication process of a virus.

The nanostructure is frequently inserted into the patient in a deactivated or non-active state. After attachment to the target structure, the nanostructure is activated as part of the utilization procedure. The nanostructure may be provided with at least one additional ligand. In that event, the activating of the nanostructure includes coupling the nanostructure via the additional ligand to another nanostructure deployed in the patient. The two coupled nanostructures assemble in the patient to form, for instance, an electrical device or circuit. Then, the activating of the nanostructure further includes operating the electrical device. In one embodiment, the electrical device includes a nanobattery, or a series or parallel coupling of nanobatteries, and the activating of the nanostructure includes using a body fluid to enable ion migration under a potential generated by the battery. The nanostructure may be passivated, except at its ends, to insulate the structure from electrolytic action of the body fluids. In addition, end cap structures may be provided to temporarily insulate the ends of the nanostructure from the body fluids. The end caps may be made of a biocompatible material such as a polymer which dissolves in body fluids. In a more specific realization of the invention, the electrical device includes a timing circuit, with the activating of the nanostructure including generating an electrical event periodically under the action of the timing circuit. This electrical device may function as a pacemaker. In that case, the devices are anchored to a predetermined site, e.g., a structural site, in cardiac tissue.

A nanobattery circuit assembled in situ in accordance with the present invention may include a timing element in the form of an organic or inorganic structure, such as a single molecule, energized in body fluid to produce pulses of electricity, changes of resistance to modulate a battery circuit. A molecular structure is configured to have its conductivity in a particular direction modulated by a flow of ions around the circuit in a fixed or variable way.

In another particular procedure pursuant to the present invention, a nanostructure may be anchored proximately to an injury site in a nerve, together with millions or billions of similar nanostructures) for purposes of facilitating an effective repair of injured nerve tissue, to restore nerve conduction. The nanostructures serve in the generation and/or conduction of electrical current in the injured nerve tissue. This electrical current may be generated via a battery assembled in situ at the site of the nerve cell injury. Alternatively, the electrical current may be generated inductively. The inducing of the current includes generating, outside of the patient, an energy field and subjecting the nanostructures inside the patient to the energy field.

Where the predetermined type of cellular structure includes a protein or protein segment, the ligand on an implanted nanostructure may include a polypeptide or antibody selected to couple with the protein or protein segment. This protein may a marker for a particular kind of cell, for instance, a cancer cell, a fat cell, or a viral infected cell, and disposed in the wall or membrane of the cell. In that event, the nanostructure is activated to destroy the cell. In one form of activation pursuant to the present invention, the nanostructure attached to the protein is heated, either inductively or via a nanobattery assembled through ligand interaction at the target site. The heating of the nanostructure results in a disruption or rupture of the cell membrane and concomitantly a fragmentation or lysis of the targeted cell.

Pursuant to the present invention, destruction of an undesirable cell may be effectuated by inserting a nanostructure into the cell and thereafter heating the nanostructure. The insertion may be accomplished by attaching the nanostructure to a target transport mechanism on the surface of the cell, by coating the nanostructure with a protein sheath which is subject to absorption by a cell, or by attaching the nanostructure to a virus which is transported through the cell membrane. The attachment of the nanostructure treatment device to the virus carrier may take place in vivo or in vitro.

A ligand in the form, for instance, of a nucleotide sequence, polypeptide or antibody may be attached to a nanostructure via a polymer, pursuant to known techniques. Alternatively, the attachment may occur via an avidin-biotin or streptavidin-biotin link.

In accordance with another feature of the present invention, the activating of a nanostructure deployed in a patient is implemented in part by changing a physical dimension of the nanostructure. This change in physical dimension may occur automatically by virtue of the attachment of the nanostructure via a ligand to an instance of the predetermined type of cellular structure. The purpose of having the nanostructure change in dimensions is to change a resonance characteristic of the nanostructure. Prior to the change in dimension, the nanostructure is unreceptive or impervious to an energy field of a particular frequency or wavelength. After the change in dimension or size, the nanostructure absorbs energy from the field, whereby current flows and heat is resistively generated.

Where an implanted nanostructure is heated inductively, the nanostructure may be completely passivated, i.e., completely enclosed in a protective or insulating sheath. Alternatively, a nanostructure such as a nanotube may be heated by connecting the nanostructure to a "nanobattery" in a "nanocircuit." That circuit may be substantially isolated from body fluids. Alternatively, the circuit may include a segment or path extending through body fluids of the patient.

Where an implanted nanostructure functions as a battery, the nanostructure has opposing ends provided with elements of different valences or electron affinities. The activating of the nanostructure includes using a body fluid to enable ion migration under a potential generated between the minerals. Alternatively, the nanostructure may be provided with mutually spaced magnetic, paramagnetic, or diamagnetic elements, currents being generated by the motion of charged magnetic particles.

As mentioned above, a nanostructure may be inserted into a patient by injection through a lumen of a medical instrument such as a hypodermic syringe, catheter, or endoscopic instrument having an end portion disposed in the patient.

A related medical composition comprises, in accordance with the present invention, a biocompatible or pharmaceutically acceptable fluid carrier or matrix, and at least one microscopic medical device including a nanostructure provided with a ligand, the medical device being disposed in the carrier or matrix. The ligand is attachable to a predetermined type of cellular structure inside a patient, while the nanostructure is activatable, after attachment of the nanostructure to an instance of the cellular structure via the ligand, to perform a preselected medical diagnostic or therapeutic function.

The nanostructure may be provided with at least one additional ligand couplable to another nanostructure after an insertion of the matrix with the medical device into the patent. The two nanostructures may be configured to form an electrical circuit upon coupling of the nanostructures via the additional ligand or functionalized complex.

The nanostructure may include an electrical circuit element such as a battery cell, a monostable multivibrator, a timer, resistive, capacitive, and/or inductive elements, and a chemical sensor or receptor.

A medical composition in accordance with the present invention comprises an effective number or concentration of microscopic medical devices each including a nanostructure provided with a ligand effectively attachable to a predetermined type of target structure inside a patient. The nanostructure is utilizable, after an effective attachment of the nanostructure to an instance of the target structure via the ligand, to perform a preselected medical diagnostic or therapeutic function.

As discussed above, each nanostructure may be provided with at least one additional ligand couplable to another nanostructure after an insertion of the matrix with the medical device into the patent, while the ligand may be taken from the group consisting of an antibody and a peptide sequence, the predetermined type of target structure being taken from the group consisting of a protein and a polypeptide.

Pursuant to the present invention, each nanostructure may be provided with a masking agent such as albumin for blocking coupling sites on such nanostructure that are free of the ligand.

A method and a related composition in accordance with the present invention provide a new era in medical treatment and diagnosis. The war against viral and bacterial infections, as well as against cancer, can be carried forward now on a cellular level using microscopic and submicroscopic devices.

The present invention more generally contemplates a composition comprising microscopic devices each including at least one nanostructure provided with at least one ligand for effectively attaching the nanostructure to a predetermined type of target structure. This composition may be used in medical or nonmedical applications. The nanostructures of the microscopic devices have covalent bonding sites which in one embodiment of the invention are saturated with ligands. Alternatively or additionally, the nanostructures of the microscopic devices are provided with at least one masking agent for blocking coupling sites on the nanostructures free of ligands. As discussed above, the nanostructures may be each provided with at least one ligand couplable to another nanostructure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 (see Original Patent) shows a transport or delivery configuration of a submicroscopic medical device 10 comprising a nanostructure 12, specifically a nanotube of a given length, provided with a ligand 14. The ligand 14 is designed and constructed to attach to a predetermined kind of target molecule in the body of a patient PB (FIG. 3 (see Original Patent)). Ligand 14 is exemplarily an antibody which is selected to latch onto an amino acid sequence in a target protein 16 (FIG. 3). As shown in FIG. 3, the target protein 16 may be located in a membrane 18 of a biological cell 20 such as a cancer cell, a viral organism, or other undesirable protein-containing biological component. Alternatively, the target protein 16 may be located inside a target cell, as described in detail hereinafter. Inside a cell, a target protein may be a DNA binding protein. Outside a cell, a target protein may be a prion, such as those implicated in so-called mad-cow disease.

Ligand 14 may be attached to the respective nanostructure, specifically nanotube 12, via any suitable method. For instance, pursuant to methods well known in the art, a polymer link or magnetic particle 21 may serve as a binding component. Alternatively, avidin and biotin may be used to link ligand 14 to nanotube 12. During manufacture, streptavidin is connected to a carboxyl terminus on nanotube 12 via an amine by a dehydration reaction. (See "Covalently Functionalized Nanotubes as Nanometre-sized Probes in Chemistry and Biology," Stanislaus S. Wong et al., Nature, Vol. 394, 2 Jul. 1998, pp. 52-55.) It is then a straightforward matter to attach biotin to ligand 14 and to then link the biotinylated ligand 14 to the nanotube 12 via the streptavidin.

Medical device 10 of FIG. 1 is typically delivered into a patient PB as part of a medical treatment and/or diagnostic composition 22 illustrated schematically in FIG. 2 (see Original Patent). The medical composition includes a biocompatible fluid carrier matrix 24 and a multitude of microscopic medical devices 10. Carrier matrix 24 may be a saline solution, or a blood plasma in the case that the medical composition 22 is injected into the vascular system of the patient. Other kinds of biocompatible fluids suitable as a delivery vehicle are known to those skilled in the art.

Composition 22 may be delivered to the patient PB by any process suitable to the type, location and numerosity of target cells 20. Where target cells 20 are in a large tumor, delivery of composition 22 may be effectuated by simple injection into the vascular system of the patient PB, inasmuch as every large tumor has a well developed blood supply. Alternatively, composition 22 may be injected directly into the tumor, for instance, via a needle which is deployed by a physician under visual guidance provided by a camera (endoscopic, laparoscopic, etc.), a magnetic resonance imaging (MRI) apparatus, a computer-aided tomography (CAT) machine, or an ultrasonic scanner (see U.S. Pat. Nos. 6,023,632 and 6,106,463). Where the target body is a microorganism which infects a particular organ or type of tissue in the body, composition 22 may be injected directly into that organ or those tissues. Generally, intravascular injection is appropriate where a disease state is systemic, rather than localized.

In the transport or delivery configuration of nanotube 12 shown in FIGS. 1 and 2 (see Original Patent), the nanotube has a folded-over or doubled-up configuration represented schematically by a divider line 26. After the medical treatment and or diagnostic composition 22 is injected or otherwise delivered to the patient, the coupling of the ligand 14 to an instance of its target protein 16, nanotube 12 naturally springs open from the folded transport and delivery configuration of FIGS. 1 and 2 to an expanded activation configuration shown in FIG. 3 (see Original Patent). This expanded configuration is characterized by having at least one physical dimension which is larger than any physical dimension of the folded configuration, thus enabling reception by the nanotube of a predetermined wavelength or frequency of energizing energy 28 emitted into the body of the patient by an external field generator 30. Generally, field generator 30 emits energy 28 in the form of electromagnetic radiation or a magnetic field. In some cases, other forms of energy may be useful, such as mechanical vibrational energy of an ultrasonic frequency or a stream of nuclear particles. In such a case, field generator 30 takes a specific form including ultrasonic electroacoustic transducers (not shown) or a particle generator (not shown).

It is to be noted that the folded transport and delivery configuration of nanotube 12 shown in FIGS. 1 and 2 is detuned with respect to the energy 28 produced by field generator 30. Generally, in the folded transport and delivery configuration, nanotube 12 has no dimension long enough to enable absorption of the particular wavelength of the field energy 28. Thus, only those nanotubes 12 which have coupled to respective target proteins 16 via the respective ligands 14 are activated to receive energy 28. The inductive absorption of this energy by the opened or expanded nanotubes 12 heats the nanotubes at least to the point where the cell membrane 18 is disrupted or ruptured, causing destruction of the cell 20 and possibly of adjacent connected cells. This method thus serves in the treatment of cancer and infectious diseases such as AIDS, hepatitis, malaria, yellow fever, anthrax, etc. The method may also be used in the treatment of autoimmune diseases. The method is effective to destroy pathogen-infected cells of a host organism. All that is necessary is the selection of suitable target proteins 16 in the cell membranes 18 and the manufacture of antibodies each matching an amino acid sequence or peptide chain of those target proteins.

It is to be noted further that the active or energy-absorbing configuration of a nanotube 12 may be one in which the nanotube is connected to one or more other nanotubes to achieve a collective length great enough for absorbing electromagnetic energy or a predetermined wavelength. That wavelength is easily selectable to be absorbable only by the activated or assembled nano-antenna and not by any natural structure in the patient.

One particular kind of target structure for a nanostructure medical device as described herein is the messenger RNA (mRNA) of various viral species, such as the hepatitis B virus and the AIDS virus. In that case, ligand 14 of nanotube 12 is designed to attach to the target mRNA. In some cases, the very attachment is sufficient to prevent effective functioning of the particular mRNA. In other cases, effectively blocking the viral replication process requires a more active interference, such as a heating of the attached nanotube 12, thereby destroying both the nanotube and the attached mRNA.

Claim 1 of 13 Claims

1. A medical composition comprising: a biocompatible fluid carrier matrix; and at least one microscopic medical device including a nanostructure provided with a ligand, said medical device being disposed in said matrix, said ligand being effectively attachable to a predetermined type of target structure inside a patient, said nanostructure having a passivation coating or layer adapted at least in part to disintegrate after a predetermined period of time in body fluids or upon attachment of the nanostructure to a respective target structure.

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