NL2019374B1 - Kit and Method for Microarterial Imaging and Radiotherapy - Google Patents
Kit and Method for Microarterial Imaging and Radiotherapy Download PDFInfo
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- NL2019374B1 NL2019374B1 NL2019374A NL2019374A NL2019374B1 NL 2019374 B1 NL2019374 B1 NL 2019374B1 NL 2019374 A NL2019374 A NL 2019374A NL 2019374 A NL2019374 A NL 2019374A NL 2019374 B1 NL2019374 B1 NL 2019374B1
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Abstract
The present invention provides, in general, compositions comprising a microparticle-based pre-targeting vector comprising a diagnostic and/or therapeutic functionality, and a second component that selectively binds to the pre-targeting vector component. This secondary component carries a diagnostic or preferably a therapeutic functionality, for in vivo parenteral topical administration and target tissue specific delivery. The invention also features compositions comprising secondary compounds that can be coupled with a label, for instance a diagnostic or therapeutic label and that selectively bind to the pre-targeting vector, and methods for its use in treating patient.
Description
Kit and Method for Microarterial Imaging and Radiotherapy
Field ofthe Invention
The present invention relates to materials and methods for that support loco-regional therapeutic treatment based on image guidance. The present invention provides, in general, compositions comprising a pre-targeting and/or diagnostic vector component, and a second component that selectively binds to the pre-targeting vector component, and is able to elicit a therapeutic response. This combination can be used for in vivo parenteral local administration and target tissue specific induction of a therapeutic response.
Background ofthe Invention
Hepatocellular carcinoma (HCC) is a major worldwide health problem and provides a typical medical application for the proposed local intervention strategy. It is the most common primary malignancy ofthe liverand the third most common cause of cancer-related mortality. The incidence of primary liver cancer is increasing in several developed countries, including the United States, and the increase will likely continue for some decades.
About 90% of patients with HCC are untreatable via surgery, or poorly responsive to chemotherapy. While externally delivered conventional radiotherapy, typically using a gamma radiation source can cause hepatic tumours to regress or even be destroyed, the dose of radiation required to destroy hepatic tumours far exceeds the tolerance of the normal liver cells immediately adjacent to the tumour. Hence, direct radiation therapy is difficult to use because of targeting and radiation dose limitations. Radio-embolization therapy provides an alternative more targeted means of selective in-situ radiation. Radioembolization is a therapy method that is often applied for primary liver tumours and metastases that are untreatable via surgery or chemotherapy. During the therapy currently microspheres or microparticles containing therapeutic radioisotopes (y-emitters such as yttrium-90 or holmium-166) are delivered intra-hepatically where they provide localized radiation that is believed to cause damage to the diseased cells. In spite ofthe clinical benefits of this local therapy, difficulties in confining the microparticles to the target fragments of the liver may result in hepato-pulmonary shunting.
Shunting results in the displacement of the therapeutic effect to non-target organs, which may include highly sensitive tissue such as the lungs. This yields ineffective dose distribution and has been described as inducing seriously toxic adverse effects in a number of cases.
To predict the likely occurrence of shunting during radioembolization procedures, patients are typically subjected to a pre-treatment diagnosis, generally referred to as a scout scan. During this scan procedure, a non-toxic diagnostic marker, typically microparticulate technetium-99-labelled macro-albumin aggregates (MAA)) is applied that mimics the behaviour of the 90Yttrium therapeutic microparticles prior to treatment. The distribution of this diagnostic marker is typically documented by Single-photon emission computed tomography (SPECT), a nuclear medicine tomographic imaging technique using gamma rays, often coupled with a single-slice CT measurement (SPECT-CT). For other diagnostic markers e.g. a scout dose of holmium-166 comprising microspheres, or optionally other visualization modalities such as magnetic resonance imaging (MRI), or ultrasound (US), may be applied, respectively. Besides providing a quantitative insight in the degree of shunting, the pre-interventional imaging also helps provide a dosimetric distribution model for the therapeutic isotopes, and an accurate three-dimensional visualisation of the tissues targeted.
After validation and/or optimization of the microparticle delivery using one or multiple scout scans, the therapeutic microparticles are typically applied. Post-therapy SPECT/CT, MRI, and/or positron emission tomography (PET) is then applied to relate the delivery of the therapeutic portion to the distribution defined in the scout scans.
Unfortunately here discrepancies in particle composition and pharmacokinetics between the diagnostic microparticles and their therapeutic counterparts results in discrepancies between the diagnostic and therapeutic procedures. Also, there is a time lag between the two treatments, as well as the fact that during the both treatments, a new injection has to be performed. As result, shunting still occurs during a significant portion of the therapeutic interventions (up to 25%). At that point, preventive measures no longer can be taken.
To create an increased level of control a technique is needed that supports selective local response to therapy, improves the logistics of local therapy delivery and/or reduces the chance of toxic side effects..
Summary of the Invention
It is therefore an object of the present invention to provide a method of local pre-targeted therapy delivery based on microparticles.
Accordingly, in a first aspect, the present invention provides a composition for use in vivo parenterallocal administration, comprising microparticles as pre-targeting vectors. These particles comprise one or more pendent reactive moieties that are able to form a high affinity interaction with a complementary reactive moiety residing on a therapeutic secondary component. This selective interaction can comprise of non-covalent and/or covalent bonds.
Accordingly, one aspect of the present invention relates to a complementary component in vivo parenteral topical administration and for forming the selective non-covalent high affinity interaction with a complementary host moiety, and/or the selective covalent bond with a host compound having a complementary functionality to the pre-targeting vector component according to the invention; wherein the secondary component comprises a complementary guest functionality, and at least a first diagnostic and/or therapeutic agent. A still further aspect of the invention relates to a kit for forming a diagnostic and/or therapeutic occlusion at a target site within a body, the kit comprising: a vector component; and a complementary component functionalised for selectively attaching to the vector component in vivo. A still further aspect of the invention relates to a method of treating diseased tissue in vivo, the method comprising the steps of: (a) providing an administration medium comprising microparticles of a pre-targeting vector component, and (b) delivering a diagnostically and/or therapeutically effective amount of the a pre-targeting vector component into the tissue of interest; and (c) subjecting the target organ/tissue to a diagnosis step to determine if significant shunting occurs to healthy tissues; and (d) injecting intravenously or locally a therapeutically effective amount of a complementary secondary component comprising a diagnostic or preferably therapeutic agent, thereby producing a therapeutically active matrix in the subject tissue. A still further aspect of the invention relates to a method of locally treating a disease, comprising administering to a target area of a patient in need thereof the kit suitable for diagnosing and treating the disease.
Description of the Figures
Fig. 1 schematically illustrates the pre-targeting concept according to the invention, in a preferred radioembolization embodiment, by the chemical and functional steps involved. A) Representation of the different chemical functionalities and components. B) A pre-targeting (guest) agent "mTc-MAA-Ad displays either pulmonary or hepatic accumulation depending on the route of administration, intravenous (i.v.) or local. C) Following i.v. administration, as a targeted (host) agent, "mTc-Cy50.5CD10PIBMA39, a prominent distribution to the kidneys, liver and stomach is observed. D) Subsequent to i.v. administration (Model I) of MAA-Ad, accumulation of "mTc-Cy50.5CD10PIBMA39 is seen in the lungs, whereas following local administration of MAA-Ad into the liver (Model II), liver uptake of "mTc-Cy50.5CD10PIBMA39 is most predominant. Organs are marked as (1) lungs, (2,) liver, (3) kidneys, (4) stomach, and (5) urinary bladder.
Fig. 2 shows a fluorescence confocal microscopy-based evaluation of Cy50.5CD10PIBMA39 (Cy5) binding to MAA-Ad (top) and non-functionalized MAA (bottom). The MAA-Ad localized particles (brightfield) reveal a higher degree of staining compared to MAA alone, indicated by the higher Cy5-related fuorescence intensities (in red).
Fig. 3 shows the influence of MAA(-Ad) on the uptake of 99mTc-Cy5o.5CDioPIBMA39 in the lungs and liver (Table 1). A) Uptake in the lungs increased when MAA-Ad was administered i.v. (Method I). B) Increasing uptake in the liver was seen when MAA-Ad was administered locally (Method II).
Fig. 4 discloses fluorescence confocal microscopy images of a Cy5-Polystyrene-Ad (PS-Ad) as mixroparticulate guest, for a non-covalent functionalization test, indicating the host guest inclusion complexes also work well when employing polymer beads.
Fig. 5 discloses fluorescence microscopic images (a) of a MAA Cy5 signal covalently bound to MAA using "Click" chemistry, versus a bright-field image, indicating that covalent selective binding via "click" chemistry also works instead of an inclusion complex.
Fig. 6 discloses fluorescence microscopic images showing the biodistribution of ""relabeled cyclodextrin polymers in mice with adamantane (Ad)-functionalized macroaggregates (MAA) administrated into the lungs. Fig. 6 (a) 99nrc-Cy5o5CDiOPiBMA39 2 hours post injection, Ad-MAA in lungs of mice, (b) 99mTc-Cy5i.sCD72PIBMA389 2 hours post injection, Ad-MAA in lungs of mice, (c) 99mTc-Cy3o.5CDioPIBMA39 2 hours post injection without Ad-MAA in lungs of mice, and (d) 99mTc-Cy3i.sCD72PIBMA389 2 hours post injection without Ad-MAA in lungs of mice, illustrating the benefit of multiple binding sites.
Detailed Description ofthe Invention
The present invention provides materials and methods for locally diagnosing and/or generating a therapeutic response to diseased or infected cells/tissue. It more specifically relates to physically anchor, or otherwise to permit an intra-arterially supplied pre-targeting vectorto remain in contact with the diseased or disease bearing region and not be immediately eliminated or washed out from that region; and to measure and diagnose the stability ofthe vectors positioning at the desired location, and eventually, to generate or solicit a therapeutic response with a suitable agent that selectively binds to the vector. By choosing the appropriate diameter and shape, the present method uses the natural filtering effect of the target tissue, such as the liver, to accumulate the particles.
The present invention is advantageously based on the principle of first locating microparticles that acts a "vector" compound in the target area, and subsequently functionalisation of the thus located microparticles, by coupling "agent" compounds with a given functionality by a highly selective affinity interaction with the vector compounds. Such interactions are often described as host-guest interactions between a host compound and a guest compound, wherein the recognition and localisation may be achieved by host-guest interaction relying on physical affinity or, selective covalent chemical bonding.
Definitions
Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. "Radio-embolization" refers to locally administering radioactive materials to patients with cancer as a form of therapy. In traditional radio-embolization, the radioactive materials have been incorporated into microspheres of regular size for injection into the arterial blood supply of the target organ or tumour. When these radioactive particles or microspheres are administered into the blood supply of the target organ, local accumulation of the microspheres induces "Selective Internal Radiation Therapy "(SIRT). Generally, the main application of SIRT has been to treat cancers in the liver, but may expand based on the present materials and methods. The present method and components allow to create a source of localized radioactive microparticles locally from a micro-particulate vector components, and by subsequently anchoring radioactive isotopes to these vectors. The present invention now allows to log the microparticles in place first, and then to foresee them with a radioactive component, thereby simplifying the preparation and administration greatly. Herein, thus, the term "radio-embolization" in particular refers to providing a microparticle first at the desired location, and then locking the radiation source to the particle, thereby resulting in a highly targeted and effective 2-component "Selective Internal Radiation Therapy "(SIRT). "Chemo-embolization" refers to locally administering chemically or biologically active materials to patients with a disease, such as cancer, an infection, an autoimmune illness or the like, as a form of therapy, whereby the chemically or biologically active materials are coupled to microspheres accumulated locally to induce a 2-component "selective internal chemotherapy".
The present invention thus makes use of at least two components, the so-called host and the guest component, whereby one is first locally accumulated, and the second component is then introduced into the patient, to selectively couple to the component already in place. The host and the guest components are functionalised to provide complementary functionality. The term "complementary functionality" herein refers to a highly selective binding chemistry, wherein two or more complementarily functionalised partner molecules are likely to react, or bind in a predetermined reaction pathway.
As stated, the host-guest recognition may advantageously be done using selective physical interactions, such as those provided in supramolecular host-guest inclusion complexes. A preferred example for such inclusion complexes are for instance an adamantane (Ad) as host moiety, and a cyclodextrin (CD) as guest moiety. Alternatively, or additionally, a host guest recognition may also be done by selective covalent chemistry, e.g. chemical bonding as for instance using "Click" chemistry between azide and alkyne moieties, whereby the two reactants advantageously are a "host" moiety bound to the vector compound, and a guest moiety bound to the agent, whereby the host and guest will react to form a covalent bond when exposed to each other under appropriate conditions.
The present invention, both compositions and method, have the clear benefit of providing a first allowing to introduce a pre-targeting vector that in itself may not need to have any strong therapeutic or diagnostic effect, to verify the accurate location, and stability of the positioning of the vector at this location, and then to modify the vector in situ using a secondary component functionalized with one or more desired activities. This not only allows to remove steps that are usually employed in radio-embolization treatments at the moment, but also reduces a number of invasive or otherwise cumbersome treatment steps. At the same time, so far difficult to use radioisotopes may be employed e.g. 177Lu and alpha-emitters. As well as other activities may be coupled with the vector that so far were not accessible or possible.
Lastly, the present method also allows to use functional compounds that were previously not useful, and does not require a specific radio-activation step of the microparticles themselves, but instead permits the use of readily available standard materials.
Micro-particulate Pre-targeting Vector
The pre-targeting vector preferably comprises a multitude of microparticles that are dimensioned and configured to ultimately get lodged in the target tissue, and thus provide a local target for a secondary component. Preferably these may be dimensioned to pass through larger blood vessels, such as arteries and veins, but eventually get lodged in small vessels and extravasations, in particular if intravenous administration is preferred. "Microparticles" refers to particles or structures that are of a suitable size and dimension, and of suitable composition to be injected into the desired target area.
The pre-targeting vector preferably comprises of microparticles which accumulate in cells (e.g. macrophages), in the interstitial cell fluid or in the microvascular bed, or diffuse in the lymphatic network of tissue wherein they have been injected.
The average particle diameter of the particles in the present invention depends on the desired target area, and to some extent also on the way of administration, e.g. intravascular versus direct injection into the target tissue area. In particular for intravascular administration, considering the diameter of a blood vessel as target site of an embolus, is preferably between 1 and 1000 pm, more preferably between 2 and 300 pm. In a preferred embodiment, these microparticles are approximately 1-150 pm in maximum diameter, and more preferably in the range of 5-70 pm, and perhaps even 10-40 pm.
Furthermore, the particles preferably have a weight average particle size distribution width wherein more than 99% of all the particles are below average particle size of 100 pm, more preferably in the range of average particle size of 50pm.
Here, the "distribution width of the particle diameter" refers to the range of particle size that would contain more than 99% of all the particles. The particle size of the microparticles of the present invention can be measured by a light scattering method or (electron) microscopy, more preferably by a laser diffraction method, wherein the particle size is reported as a volume equivalent particle diameter. Alternatively, the size may be determined by visible light, or electron microscopy, as appropriate.
Suitable microparticles may include synthetic organic polymeric particles or inorganic glass or metal (e.g. FeO) beads, but also may include naturally occurring and purified compounds such as polypeptides or the like. The microparticles may be organic, or inorganic, or can comprise of mixtures or can consist of combined organic/inorganic materials.
Suitable organic vector components include polymeric components, whether biologically originating, or synthetic.
Examples of useful synthetic polymers formed by chemical cross-linking include polyethylene glycol (hereinafter, "PEG"), polypropylene glycol (hereinafter, "PPG"), polyvinyl alcohol (hereinafter, "PVA"), polystyrene ("PS"), polyacrylic acid, hydroxyethyl acrylate, polyhydroxy ethyl methacrylate, polyvinyl pyrrolidone, carboxymethyl cellulose, dextrans or other sugar-based polymers; homopolymers or (block) copolymer or the water-soluble polymer of the water-soluble polymer selected from the group consisting of hydroxymethyl cellulose and hydroxyethyl cellulose, a- hydroxy acids, the a- hydroxy acid cyclic dimer, a block copolymer of a monomer selected from the group consisting of hydroxy dicarboxylic acids and cyclic esters may be employed.
Particularly useful materials for the vector include hydrogel beads, such as those made from polyhydroxy polymers such as polyvinyl alcohol (PVA) or copolymers of vinyl alcohol, which may be readily tagged with the host moiety by reaction of pendent hydroxyl moieties within the polymer network, using for instance activating agents such as carbonyldiimidazole. Alternatively, particles that are prepared by emulsion or dispersion polymerisation may be employed.
Suitable inorganic vector components include metal particles, such iron, gold, or silver particles, glass beads, porous Silica beads, refractory beads and the like.
The shape of the particles of the present invention may be essentially any shape found useful to lodge the microparticles at the desired site.
Non-spherical particles like MAA or carbon nanotubes would provide a higher degree of accumulation due to their shape, and may remain in place more firmly. On the other hand, essentially spherical particles may also be employed for a better flow in intravascular administration, or combinations thereof. The term "essentially spherical" as used herein refers to a generally spherical shape having a maximum diameter/minimum diameter ratio of from about 1.0 to about 2.0, more preferably from about 1.0 to about 1.5, and most preferably from about 1.0 to about 1.2. This definition is intended to include true spherical shapes and ellipsoidal shapes, along with any other shapes that are encompassed within the maximum diameter/minimum diameter ratio. This shape is assumed in situ and in absence of shear forces, whereas during the administration, the shape may change under pressure and shear.
The term "surface," as used herein, means the exterior portion of a microparticle that is accessible to the complementary "guest" component. This may be the surface in the case of non-porous particles, or the accessible surface including pores and voids in the case of a porous particle, or combinations thereof.
The term "interior portion," as used herein, means any portion of the particle that is interior to the surface. Generally, the vector particles according to the invention are solid or highly viscous polymeric particles, and not composed of micelles or cell walls with a fluid interior at the temperature and conditions of the administration.
The pre-targeting vector microparticles according to the present invention are typically host-tagged particles, preferably carrying pendent host tags or host moieties at their outer surface, or at least in such manner that the host moieties are accessible to the complementary guest component, e.g. where a porous particle is employed, such that the entire particle is rendered active for forming the host-guest complex or covalently bonded component. It should be noted that the host and guest functionality may be reversed, e.g. a pre-targeting vector may carry a guest molecule or moiety, where the modification of the secondary component may be negatively affected by carrying a host due to e.g. pharmacokinetics, or renal excretion.
The pre-targeting vector microparticles according to the present invention preferably also comprises an imaging label, e.g., a diagnostic and/or a detectable label.
The optionally encapsulated imaging label, e.g., a diagnostic label and/or a detectable label may be or comprise an imaging label itself, e.g., as a detectable label. This advantageously permits to determine if and when the pre-targeting vector microparticles are in the desired location, and of any loss occurs due to blood flow or degradation that may negatively impact a subsequent treatment.
Secondary Compound Composition
The secondary compounds according to the present invention have a smaller size than the pre-targeting vectors and can be tuned for their pharmacokinetics. They may be organic or inorganic, and are prefarbly based on synthetic, or naturally occurring compounds, or combinations thereof. The particulate materials may be formed from monomers or preferably of polymeric materials such as, amino acid sequences, polylactic acid, polyglycolic acid, polycaprolactone, polystyrene, polyolefins, polyesters, polyurethanes, polyacrylates and combinations of these polymers, and homo-or copolymers, and blends thereof. The particulate materials may further comprise suitable binding agents such as gelatin, polyethylene glycol, polyvinyl alcohol, glycerin, (poly)saccharides, DTPA, DOTO, NOTA other hydrophilic materials, and combinations of these. Suitable gelatins may include bovine collagen, porcine collagen, ovine collagen, equine collagen, synthetic collagen, agar, synthetic gelatin, and combinations of these. It is note that for covalent, preferably click-chemistry modifications, comparatively short and small components may be employed.
Examples of useful synthetic polymers formed by chemical cross-linking include polyethylene glycol (hereinafter, "PEG"), polypropylene glycol (hereinafter, "PPG"), polyvinyl alcohol (hereinafter, "PVA"), polyacrylic acid, hydroxyethyl acrylate, polyhydroxy ethyl methacrylate, polyvinyl pyrrolidone, carboxymethyl cellulose, dextrans or other sugar-based polymers; homopolymers or (block) copolymer or the water-soluble polymer of the water-soluble polymer selected from the group consisting of hydroxymethyl cellulose and hydroxyethyl cellulose, a- hydroxy acids, the a- hydroxy acid cyclic dimer, a block copolymer of a monomer selected from the group consisting of hydroxy dicarboxylic acids and cyclic esters may be employed.
Partially water-soluble polymers may be used, wherein typically biocompatibility is higher than for hydrophobic polymers. Also, due to the presence of hydroxyl groups, PEG, PPG, PVA, poly hydroxyethyl acrylate, poly hydroxyethyl methacrylate (hereinafter, "poly-HEMA") permits easy functionalization.
The secondary components are in any case preferably storage stable, and susceptible to nucleophilic substitution reactions, which may be used to functionalize the particles controlled manner to provide the guest moiety for inclusion complexes. The latter are preferably covalently bound, preferably at the particle surface, as appropriate, depending on the activation chemistry selected.
The weight average molecular weight of useful polymers, is preferably 200 or more. Further, for a discharge ex vivo to be facilitated by the living body, it is preferably 50,000 or less. The weight average molecular weig of the vector component may be suitably selected such that the desired pharmacokinetics and biological half-life are achieved. The weight average molecular weight of the polymers employed may be advantageously determined by gel permeation chromatography. The choice of the composition and the molecular weight depends also on the clearance from the body. Rapid and complete clearance of non-bound secondary components is critical. For example resorption of a radioisotopes in the kidneys may result in kidney failure as side effect from therapy, and hence fast clearance is desired.
Useful secondary components may include bio-resorbable components, which can be broken down by the metabolism, and excreted in a suitable time period to be removed alongside with the embolized tissue, depending on the desired duration of the vector component in the tissue.
Concentration
It is necessary to obtain the desired number of microparticles to be injected into the vascular system and/or tissue of a patient, in order to achieve a sufficiently high amount of diagnostic and/or therapeutic agents to be present. While the number of particles which may be injected or otherwise delivered will vary depending upon the patient's blood pressure, blood flow rate, metabolism, body weight, organ weight, etc., it has been found that approximately 200 to 2,500,000 or more particles suspended in a biologically safe solution and delivered to the patient may suffice, although larger quantities of particles may be necessary and desirable depending on various circumstances and conditions of use, e.g., tumour size, etc.
By knowing the concentration of particles in a given volume of dispersion, one merely needs to withdraw and inject the desired volume of liquid containing the desired number of particles.
Modification of the pre-targeting and secondary targeting vector material
According to the present invention, the pre-targeting vector microparticle material is associated with at least one host moiety, while the secondary vector material is associated with at least one guest moiety.
Preferably, the pre-targeting vector is covalently linked to a host molecule, in which case the guest-modified pre-targeting vector comprises one or more host functional groups. As used herein, such a pre-targeting vector has been linked to a first guest molecule and thereby comprises one or more host functional groups, is also called the " host -modified micro-particle" or a "pre-target vector". The secondary vector material is also linked to an at least one guest moiety, thus forming the "guest -modified secondary vector"
The modification of the vector molecules to comprise the host or guest moiety may be done by any suitable method that allows to link the gust moiety to the vector surface.
The linking of the guest or host molecule to the vector or secondary component is preferably done by conventional conjugation techniques known to the person skilled in the art. This guest molecule which is part of the guest-modified microparticle, then binds (non- )covalently to a host functional group residing on a preferably multivalent host structure. To be more specific, this interaction takes place by a one-to-one interaction between a guest functional group in the guest molecule and a host functional group in the host structure. Obviously, a higher load of guest molecules may results in a better complexation ratio, while too high of a load may prevent interactions by sterical hindrance. Accordingly, multivalent guests are preferred for non-covalent interactions, which may comprise multiple binding sites in one molecule, or microparticles that comprise separately multiple binding sites. The same applies mutatis mutandis to the host molecule, and the host-modified secondary vector.
Guests and hosts
The terms "guest" and "host" as used herein refer to two different, but complementary, binding partners that non-covalently, or covalently interact with each other.
As used herein, the term "guest moiety" or "group" means the part or moiety of a monomer of the guest molecule, which enables the binding to a complementary host functional group. A "guest molecule" is in turn a molecule that comprises one or more guest functional groups, where a monovalent guest molecule comprises one guest functional group and a multivalent guest molecule comprises at least two guest functional groups. As used herein, the term "host functional group" means the part or moiety of a monomer of the host molecule, which enables the binding to a complementary guest functional group. A "host molecule" is in turn a molecule that comprises one or more host functional groups, where a monovalent host molecule comprises one host functional group and a multivalent host molecule comprises at least two host functional groups. Preferably, one guest moiety interacts with one host moiety. Where non-covalent host-guest pairs are employed, according to the present invention, the interaction between the guest and the host may be reversible, and is determined by the affinity strength as expressed by dissociation constants. Typically a guest molecule does not normally interact with another guest molecule.
Examples for a non-covalent guest-host interaction include beta-cyclodextrin-adamantane, beta-cyclodextrin-ferrocene, gamma-cyclodextrin-pyrene, cucurbituril-viologen, and/or a Ni(NTA)-His tag. Examples for a covalent interaction include an Azide (N3)-alkyne interaction as a host-guest interaction. For example the dibenzocyclooctyne group (DBCO), or similar compounds such as BCN allows copper-free "Click" chemistry to be applied to vectors to be used in live organisms. DBCO groups will preferentially and spontaneously label molecules containing azide groups (-N3). Also, within physiological temperature and pH ranges, the DBCO group does not react with amines or hydroxyls naturally present in many biomolecules. Also, the reaction of the DBCO group with the azide group is significantly faster than with sulfhydryl groups, making this a highly selective reaction.
The term "inclusion complex" refers to any material wherein the host compound absorbs or embeds a guest compound to form a complex. For example, the guest compound may be embedded in a cavity formed by the host compound. The terms "inclusion material", "inclusion complex", "inclusion compound" are used as synonyms in this application.
Preferably, the guest-host components are each readily available, and enable to perform the methods of the present invention on a relatively large scale and/or in low cost devices.
As used herein, the term "guest-host molecule interactions" includes the non-covalent binding between respective guest and host functional groups. In a preferred setting, hydrophobic interactions, such as lipophilic interactions, are being used instead of interactions that are based on charge.
The functionality may be reversed, i.e. using the host molecule as the molecule that is linked to the vector, but as used herein, the host molecule or host structure is not linked to the vector directly, primarily via the guest molecule. The vector particle preferably may comprise a multivalent host structure, comprising multiple host functional groups, some of the host functional groups may be (non-) covalently bound to a guest molecule, while others remain free.
Preferred, essentially non-covalent host compounds are cyclodextrins, with adamantane moieties acting as host molecules. Cyclodextrins are cyclic polysaccharides containing naturally occurring D(+)-glucopyranose units in an a-(l,4) linkage. The most common cyclodextrins are alpha (a)-cyclodextrins, beta (3)-cyclodextrins and gamma (y)-cyclodextrins which contain, respectively, six, seven or eight glucopyranose units. Structurally, the cyclic nature of a cyclodextrin forms a torus or donut-like shape having an inner apolar or hydrophobic cavity, the secondary hydroxyl groups situated on one side of the cyclodextrin torus and the primary hydroxyl groups situated on the other. Preferably beta- cyclodextrin is used, which is the best binding partner for adamantane. The cyclodextrin may contain additional groups, such as an amine to attach it to a scaffold, one or more thiols to bind the cyclodextrin to a gold surface, or hydroxypropyl groups to increase solubility and biocompatibility. Other members of the cyclodextrin family (most likely alpha and gamma) can also be used for host-guest interaction, although different guests have to be introduced to achieve this. Accordingly, a good, but not the only, example of supramolecular host-guest interactions that can be applied in the invention is the non-covalent interaction between adamantane (as the guest molecule) and β-cyclodextrin (as the host molecule).
The side on which the secondary hydroxyl groups are located has a wider diameter than the side on which the primary hydroxyl groups are located. The hydrophobic nature of the cyclodextrin inner cavity allows for the inclusion of a variety of compounds. (Comprehensive Supramolecular Chemistry, Volume 3, J.L. Atwood et al., eds., Pergamon Press (1996); T. Cserhati, Analytical Biochemistry, 225:328-332 (1995); Husain et al., Applied Spectroscopy, 46:652-658 (1992); FR 2 665 169). Various cyclodextrin containing polymers and methods of their preparation are also known in the art. (Comprehensive Supramolecular Chemistry, Volume 3, J.L. Atwood et al., eds., Pergamon Press (1996)). A process for producing a polymer containing immobilized cyclodextrin is described in U.S. Patents 5,608,015, or 5,276,088 describe methods of synthesizing cyclodextrin polymers by either reacting polyvinyl alcohol or cellulose or derivatives thereof with cyclodextrin derivatives or by copolymerization of a cyclodextrin derivative with vinyl acetate or methyl methacrylate. The resulting cyclodextrin polymer contains a cyclodextrin moiety as a pendant moiety off the main chain of the polymer particle. Cyclodextrin-based polymers have been used for therapeutic applications (Kandoth et al. Two-photon fluorescence imaging and bimodal phototherapy of epidermal cancer cells with biocompatible self-assembled polymer nanoparticles. Biomacromolecules 2014 (15):1768-1776) and imaging agents (Yan et al. Poly beta-cyclodextrin inclusion- induced formation of two-photon fluorescent nanomicelles for biomedical imaging. Chemical Communications 2014 (50):8398-8401) and they showed excellent biocompatibility.
Adamantane is a lipophilic small molecule that may be attached to a vector, or conjugated to a microparticle that can be physically lodged in the target tissue. The adamantane structure combines rigidity with the ability to form diamondoid structures, and offers high binding affinities with cyclodextrins. In one aspect, the guest molecule may be adamantane, whereas the host molecule is preferably then a cyclodextrin that non-covalently interacts with adamantane. Both compounds are relatively cheap and easy to produce in controlled settings and non-toxic.
Scaffolding and Multivalent Guest Structures
The guest moiety may be connected to the microparticle by a "scaffold", i.e. a binding unit comprising a spacer molecule or otherwise suitable molecular structure. The scaffold may be intended to ensure that the guest moiety is presented to the incoming host moiety, and/or may permit to modify the microparticle easily. Also, several guest moieties or guest functional groups may be interconnected through a scaffold molecule to form a multivalent guest structure.
The term "multivalent" as used herein refers to a number of host or guest molecules, or functional groups thereof, that are part of the same molecule or structure. Multivalent interactions contain at least two functional groups of the same type (e.g. at least two guest functional groups, or at least two host functional groups) bound to each other through a backbone (or scaffold) that allows the multimerization of the matching guest or host molecule. The upper limit in multivalency depends on the purpose of the layer-by-layer manufacturing of guest-host molecule interactions, as disclosed herein. Without wishing to be bound to any particular theory, it is believed that multivalency enhances the affinity, and thus improves the binding, as monomeric guest molecules tend to show a significantly lower non-covalent interaction.
According to the present invention, a "multivalent host structure" or a "multivalent guest structure", is a structure comprising at least two host functional groups or guest functional groups, respectively. It can in principle be a dimer or polymer of suitable host or guest monomers, but typically the host or guest molecules have been attached or engrafted onto a polymer of a different type that allows for the attachment of the host or guest molecules. This is preferably used for non-covalent interactions, thereby increasing the binding strength.
In one preferably non-covalent embodiment of the present invention, a "multivalent host structure" or "multivalent guest structure" preferably comprises a scaffold or linker structure onto which the at least two host molecules or at least two guest molecules have been attached or engrafted resulting in that the scaffold structure comprises at least two host functional groups or at least two guest functional groups. The scaffold structure can be anything that allows attachment of the host or guest molecules of choice. The scaffold structure may of course also be part of, or integrally form the microparticle. In another embodiment, the scaffold molecule is a polypeptide comprising less than about 30, such as, e.g. less than about 25, less than about 20, less than about 15, less than about 10, less than about 5 or less than about 6 amino acids. It may also be an oligo peptide such as, e.g. a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. In one embodiment the repeat unit of the poly or oligepeptide is β-alanine.
Host Components
Suitable host components are components that are modified to selectively link up or react with the pre-targeting vector comprising the guest moiety. The selectivity of this linkage preferably allows to introduce the host component intravenously, rather than into the tissue, as the host component then automatically binds to the vector.
In one preferred embodiment, a moiety with the worst pharmacokinetics, e.g. highest lipophilicity, is defined as guest and will be part of the pre-targeting microparticles. This means its influence on the targeting is minimal.
The complementary host is then the moiety with the most favourable pharmacokinetics e.g. the least non-specific interactions.
In the case of Adamantane -Cyclodextrin complex, this would result in guest-host, as used herein.
For N3-alkyne covalent coupling, this would result in host-guest, meaning the azide should be part of the secondary vector.
Hence once the pre-targeting vector is in place, the secondary, host component may for instance be simply introduced into the blood stream, as it will bind selectively to the guest once encountered.
This not only reduces the steps required to treat and/or diagnose a patient, but also permits the use of various agents, and for instance the use of radioactive isotopes that are presently not used, as presently in SIRT, the microparticles themselves are prepared to contain the radioactive components, and thus the choices are limited to which isotopes can be introduced in the few reactors available for this purpose.
Also, it may permit to determine a dosage for particular treatment not at the reactor, as presently done for each treatment separately, but simply by calculating and administrating the amount of suitably modified host components which can be done at a patient treatment site, e.g. a hospital pharmacy.
Also, several different components may be administered, allowing for a combination therapy.
The host structure or secondary component thus may comprise a targeting moiety or molecule coupled to the particle, and the targeting moiety that in this manner helps deliver the bioactive agent and/or the imaging agent to a desired, i.e. vector location in a patient.
An exemplary method for preparing a host structure may include providing host nanoparticles comprising a pharmaceutically acceptable polymer and coupling, e.g., by coating, covalent linkage, or co-localization, to the surface of the nanoparticles the host moiety for coupling to the guest, and an imaging agent, a detectable label, or otherwise targeting moiety.
The method may further include one or more of forming a particle suspension, passing the particle suspension through a filter, removing impurities from the particle suspension, centrifugation to pellet the particles, dialyzing the particle suspension, and/or adjusting the pH of the particle suspension. The method may also include quenching the covalent linking reaction.
Suitable host components may include organic or inorganics components or mixtures thereof. For example, the host components can be selected from monomers-polymers and nanoparticles. Suitable polymers for example can be selected from poly(isobutylene-alt-maleic anhydride) (PIBMA), PAMAM, poly-acrylic acid, polysaccharides, polypeptides and oligopeptides. Some such polymers, such a PIBMA, has the further advantage that it prevents interaction with the immune system and thereby also functions as a cloaking group.
For many applications, it is also of importance that the selected structure is non-toxic. For some applications eliciting of a immune response may be a means to induce a therapeutic effect.
Suitable polymeric host components may comprise a pharmaceutically acceptable polymer core and a one or more bioactive agents and/or imaging agents. Preferably, the secondary component may comprises a pharmaceutically acceptable polymer core, and one or more bioactive agents, such as a drug or medicament encapsulated in the core.
Multivalent host structure
Preferably, for non-covalent interactions, the complementary component comprises multiple host moieties, thereby increasing the affinity for the guest functional groups of the guest-modified vector.
Preferably, the host structure according to the present invention is multivalent, i.e. comprises at least two host functional groups. In a preferred embodiment, the first multivalent host structure comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 9 or at least 10 host functional groups. In a preferred embodiment, the host comprises a scaffold structure, such as a polymer comprising as least about 5, such as at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35 or at least about 40 monomer repeat units. A preferred second component vector molecule may comprise multiple host sites, to generate multivalent structures containing either the host functional group of cyclodextrin adamantane. A preferred example is poly-isobutylene-alt-maleic anhydride (PIBMA), which can be easily functionalized, is non-toxic, and presents a multitude of negative charges after functionalization which increases water-solubility and provide cloaking.
Other preferred structures that could be applied in the methods of the present invention to generate multivalent structures comprising guest or host functional groups are other polymers containing anhydrides, PAMAM, nanoparticles (e.g. quantum dots), polyacrylic acid, and polysaccharides.
Diagnostic/Therapeutic Agents A benefit of the subject process is that various compounds may be employed as diagnostic or therapeutic labels, and may include chelates, a diagnostic, a therapeutic agent, or any combination thereof, using a simple pre-targeting platform. The second, complementary component may comprise a therapeutic agent or an imaging agent, or combinations thereof, e.g., it may include a diagnostic agent and/or a detectable label.
Immunogenic Agents: The term "immunogen" refers to a substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response (e.g., a specific antibody, specifically sensitized T-lymphocytes or both), while the term "immunogenic" relates to a reaction triggered by the presence of the immunogen.
Both the pre-targeting vector component and the secondary component may also carry various labels or agents other than host or guest moieties.
In certain embodiments, the one or more bioactive agents are covalently or non-covalently associated with the secondary component.
For example, a nucleic acid or protein included in the particle may comprise an imaging agent itself, e.g., a detectable label that may be attached to DNA or a protein. Alternatively, the secondary component may comprise an imaging agent that is separate from a nucleic acid or a protein, e.g., encapsulated in the core or disposed on or coupled to the surface. Additionally, the component may comprise one or more targeting moieties or molecules coupled to the component and/or the protein or nucleic acid, and the targeting moiety can help deliver the nucleic acid, the protein, and/or the therapeutic, imaging, and/or diagnostic agent.
The component may comprise an imaging agent, e.g., a diagnostic agent and/or a detectable label. The optionally encapsulated bioactive agent may be or comprise an imaging agent itself, e.g., a detectable label may be attached to a therapeutic agent. Alternatively, the particle may comprise an imaging agent that is separate from the bioactive agent.
In a preferred embodiment, a plurality of radioisotopes, bioactive agents, such as bioactive agents or contrast agents may be loaded onto a single host component, or spread over the guest and host component.
In one embodiment, the potentially radioactive isotope may be an isotope possessing a high absorption cross-section to neutrons, protons, electrons, or high energy photons. In a related embodiment, the potentially radioactive isotope has a high absorption cross-section to neutrons, and is selected from the group consisting of 10B, 149SAM, 1S7Gd, and 155Gd or any combination thereof, thereby providing a target area for fast neutron therapy.
Different isotopes may also be conjugated to the complementary compound, e.g. allowing the use of 177Lu, 99mTc, U1ln isotopes, or combination thereof, for instance.
In one embodiment, a magnetic resonance contrast agent may be employed, as for instance those selected from Manganese Oxide, perfluorocarbons, Feridex, Gadolinium, Combidex, Bang Magnetic Particles, Gd-DTPA, Gadolinium And Manganese Derivatives, Superparamagnetic Iron Oxide Particles, gadopentetate dimeglumine, Gd- DOTA, Gd-DTPA-BMA, Gd-HP-DO3A, Gd-DTPA-BMEA, Gd-DO3A-butrol, Gd-BOPTA, Mn-DPDP, Gd-EOB-DTPA, Gd-BOPTA, AMI-25, SH U 555A, gadoflourine-M, AMI-227, EP-2104R, P947, Gd-DTPA mesophorphryn, SH U 555 C, NC-100150, MS-325, gadoflourine-M, gadomelitolm manganese chloride, ferric amonium citrate, and barium sulfate suspensions. In one embodiment, a negative contrast agent may be employed, as for instance those based on superparamagnetic iron oxides: SPIO (Superparamagnetic Iron Oxide), typically employed for liver tropism, and USPIO (Ultrasmall Superparamagnetic Iron Oxide) typically for ganglion tropism.
These particles may predominantly have an effect on magnetic susceptibility (T2), and thus may produce a drop in signal, namely in T2* weighting.
In one embodiment, a contrast agent that can act as a Raman spectroscopy reporter, thereby allowing detection of the component with Raman spectroscopy.
In another embodiment, a contrast agent that can act as a fluorescence spectroscopy reporter, thereby allowing detection of the component with fluorescence spectroscopy.
In another one embodiment, the agent may comprise a photoacoustic contrast agent, thereby allowing detection of the component acoustically.
Also different bioactive agents may be attached to the complementary component, as well as compounds that enhance the interaction with other cells e.g. immune cells, thereby triggering for instance an enhanced and targeted immune response.
Bioactive agents according to the invention include but are not limited to a nucleic acid, DNA (e.g., a gene therapy vector or plasmid), an RNA (e.g., an mRNA, the transcript of an RNAi construct, or an siRNA), a small molecule, a peptidomimetic, a protein, peptide, lipid, surfactant and combinations thereof. Examples of therapeutic agents include but are not limited to a nucleic acid, a nucleic acid analog, a small molecule, a peptidomimetic, a protein, peptide, lipid, or surfactant, and combinations thereof. In certain embodiments, the imaging agent further comprises a detectable label.
In another embodiment, combinations of the above agents may be present, either on a single secondary component, or a mixture of differently functionalised secondary components.
Administration of the components
Administration of the pre-targeting vector
The vector components according to the present invention are administered locally, parenterally and/or topically, i.e. they are injected or infused into a particular area, and/or into a particular organ or tissue in a patient body. Examples include intrahepatic injections or infusions, intrapancreatic injections, or functionally, generally, intratumoral injections; intradermal and/or peritumoral injections or infusions. The components, in particular the pretargeting vector, are therefore chosen and designed in among other factors size, size distribution, compressibility, water content, flowability, deformation creep and/or stability, as well as optimal pharmacokinetics, e.g. rapid clearance and minimal background of non-complexed components, such that they can be infused or injected, and that they are dimensioned and functionalised to show minimal movement once they are distributed inside the relevant organ, with minimal or no shunting or otherwise bypassing occurring.
The delivery of the vector material via injection or implantation provides a means to effectively mechanically target the biomaterial to a specific site or location, thereby localizing the biomaterial and minimizing systemic side effects.
Moreover, the administration of the vector material via implant or needle based injection is minimally invasive and usually can be performed on an outpatient basis, resulting in a lower cost than other surgical forms.
Preferably, "delivering" comprises positioning a delivery device, e.g. a syringe or infusion catheter in proximity to a target region of a blood vessel, or directly into a target tissue not via vasculature, and ejecting the microparticles from the delivery device such that the particles are positioned in the target region.
Administration of the secondary Component
The complementary secondary vector components preferably are administered intravenously, or more generally intravascularly, since the components are accumulated at the pre-targeting vector component location, or likely excreted if not bound to the vector. This permits to reduce the number of steps in a treatment and diagnosis, which reduces the negative effect on a patient. Alternatively, the complementary secondary component may be injected locally, e.g. by inserting a cannula into the desired region, and injecting the material into the vicinity of the vector component.
Administration Medium
Components according to the present invention are particularly useful for embolizing liver tissue. In this case, the microparticles can be used as component dispersed in an appropriate dispersion medium.
The administration medium of the components may be a buffer/ serum solution, and may further comprise injection dispersing agent such as polyoxyethylene sorbitan fatty acid ester or carboxymethyl cellulose, such as methyl paraben or propyl paraben preservatives, sodium chloride, preservatives used in tonicity agents or injections, such as mannitol or glucose, stabilizer, solubilizing agents or excipients. The present invention thus preferably relates to a complementary component in vivo parenteral topical administration and for forming the selective non-covalent high affinity interaction with a complementary host moiety, and/or the selective covalent bond with a host compound having a complementary functionality of the vector component according to the invention; wherein the component comprises a complementary guest functionality, and at least a first diagnostic and/or therapeutic agent.
Preferably, the agent is selected from the group consisting of: a diagnostic agent, an imaging agent, a contrast agent, and a therapeutic agent, preferably a radioactive isotope or a chemotherapeutic agent.
Preferably, the agent is selected from the group consisting of one or more: anticancer agents, antibiotics, antihistamines, hormones, steroids, therapeutic proteins, biocompatible materials, imaging agents and contrast agents.
Preferably, the diagnostic agent is selected from the group consisting of magnetic resonance contrast agents, radioopaque contrast agents, ultrasound contrast agents, and nuclear medicine imaging contrast agents, more preferably, wherein the radioactive isotope is selected from the group consisting of: Y-90, P-32, P-33, Sc- 47, Cu-64, Cu-67, As-77, Ph-105, Pd-109, Ag-111, Pr-143, Sm-153, Tb-161, Ho-166, Lu-177, Re-186, Re-188, Re-189, lr-194, Au-199, Pb-212,1-131, Ac-225, Ra-223, Ra-224, and Bi-213.
The present invention also relates to a kit for forming an optionally bioresorbable diagnostic and/or therapeutic occlusion at a target site within a body, the kit comprising: a vector component composition as set out herein above; and a complementary secondary component as set out herein above, the complementary component being functionalised for selectively attaching to the vector component in vivo. Preferably, the complementary component comprises a therapeutic agent for delivery to the targeted target area.
The present invention also relates to a method, and to a compound or kit of compounds for use in treating a condition in vivo in a patient, the method comprising the steps of: (a) providing an administration medium comprising microparticles of a pre-targeting vector component, and (b) delivering a diagnostically and/or therapeutically effective amount of the a pre-targeting vector component into the target tissue, preferably into the tumour or tumour bearing tissue patient; and (c) subjecting the target tissue to a diagnosis step to determine if significant shunting occurs; and (d) administering a therapeutically effective amount of a complementary component comprising a therapeutic agent to the patient, thereby producing a therapeutically active matrix in the subject tissue.
Preferably, (b) comprises delivering the pre-targeting vector in a target region of a blood vessel.
Preferably, "delivering" further comprises positioning a delivery device in proximity to a target region of the blood vessel, and ejecting the pre-targeting vector particle(s) from the delivery device such that the particles are positioned in the target region.
Preferably, the target area is selected from one or more of liver, pancreas, thyroid, heart, peripheral nerve scaffold, breast, bladder, cartilage, bone, tendon, ligament, blood vessel, skin, lymph nodes, spinal cord, and/or tumour tissue The present invention also relates to a method, and compound of use for topically treating a disease, comprising administering to a target area of a patient in need thereof a kit according to the invention suitable for diagnosing and treating the disease. The following, non limiting examples illustrate the invention.
Example 1
In this example, a particularly useful example is employed as a vector component, i.e. a host-modified Technetium 99mTc macro aggregated albumin (99mTc-MAA), in an injectable form, comprising a sterile aqueous suspension of Technetium-99m (99mTc) labelled to human albumin aggregate particles. Its use advantageously permits to use for diagnostic purposes SPECT-CT, to visualize the occurrence of shunting, as 99mTc-MAA is a well-known imaging agent. Now modifying the material allows to combine a method in current practice with the method according to the present invention. In this way, clinically Technetium-99m macro-aggregated albumin (MAA) scintigraphy may be used to assess lung or digestive shunting prior to therapy, based on tumoural targeting and dosimetry. Computed tomography (CT) may then be performed during the angiography to aid in digestive vascularization recognition, as well as perfused tissue and tumour targeting evaluation. MAA scintigraphy may not only be used for lung-shunt evaluation, but can also aid in digestive shunt recognition and dosimetric evaluation and the marking of diseased tissue for radio-occult lesion localization.
All chemicals were obtained from commercial sources and used without further purification. NMR spectra were obtained using a Bruker DPX 300 spectrometer (300 MHz, *H NMR) or a Bruker AVANCE III 500 MHz with a TXI gradient probe. All spectra were referenced to residual solvent signal or TMS. HPLC was performed on a Waters system by using a 1525EF pump and a 2489 UV detector. For preparative HPLC a Dr. Maisch GmbH, Reprosil-Pur 120 C18-AQ, 10 pm column was used and a gradient of 0.1 % TFA in H2O/CH3CN (95:5) to 0.1 % TFA in H2O/CH3CN (5:95) in 40 min as employed. For analytical HPLC a Dr. Maisch GmbH, Reprosil-Pur C18-AQ. 5 pm (250x4.6 mm) column was used and a gradient of 0.1% TFA in H2O/CH3CN (95:5) to 0.1% TFA in H2O/CH3CN (5:95) in 40 min was employed. MALDI-ToF measurements were performed on a Bruker Microflex. High resolution mass spectra were measured on an Exactive orbitrap high-resolution mass spectrometer (Thermo Fisher Scientific, San Jose, CA) and processed with the use of Thermo Scientific Xcalibur software (V2.1.0.1139). For dialysis Sigma Pur-A-LyzerTM Mega 3,500 units were used.
Synthesis
Adamantane-tetrafluorophenol (Ad-TFP) 1-Adamantanecarboxylic acid (500 mg, 2.8 mmol) and 2,3,5,6-tetrafluorophenol (718 mg, 4.3 mmol) were dissolved in 10 mL dry DCM and stirred for 10 minutes. Subsequently, N,N-dicyclohexylcarbodiimide (858 mg, 4.3 mmol), dissolved in 5 mL dry DCM, was added dropwise. After stirring for 2 days at RT, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting yellow product was purified by silica column chromatography (DCM:Hexane, 1:1). Pure fractions were pulled and concentrated under vacuo to obtain the product as a white crystalline powder (785 mg, 86%). XH NMR (300 MHz, CDCI3, 25 °C)= 6 7.06 - 6.89 (m, 1H, CH of TFP), 2.09 (s, 9H, C-CH2-CH and CH2-CH-CH2), 1.78 (s, 6H, CH-CFk-CH). High resolution mass: [CiyHnF^r calculated 329.3, found 329.1.
Cy5(SO3)Sulfonate-(SO3)CO-TFP
Cy5-(SO3)Sulfonate-(SO3)CO-TFP was synthesized according a procedure previously described in S. J. Spa, A. Bunschoten, Μ. T. M. Rood, R. J. B. Peters, A. J. Koster and F. W. B. van Leeuwen, Eur. J. Inorg. Chem., 2015, 2015, 4603-4610.
Cv5(SC>3)Sulfonate-(SC>3)Amine
Cy5-(SO3)Sulfonate-(SO3)Amine was synthesized according to the method disclosed in M.T. Rood, S. J. Spa, Μ. M. Welling, J. B. Ten Hove, D. M. van Willigen, T. Buckle, A. H. Velders and F. W. B. van Leeuwen, Sci. Rep., 2017, 7, 39908.
Cy5o.5CDioPIBMA39
The synthesis of Cy5o.sCDioPIBMA39 was performed as described under the previous item above.
Poly(isobutylene-alt-maleic anhydride) Mw 6,000 (30 mg, 5.0 pmol, Sigma-Aldrich) and Cy5-(SO3)Sulfonate-(SO3)Amine (5.0 mg, 5.6 pmol) were dissolved in 3 mL dry DMSO and N,N-diisopropylethylamine (DIPEA, 50 pL, 250 pmol Sigma-Aldrich) was added. After stirring at 80 °C for 7 h, 6-monodeoxy-6-monoamino-3-cyclodextrin (95 mg, 80 pmol, Cyclodextrin Shop) was added and the reaction mixture was left to stir for another 72 h at 80 °C. After cooling to RT, the polymer was first dialyzed against H2O for 1 day, then against 100 mM phosphate buffer pH 9.0 for 24 h, and subsequently against H2O for another 5 days, while refreshing the dialysis medium daily. The solution was lyophilized to give a blue powder (87 mg, 5 pmol) and was stored at -20°C. Before usage, a small amount was aliquoted in PBS at 1 mg/mL concentration and stored (< one month) at 7°C. ΧΗ NMR: see previous reported literature.
Functionalization of macro-aggregates with adamantane (MAA-Ad)
Macro-aggregates from albumin (TechneScan®, MAA) were obtained from Mallinckrodt Medical B.V., Petten, The Netherlands. Lyophilized albumin macro-aggregates (2 mg) were dissolved in 1 mL of saline (0.9% NaCI, sterile and pyrogen-free, B. Braun Medical Supplies, Inc., Oss, The Netherlands) and portions of 0.1 mL (containing 0.2 mg MAA) were stored in Eppendorf tubes at -20 °C until further use. For functionalization, one portion was defrosted and 20 0L of Ad-TFP (10 mg/mL DMSO) was added. After agitation in a shaking water bath for 1 h at 37 °C, the solution was washed 2 times with phosphate buffered saline (PBS) by 2 centrifugation steps (3 min x 1,200 rpm). The obtained MAA-Ad was diluted in 1 mL of PBS to 0.2 mg/ml. To estimate the number of Ad conjugated to MAA, the MAA functionalization was also performed with Cy5-TFP according the same procedure as with Ad-TFP. Subsequently, the absorbance at 650 nM of the MAA-Cy5 constructs was measured using a NanoDrop Spectrophotometer (Thermo Fisher Scientific Inc. Wilmington, DE, USA). From the absorbance, the dye concentration was calculated using the law of Lambert Beer (A = ε· I · C) with ecy5 = 250 x 103 mol_1cm_1. The number of Cy5/MAA aggregates was then calculated by dividing the calculated Cy5 concentration by the known MAA concentration, resulting in a ratio of 3.07(±0.24) x 108 Cy5/MAA particle on average. Assuming that Ad-TFP reacts in a similar fashion as Cy5-TFP, it was estimated that the ratio of Ad/MAA would be in the same order of magnitude.
Radiolabeling of CV50.5CD10PIBMA39
Radiolabeling of Cy5o.sCDioPIBMA39 was performed as follows: to 10 0L of Cy5o.sCDioPIBMA39 (1 mg/mL PBS), 4 pL of SnCb.2H2O (0.44 mg/mL saline, Technescan PYP, Mallinckrodt Medical B.V.), and 100 pL of a freshly eluted 99mTc-Na-pertechnetate solution (500 MBq/mL, Mallinckrodt Medical B.V.) were added and the mixture was gently stirred in a shaking water bath for 1 h at 37 °C, as described in Μ. M. Welling, A. Paulusma-Annema, H. S. Balter, E. K. J. Pauwels and P. H. Nibbering, Eur. J. Nucl. Med., 2000, 27, 292-301. Subsequently, the labeling yield was estimated over time by ITLC analysis according the following procedure: 2 mL of the reaction mixture was applied on 1x7 cm ITLC-SG paper strips (Agilent Technologies, USA) for 10 min at room temperature with PBS as mobile phase. After 1 h the highest labeling yield of Cy5o.sCDioPIBMA39with technetium-99m was assessed (49.6±12.8) and the reaction mixture was purified by size exclusion chromatography with sterile PBS as mobile phase using Sephadex™ G-25 (desalting columns PD-10, GE Healthcare Europe GmbH, Freiburg, Germany). Fractions containing 99mTc-Cy5o.sCDioPIBMA39 were collected and directly applied in the imaging experiments. According the data calculated from the PD-10 purification a labeling yield of 49.2±6.9 was obtained, which was in accordance with the yield estimated by ITLC analysis.
Stability of 99mTc-Cv5o,5CDioPIBMA39
To assess the stability of the radiolabeling, after 24 h the release of radioactivity from PD-10 purified 99mTc-Cy5o.5CDioPIBMA39 was determined with ITLC (according the same method as described for 'Radiolabeling of Cy5o.5CDioPIBMA39')> and this turned out to be less than 5% of the total radioactivity.
Supramolecular interaction between MAA-Ad and 99rnTc-Cy5o.5CDioPIBMA39
To determine the supramolecular interaction between MAA-Ad and Cy5o.sCDioPIBMA39 in vitro, 0.1 mL of MAA-Ad in PBS (0.2 mg/mL) and 0.1 mL of 99mTc-Cy5o.5CDioPIBMA39 in PBS (1 mg/mL, 1 MBq) were mixed and the solution was incubated for 1 h in a shaking water bath at 37 °C. Thereafter, the radioactivity of the total amount added and the radioactivity of the pellet after two washing steps with PBS were measured in a dose-calibrator, to determine the amount of binding of 99mTc-Cy5o.5CDioPIBMA39 to MAA-Ad. After correction for background activity the amount of binding was expressed as the percentage of the total amount of radioactivity (%binding). To assess the effect of the Ad moieties, the same experiment was also performed with non-functionalized MAA and the resulting %binding of 99mTc-Cy5o.sCDwPIBMA39to MAA and MAA-Ad were compared. As shown in SI Fig. 2, compared to the binding to non-functionalized MAA, a significant (p <0.01) higher binding of 99mTc-Cy5o.sCDioPIBMA39 to MAA-Ad was calculated (using a two tailed student t-Test, n = 4).
The supramocelucal interaction between MAA-Ad and Cy5o.sCDioPIBMA39 was also visualized by confocal microscopy, employing the Cy5 component of the polymer.2 For this purpose, the same experiment was repeated, but this time non-radioactive Cy5o.5CDioPIBMA39 was added to the MAA and MAA-Ad solutions. After washing, 10 BL of MAA (with or without-Ad) Cy5o.sCDioPIBMA39 solution was pipetted onto culture dishes with glass insert (035mm glass bottom dishes No. 15, poly-d-lysine coated, γ-irradiated, MatTek corporation). Images were taken on a Leica SP5 WLL confocal microscope under 63x magnification using Leica Application Suite software. Cy5 fluorescence was measured with excitation at 633 nm, emission was collected at 650-700 nm.
Example 2: In vivo studies
Animals
All in vivo studies were performed using 2-3 month old Swiss mice (20-25 g, Crl:OFl strain, Charles River Laboratories, USA). All animal studies were approved by the institutional Animal Ethics Committee (DEC permit 12160) of the Leiden University Medical Center. All mice were kept under specific pathogen-free conditions in the animal housing facility of the LUMC. Food and water were given ad libitum.
General SPECT imaging and biodistribution protocol SPECT imaging was performed as follows: at 2 h after injection of 99mTc-labeled compounds mice were placed and fixed onto a dedicated positioned bed of a three-headed U-SPECT-2 (MILabs, Utrecht, The Netherlands) under continuous 1-2% isoflurane anesthesia. Radioactivity counts from total body scans or selected regions of interest (ROI) were acquired for 60 min using a 0.6 mm mouse multi-pinhole collimator in list mode data. For reconstruction from list mode data, the photo peak energy window was centered at 140 keV with a window width of 20%. Side windows of 5% were applied to correct for scatter and down scatter corrections. The image was reconstructed using 24 Pixel based Ordered Subset Expectation Maximization iterations (POSEM) with 4 subsets, 0.2 mm isotropic voxel size and with decay and triple energy scatter correction integrated into the reconstruction with a post filter setting of 0.25 mm, as described in W. Branderhorst, B. Vastenhouw and F. J. Beekman, Phys. Med. Biol., 2010, 55, 2023-2034. Volume-rendered images were generated from 2-4 mm slices and analyzed using Matlab R2014a software (version 8.3.0.532, MathWorks8 Natick, MA). Images were generated from maximum intensity protocols (MIP) adjusting the color scale threshold to optimal depiction of the tissues of interest, as set out in Μ. N. van Oosterom, R. Kreuger, T. Buckle, W. A. Mahn, A. Bunschoten, L. Josephson, F. W. B. van Leeuwen and F. J. Beekman, EJNMMI Res., 2014, 4, 56-56.
After imaging, the mice were euthanized by an intraperitoneal injection of 0.25 mL Euthasol (ASTfarma, Oudewater, The Netherlands).
To determine the biodistribution of the tracer, organs were collected from mice and counted for radioactivity in a dose-calibrator (VDC 101, Veenstra Instruments, Joure, the Netherlands) or a gamma counter (Wizard2 2470 automatic gamma scintillation counter, Perkin Elmer). After collecting and counting all tissues together with the remaining activity in the carcass, the total amount of remaining radioactivity in the animal was counted and, after correction for physical decay, the urinary excretion expressed as the percentage of the total injected dose (%ID) was calculated. Radioactivity counts in tissues were expressed as the percentage of the total injected dose of radioactivity per gram tissue (%lD/g). Additionally, reconstructed images were generated and analyzed using Amide 1.0.2 software, available from Sourceforge, and as disclosed in A. M. Loening and S. S. Gambhir, Mol. Imaging, 2003, 2, 131-137.
Mapping the distribution of 99mTc-labeled MAA-Ad in mice via i.v. administration ( Model I, not according to the invention)
To determine whether MAA embolizations are tolerated by mice and whether MAA-Ad is delivered to the capillaries of the lungs, MAA-Ad was radiolabeled according to the manufacturer's instructions, and 0.1 mL of 99mTc-MAA-Ad in PBS (0.02 mg, 2 mg/mL) was injected into a tail vein of a mouse (Fig. 1A, Model I). At 2 h after injection, the organ distribution of the tracer in mice were imaged using SPECT and quantified with biodistribution studies (see SPECT imaging protocol and biodistribution studies described above, and Fig. 1).
Local administration, model II (Example according to the invention)
An embolization setup in the liver was performed to mimic the clinical setup for liver radioembolization (Fig. 1A, Model II). For this purpose, animals were anesthetized by intraperitoneal injection of a mixture containing Hypnorm (Vetapharma, Leeds, United Kingdom), dormicum (Roche, Basel, Switzerland), and water (1:1:2). After shaving and cleaning with ethanol (70%), the abdominal cavity was incised for 0.5 cm and the spleen was exposed outside the mouse. Of the "mTc-MAA-Ad solution (2 mg/mL), 100 pL was injected into the spleen using a Myjector U-100 insulin syringe (29G x%" 0.33x12 mm, Terumo Europe, Leuven, Belgium) and after 5 seconds the needle was removed and the spleen was positioned inside the peritoneal cavity. The incision was sutured by 2-4 stitches and the animals were placed under a heating lamp to maintain the body temperature at 37 °C. At 2 h after injection, the organ distribution of the tracer in mice were imaged using SPECT and quantitated with biodistribution studies as described above (see Fig. 1).
Mapping the distribution of 99mTc-Cv5o.sCDioPIBMA39 in mice
To determine the natural distribution of 99mTc-Cy5o.5CDioPIBMA39 (Fig. 1C), 0.1 mL of PBS containing 99mTc-Cy5o.sCDioPIBMA39 (1 mg/mL, 20 MBq) was i.v. injected (see Fig. 2). 2 h after injection SPECT imaging and biodistribution studies were performed as described above.
Mapping the distribution of 99mTc-Cy5o.5CDioPIBMA39 after MAA(-Ad) pre-administration The influence of MAA or MAA-Ad on the distribution of 99mTc-Cy5o.sCDioPIBMA39 was evaluated as follows: first, 0.1 mL containing MAA-Ad or non-functionalized MAA in 0.1 mL (0.02 mg, 2 mg/mL) was injected by either i.v. administration (Fig. ID, Model I) or local administration (Fig. IB, Model II). After 2 h, 0.1 mL of 99mTc-Cy5o.5CDioPIBMA39 in PBS (1 mg/ml, 20 MBq) was i.v. injected (see Fig. 2) and another 2 h later SPECT imaging and biodistribution studies were performed as described above.
Figure 1 shows the SPECT imaging of (Model I, comparison without pretargeting ) 99mTc-labeled Ad-MAA (for mapping biodistribution of MAA-Ad) or (Model II, according to the invention) pre-targeting with unlabeled MAA-Ad or (Model C) none followed by intravenous 99mTc-Cy5o.sCDioPIBMA39. SPECT imaging is performed 2 h thereafter to visualize radioactivity in the (1) lungs, (2) liver, (3) kidneys, (4) stomach, and (5) urinary bladder.
This clearly illustrates the effectiveness and high selectivity that can be obtained for the subject process and materials.
Figure 2 then illustrates the binding of 99mTc-Cy5o.sCDioPIBMA39 to MAA-Ad and MAA, quantified by radioactivity and expressed as a percentage of the total amount of radioactivity (99mTc-Cy5o.5CDioPIBMA39) added. The data in Figure 2 indicates a 5.7 times higher binding to MAA functionalized with the Ad guest moiety, as compared to non-functionalized MAA. Significance of difference is marked with ** (P < 0.01).
The following table (Table 1) shows the resultant measurements
Table 1 shows the bio-distribution of 99mTc-Cy5o.5CDioPIBIVIA39 following injection of: none (reference distribution), - MAA, or MAA-Ad and the bio-distribution of 99mTc-MAA-Ad administered via Models I and II.
The data is expressed as the mean ± SD of the percentage of the injected dose per gram tissue (%ID/g) of 5 observations)), and is calculated from radioactivity counts in various tissues at 2 h post-injection of the tracer.
N.A.: data not available
Table 2 shows the biodistribution of 99mTc-labeled cyclodextrin polymers in mice with adamantane (Ad)-functionalized macro-aggregates (MAA) administrated into the lungs. Data (expressed as the mean ± sd of the percentage of the injected dose per gram tissue of at least 4 observations) are calculated from radioactivity counts in various tissues (%lD/g) of various tissues at 2 hr post-injection of the tracer.* = P<0.05 compared to none or non-functionalized MAA.
This is also illustrated by Figures 6 (a) to (d), wherein in particular Fig. 6 (a) and (b) shows the benefit of the benefit of multiple binding sites, as compared to the absence of the pre-targeting vector (c) and (d), respectively.
Example 3: Using Polymeric Microparticles
Example 2 was repeated, however using polystyrene beads as pre-targeting vector material. Cy5-Polystyrene-Ad(PS Ad) was prepared, and incubated with Cy31.5CD72PIBMA389.
The resultant distribution of the materials, and the low occurrence of shunting was illustrated by fluorescence spectroscopy (see Figure 3). This shows that any suitably dimensioned particulate materials may be employed.
Ad-CD host guest interaction between Polystyrene(Cv5.5)-Ad particles and Cy31.5CD72PIBMA398 polymer.
To a solution of Polystyrene(Cy5.5)-Ad (90 · 106 particles / pL; 1 pm in size) in 100 pL H20, Cy31.5CD72PIBMA398 was added (0.35 nmol) and the mixture was gently shaken for lh at RT. Subsequently the particles were washed by sequential filtering over 100 kD Amicon filters (2 min, 10 ref) and recollected in 100 pL H20. A drop of the solution was put on a petri dish and the particles were allowed to settle down on the glass before imaging under a SP5 Leica microscope. The Polystyrene particles were visualized by excitation at 633 nm and the emission was collected at 650 to 600 nm. The Cy31.5CD72PIBMA398 was visualized by excitation at 514 nm laser and the signal was collected at 550- 600 nm.
Example 4: Using Click chemistry MAA functionalization with DBCO and subsequently with Cy5-(SO3)azide-(SO3)COOH To a solution of MAA (20 pg, 20 mg/mL) in 100 pL Phosphate buffer (0.1 M, pH 8.4), 6.4 pL (32 pg, 80 nmol) of a dibenzocyclooctyne-N-hydroxysuccinimidyl ester solution in DMSO (5 mg/mL) was added. After stirring overnight at RT the MAA was washed by pelleting (3 min, 13.4 ref). The MAA was then resuspended in 100 pL Phosphate buffer (0.1 M, pH 8.4) and 5.7 pL (28 pg, 40 nmol) of a Cy5-(SO3)azide-(SO3)COOH solution in H2O (5 mg/mL) was added. After stirring for 2h at RT the particles were washed again by pelleting (3 min, 13.4 ref) until the filtrate was no longer blue. The functionalized MAA was resuspended in 100 pL H2O and a drop of the solution was added to a petri dish. After the particles were settled down they were imaged using a SP5 Leica microscope. The MAA was visualized by brightfield and the Cy5-(SO3)Azide-(SO3)COOH was visualized by excitation at 633 nm and the emission was collected at 650 to 600 nm.
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NAZILA KAMALY ET AL: "Targeted polymeric therapeutic nanoparticles: design, development and clinical translation", CHEMICAL SOCIETY REVIEWS, vol. 41, no. 7, 2012, pages 2971, XP055155337, ISSN: 0306-0012, DOI: 10.1039/c2cs15344k * |
XING YAN ET AL: "Pretargeted approach for tumor PET imaging using supramolecular nanoparticles with in vivo bioorthogonal chemistry", JOURNAL OF NUCLEAR MEDICINE, vol. 55, no. Suppl. 1, May 2014 (2014-05-01), & ANNUAL MEETING OF THE SOCIETY-OF-NUCLEAR-MEDICINE-AND-MOLECULAR-IMAGING (SNMMI); ST LOUIS, MO, USA; JUNE 07 -11, 2014, pages 277, XP002780584 * |
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