Crosslinked radiopaque networks for medical applications

Abstract

In some aspects, the present disclosure relates to a system for forming a radiopaque product comprising an iodinated compound comprising one or more diene-containing moieties and a multi-arm polymer comprising a plurality of dienophile-containing moieties, wherein the diene-containing moiety of the iodinated compound is coupled to the dienophile-containing moiety of the multi-arm polymer by a Diels-Alder reaction. Other aspects of the present disclosure relate to cross-linked networks formed by combining such iodinated compounds with such multi-arm polymers, wherein a diene-containing moiety and a dienophile-containing moiety are coupled by a Diels-Alder reaction. Other aspects of the present disclosure relate to methods of treatment comprising administering to a subject a mixture comprising such an iodinated compound and such a multi-arm polymer wherein a diene-containing moiety is coupled to a dienophile-containing moiety upon administration by developing a Diels-Alder reaction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 410,154, filed on September 26, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to iodinated compounds, cross-linked radiopaque networks formed from iodinated compounds, and methods of making and using iodinated compounds and networks, among other things. The iodinated compounds and networks of the present disclosure can be used, for example, to form hydrogels for various medical applications. Background Art

[0004] In vivo cross-linked hydrogels based on star-shaped polyethylene glycol (star-PEG) polymers functionalized with reactive ester end groups that react with lysine trimers (Lys-Lys-Lys) as cross-linking agents to rapidly form cross-linked hydrogels have become clinically important materials as adjuvants in radiotherapy. See “Augmenix Announces Positive Three-year SpaceOAR Clinical Trial Results,” Imaging Technology News, October 27, 2016.

[0005] Hydrogels in which some of the star-shaped PEG branches are functionalized with 2,3,5-triiodobenzamide (TIB) groups replacing some of the ester end groups have also been developed, such as SpaceOAR This provides enhanced radiocontrast. Tissue Marker,” BusinessWire, January 28, 2013. The hydrogel remained stable and visible in tissue for three months, long enough for radiation therapy, after which it was absorbed and cleared from the body. Id.

[0006] While the above methods are effective, using the arms of the star polymer to functionalize the hydrogel with iodine means that there are fewer arms available for crosslinking. This can be overcome by adding more polymer, but the solid loading increases, which can have an adverse effect on viscosity. Reducing the molecular weight can reduce the solid loading, but this can also lead to lower melting points and processability issues. An additional impact of the reduced crosslink density per star polymer is that the resulting gel has a slower solidification rate, which means that the gel is liquid and mobile in the body for a longer time, which provides opportunities for unexpected side reactions and material displacement. In addition, TIB is slightly soluble in water, which means that there is an upper limit to how much iodine can be added before the solubility of the gel is affected and it becomes difficult to form a smooth, consistent hydrogel. In cases where the concentration of TIB groups is so high that the star PEG precipitates out of solution, the TIB groups can even physically crosslink the system before the reaction, which requires greater force to disperse. In addition, star PEGs labeled with 2,3,5-triiodobenzamide end groups often discolor due to thermal degradation. While this does not affect its function, it is a cosmetic defect that is preferably avoided.

[0007] Additionally, trilysine was used as a cross-linker to form cross-linked hydrogels with TIB-functionalized star-PEG. Unfortunately, amine-based biofluids are ubiquitous in vivo and act as naturally derived cross-linkers that compete with trilysine, resulting in lower density of non-targeted cross-links in some cases. Finally, buffer solutions were added to the hydrogel precursors prior to injection to maintain pH and avoid uncontrolled cross-linking conditions, which increased the overall complexity of troubleshooting, manufacturing, and quality control.

[0008] For these and other reasons, an alternative strategy for iodine-labeling cross-linked hydrogels with high reaction selectivity and without the need for any buffer solution is highly desirable. Summary of the invention

[0009] The present disclosure provides an alternative method to the above method based on the Diels–Alder reaction.

[0010] In some aspects, the present disclosure relates to a system for forming a radiopaque product, comprising (a) an iodinated compound and (b) a multi-arm polymer, wherein the iodinated compound comprises one or more diene-containing moieties, more typically two or more diene moieties, and the multi-arm polymer comprises a plurality of dienophile-containing moieties, wherein the diene-containing moieties of the iodinated compound are coupled with the dienophile-containing moieties of the multi-arm polymer via a Diels-Alder reaction.

[0011] In some embodiments, the diene-containing moiety is a furan-containing moiety and the dienophile-containing moiety is a maleimide-containing moiety.

[0012] In some embodiments that may be used in conjunction with any of the above aspects and embodiments, the iodinated compound comprises a core, one or more furan-containing moieties attached to the core, and one or more iodine-containing moieties attached to the core. In some of these embodiments, (a) the one or more furan-containing moieties may be attached to the core via an ester group, the one or more iodine-containing moieties may be attached to the core via an amide group, and / or (b) the core may be a residue of a hydroxy acid compound, wherein the one or more furan-containing moieties correspond to the residue of a carboxylic acid-substituted furan-containing compound, the one or more iodine-containing moieties correspond to the residue of an amino-substituted iodinated compound, and / or (c) the one or more iodine-containing moieties may comprise an aromatic structure substituted with one or more iodo groups and optionally one or more hydrophilic functional groups, which may be, for example, selected from hydroxyl and C1-C4-hydroxyalkyl.

[0013] In some embodiments that may be used in conjunction with any of the above aspects and embodiments, the multi-arm polymer comprises a plurality of hydrophilic polymer arms. In certain embodiments, the hydrophilic polymer arms may be formed from one or more hydrophilic monomers selected from the group consisting of ethylene oxide, N-vinyl pyrrolidone, oxazoline, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or N-isopropylacrylamide. In certain embodiments, two or more of the plurality of hydrophilic polymer arms may each comprise one or more dienophile end groups, in which case the dienophile end groups may be attached to the two or more hydrophilic polymer arms via a hydrolyzable ester group.

[0014] In some embodiments that can be used in combination with any of the above aspects and embodiments, the system includes a first composition comprising an iodinated compound in a first container, and a second composition comprising a multi-arm polymer in a second container, the iodinated compound comprising one or more diene-containing moieties, the multi-arm polymer comprising a plurality of dienophile-containing moieties. For example, the first container and the second container can be independently selected from vials and syringe tubes and other containers. In certain embodiments, the system can also include a delivery device.

[0015] Other aspects of the present disclosure relate to a cross-linked network formed by combining an iodinated compound comprising one or more diene-containing moieties according to any of the above aspects and embodiments with a multi-arm polymer comprising a plurality of dienophile-containing moieties according to any of the above aspects and embodiments, wherein the diene-containing moieties of the iodinated compound are coupled with the dienophile-containing moieties of the multi-arm polymer via a Diels-Alder reaction.

[0016] In some embodiments, the cross-linked network is a hydrogel.

[0017] In some embodiments that may be used in combination with any of the above aspects and embodiments, the cross-linked network has a radiopacity greater than 250 Hounsfield units.

[0018] Other aspects of the present disclosure relate to methods of treatment, comprising administering to a subject a mixture comprising an iodinated compound according to any of the above aspects and embodiments, wherein the iodinated compound comprises one or more diene-containing moieties, and the multi-arm polymer comprises a plurality of dienophile-containing moieties, such that after administration, the diene-containing moieties of the iodinated compound are coupled with the dienophile-containing moieties of the multi-arm polymer by undergoing a Diels-Alder reaction (and thereby forming a Diels-Alder adduct).

[0019] Potential benefits associated with the present disclosure include one or more of the following: radiocontrast agents are maintained, highly selective crosslinking can be achieved, thereby minimizing non-target crosslinking, buffer solutions can be avoided, the melting point of the solid components of the hydrogel can be maintained above 40°C, thereby improving storage and handling, the homogeneity of the final hydrogel can be improved, in vivo persistence can be obtained, and the curing kinetics can be maintained.

[0020] The above and other aspects, embodiments, features and advantages of the present disclosure will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1A A method of adding a furan-containing moiety to a hydroxy acid according to one embodiment of the present disclosure is schematically illustrated.

[0022] Figure 1B Schematically showing the coupling of an iodinated amino compound to Figure 1A method on the product.

[0023] Figure 2A A method of adding a furan-containing moiety to a hydroxy acid according to another embodiment of the present disclosure is schematically illustrated.

[0024] Figure 2B Schematically showing the coupling of an iodinated amino compound to Figure 2A method on the product.

[0025] Figure 3A A method of adding a furan-containing moiety to a hydroxy acid according to another embodiment of the present disclosure is schematically illustrated.

[0026] Figure 3B Schematically showing the coupling of an iodinated amino compound to Figure 3A method on the product.

[0027] Figure 4 Schematically illustrated is a method of adding a maleimide-containing moiety to a multi-arm polymer comprising a core region and a plurality of polyethylene oxide (PEO) arms according to one embodiment of the present disclosure.

[0028] Figure 5 Schematically shows that according to one aspect of the present disclosure Figure 4 The multi-arm polymer product containing maleimide Figure 1B A method for cross-linking iodinated products containing furan.

[0029] Figure 6 Schematically shows that according to one aspect of the present disclosure Figure 4 The multi-arm polymer product containing maleimide Figure 2B A method for cross-linking iodinated products containing furan.

[0030] Figure 7 Schematically shows that according to one aspect of the present disclosure Figure 4 The multi-arm polymer product containing maleimide Figure 3B A method for reacting a furan-containing iodinated product. DETAILED DESCRIPTION

[0031] In some aspects, the present disclosure relates to a radiopaque product comprising a Diels-Alder reaction product of an iodinated compound comprising one or more diene-containing moieties and a multi-arm polymer comprising a plurality of dienophile-containing moieties.

[0032] In some embodiments, the diene-containing moiety is a furan-containing moiety. In some embodiments, the dienophile-containing moiety is a maleimide-containing moiety.

[0033] In some embodiments, the iodinated compound comprises two or more diene moieties, in which case the reaction product can be a cross-linked reaction product. In some cases, the cross-linked reaction product is a hydrogel.

[0034] Although specific examples of iodinated compounds comprising one or more diene-containing moieties and specific examples of multi-arm polymers comprising multiple dienophile-containing moieties are described herein, it should be understood that iodinated compounds comprising one or more dienophile-containing moieties and multi-arm polymers comprising multiple diene-containing moieties can also be formed using suitable methods.

[0035] In various aspects, the present disclosure provides a method for forming an iodinated compound, the iodinated compound comprising one or more diene-containing moieties and one or more iodine-containing moieties. In some embodiments, the iodinated compound comprising one or more diene-containing moieties can be formed based on a hydroxy acid compound comprising one or more hydroxyl groups and one or more carboxylic acid groups. As can be seen from the following discussion, the hydroxy site can be used to add a furan-containing moiety, and the carboxylic acid group site can be used to add an iodine-containing moiety. In order to serve as a cross-linking agent, the iodinated compound preferably comprises a plurality of diene-containing moieties. Such a multifunctional compound can be formed by a hydroxy acid compound comprising a plurality of hydroxyl groups and one or more carboxylic acid groups.

[0036] A variety of hydroxy acid compounds containing one or more hydroxyl groups and one or more carboxylic acid groups can be used in conjunction with the present disclosure. Some examples of such compounds include 2,3-dihydroxysuccinic acid, 2,3,4-Trihydroxyglutaric acid, 2,3,4,5-Tetrahydroxyadipic acid, 6-Hydroxy-5,5-bis(hydroxymethyl)hexanoic acid, Citric acid, 2,3-Dihydroxypropionic acid, 2,3,4-Trihydroxybutyric acid, and 4-hydroxy-2,3-bis(hydroxymethyl)butyric acid, In some embodiments, the hydroxyl group can be formed from a polyacid by a suitable reduction reaction. For example, the dicarboxylic acid diol compound 2-hydroxy-2-hydroxyethylsuccinic acid can be formed by reducing citric acid in the presence of lithium aluminum hydride (LiAlH4):

[0037]

[0038] In the first step, an ester coupling reaction is carried out between the hydroxyl group of a hydroxy acid compound (e.g., selected from one of those described above, etc.) comprising one or more hydroxyl groups and one or more carboxylic acid groups and the carboxylic acid group of a carboxylic acid-substituted furan-containing compound, such as a furan-containing compound partially substituted with a C1-C6 carboxylic acid, such as 3-(4-ethylfuran-2-yl)propionic acid, 3-(furan-2-yl)propionic acid, 2-(furan-2-yl)acetic acid, 4-(furan-2-yl)butyric acid, 4-(4-ethylfuran-2-yl)butyric acid, or 2-(4-ethylfuran-2-yl)acetic acid, and the like.

[0039] For example, Figure 1A As shown, for example, using a suitable coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 3-(4-ethylfuran-2-yl)propionic acid 112, 2-Hydroxy-2-hydroxyethylsuccinic acid 110, a carboxylic acid group and a dicarboxylic acid diol compound, The hydroxyl groups of the furanyl groups undergo ester coupling reactions to form multifunctional furanic compounds, in particular, difuran-functionalized diacids 114 having two ester bonds.

[0040] As another example, Figure 2A As shown, for example, using a suitable coupling reagent, 3-(4-ethylfuran-2-yl)propanoic acid 112 can be obtained. The carboxylic acid group and 6-hydroxy-5,5-bis(hydroxymethyl)hexanoic acid 210, The hydroxyl groups of the compounds undergo an ester coupling reaction to form a multifunctional furan compound 214 having three ester bonds.

[0041] In the second step, the carboxylic acid group of the multifunctional furan compound product of the first step is reacted with the amino group of the amino-substituted iodinated compound in an amide coupling reaction (eg, using a suitable coupling reagent, such as a carbodiimide coupling reagent).

[0042] For example, the iodinated compound substituted by amino can be an iodinated aromatic compound substituted by amino, which comprises a monocyclic or polycyclic aromatic structure substituted by one or more iodo groups and amino. In some of these embodiments, monocyclic or polycyclic aromatic structures can also be substituted by one or more hydrophilic functional groups. Such hydrophilic functional groups can be selected from, for example, hydroxyl and hydroxyalkyl, such as C1-C4-hydroxyalkyl (for example, C1-C4-monohydroxyalkyl, C1-C4-dihydroxyalkyl, C1-C4-trihydroxyalkyl, C1-C4-tetrahydroxyalkyl etc.) etc. Hydroxyalkyl can be directly or by any suitable linking portion connected to monocyclic or polycyclic aromatic structure, and linking portion can be selected from, for example, amide group, amine group, ether group, ester group or carbonate group etc.

[0043] For example, in some embodiments, the amino-substituted iodinated compound can be a 5-amino-1,3-substituted-2,4,6-triiodobenzene compound, wherein the substituents at the 1-position and the 3-position each include a hydrophilic functional group, such as a hydroxyalkyl group, which can be selected from those described above and can be directly or through any suitable linking moiety attached to the benzene structure. In a specific example, the iodinated amino compound can include a 5-amino-1,3-hydroxyalkyl-substituted-2,4,6-triiodo-1,3-benzenedicarboxylic acid amide compound, such as a 5-amino-N,N′-bis(hydroxyalkyl)-2,4,6-triiodo-1,3-benzenedicarboxylic acid amide compound, such as 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxylic acid amide (also known as 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalic acid amide), wherein the 5-amino group is used to form an amide bond with the furan product of the first step.

[0044] exist Figure 1B In the particular embodiment shown, Figure 1A The carboxylic acid group of the polyfunctional furan product 114 is subjected to an amide coupling reaction with the amino group of 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide 116 (CAS#76801-93-9) in the presence of a carbodiimide coupling reagent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl)). The resulting iodinated polyfunctional furan compound 118 contains six iodine groups and two furanyl groups, and is suitable as an iodinated cross-linking agent for other molecules containing a dienophile-containing moiety (e.g., a maleimide-containing moiety), as described below.

[0045] exist Figure 2B In another specific embodiment shown, Figure 2A The carboxylic acid group of the polyfunctional furan product 214 is subjected to an amide coupling reaction with the amino group of 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide 116 in the presence of a carbodiimide coupling reagent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl)). The resulting iodinated polyfunctional furan compound 218 contains three iodine groups and three furan groups, and is suitable as a cross-linking agent for other molecules containing a dienophile-containing moiety (e.g., a maleimide-containing moiety), as described below.

[0046] In other embodiments, iodinated compounds containing a single diene-containing moiety can be formed from hydroxy acid compounds containing a single hydroxyl group and one or more carboxylic acid groups, although they are not suitable for use as crosslinking agents for other molecules containing dienophile-containing moieties. A variety of hydroxy acid compounds containing a single hydroxyl group and one or more carboxylic acid groups are available, including citric acid, wait.

[0047] In the first step, an ester coupling reaction is carried out between the carboxylic acid group of a carboxylic acid substituted furan (such as one of those described above, etc.) and the hydroxyl group of a hydroxy compound. Figure 3A As shown, using a suitable coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), an ester coupling reaction can be carried out between the carboxylic acid group of 3-(4-ethylfuran-2-yl)propionic acid 112 and the hydroxyl group of citric acid 310 to form a monofunctional furan compound 314 having one ester bond.

[0048] In the second step, the carboxylic acid group of the monofunctional furan product of the first step is reacted with the amino group of an amino-substituted polyiodinated aromatic compound (e.g., as described above, etc.) in an amide coupling reaction (e.g., by a suitable coupling reagent). Figure 3B As shown, Figure 3A The three carboxylic acid groups of the monofunctional furan product 314 are subjected to an amide coupling reaction with the amino group of 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide 116 in the presence of a carbodiimide coupling reagent (e.g., EDC HCl). The resulting iodinated monofunctional furan compound 318 contains nine iodine groups and one furanyl group and can be used, for example, as a modifier compound, as described below, for introducing radiopacity into other molecules containing a dienophile-containing moiety (e.g., a maleimide-containing moiety).

[0049] Multi-arm polymers comprising a plurality of dienophile-containing moieties include those comprising a plurality of polymer arms (e.g., having two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more arms), wherein two or more polymer arms of the multi-arm polymer each comprise one or more dienophile end groups. Examples of dienophile groups include those comprising maleimide groups, The dienophile-containing portion of the invention will now be described.

[0050] In some embodiments, a composition containing a multi-arm polymer can be provided, wherein the percentage of polymer arms containing one or more dienophile moieties can correspond to between 50% and 100% of the total number of polymer arms in the composition (e.g., any range of 50% to 70% to 80% to 90% to 95% to 99% to 100% of the total number of polymer arms). The typical average molecular weight range of the multi-arm polymer used herein is 15 to 20 kDa or the like. In various embodiments, the multi-arm polymer used herein has a melting point of 40° or greater, preferably 45° or greater.

[0051] In various embodiments, the polymer arm is a hydrophilic polymer arm. Such a hydrophilic polymer arm can be composed of any of a variety of synthetic, natural or synthetic-natural hybrid polymers, including, for example, poly(alkylene oxides), such as poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG), poly(propylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(N-vinyl pyrrolidone), polyoxazolines (including poly(2-alkyl-2-oxazolines) such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline) and poly(2-propyl-2-oxazoline)), poly(vinyl alcohol), poly(propylene alcohol), poly(hydroxyethyl acrylate), poly(hydroxyethyl methacrylate), poly(N-isopropylacrylamide) (PNIPAAM), polysaccharides, and combinations thereof.

[0052] In some embodiments, the polymer arms extend from the core region. In some of these embodiments, the core region includes the residues of the polyols for forming the polymer arms. Exemplary polyols can be selected from, for example, straight chain, branched and cyclic aliphatic polyols (including straight chain, branched and cyclic polyhydroxyalkanes), straight chain, branched and cyclic polyhydroxy ethers (including polyhydroxy polyethers), straight chain, branched and cyclic polyhydroxy alkyl ethers (including polyhydroxy alkyl polyethers), straight chain, branched and cyclic sugars and sugar alcohols (such as glycerol, mannitol, sorbitol, inositol, xylitol, quebracho, threitol, arabitol, erythritol, adonitol, galactitol, fucose, ribose, arabinose (arabinose), xylose, lyxose, rhamnose, galactose, glucose, sucrose ... The present invention relates to a polyol comprising a sucrose, fructose, sorbose, mannose, pyranose, altrose, talose, tagatose, pyranoside, sucrose, lactose and maltose), polymers of linear, branched and cyclic sugars and sugar alcohols (defined herein as two or more units) (including oligomers of linear, branched and cyclic sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers and decamers), sugars and sugar alcohols include the aforementioned sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin and polyhydroxy crown ethers and polyhydroxy alkyl crown ethers). Exemplary polyols also include aromatic polyols, including 1,1,1-tris(4'-hydroxyphenyl)alkanes, such as 1,1,1-tris(4-hydroxyphenyl)ethane and 2,6-bis(hydroxyalkyl)cresol and the like.

[0053] In certain beneficial embodiments, the core region comprises the residue of a polyol containing two, three, four, five, six, seven, eight, nine, ten or more hydroxyl groups. In certain beneficial embodiments, the core region comprises the residue of a polyol that is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol or erythritol.

[0054] In certain embodiments, the dienophile-containing moiety is linked to the polymer arm through a hydrolyzable ester group.

[0055] A multi-arm polymer having arms comprising one or more dienophile-containing moieties can be formed, for example, from a multi-arm polymer having polymer arms comprising one or more hydroxyl end groups. For example, an ester coupling reaction can be performed between a carboxylic acid group of a carboxylic acid-substituted dienophile-containing compound and a hydroxyl group of a multi-arm polymer having polymer arms comprising one or more hydroxyl end groups (e.g., using a suitable coupling reagent such as a carbodiimide coupling reagent).

[0056] exist Figure 4In the specific embodiment shown, a carboxylic acid-substituted maleimide compound 412, specifically 4-maleimidobutyric acid (CAS#57078-98-5), is reacted with a multi-arm polymer 410 in an ester coupling reaction, wherein the multi-arm polymer 410 comprises a core region containing a polyol residue R (e.g., a tripentaerythritol polyol residue) and 8 hydroxyl-terminated polyethylene oxide arms, wherein n is 30 to 140, for example using dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC) as a carbodiimide coupling reagent to form a multi-arm polymer 415 having a core region and 8 polyethylene oxide arms, each polyethylene oxide arm being terminated with a maleimide-containing portion, the maleimide-containing portion being attached to the polyethylene oxide arm via an ester group, which can be hydrolyzed in vivo.

[0057] As previously described, in various aspects, the present disclosure relates to a radiopaque product comprising the reaction product of (a) an iodinated compound comprising one or more diene-containing moieties, such as one or more furan-containing moieties, various examples of which are described above, and (b) a multi-arm polymer comprising a plurality of dienophile-containing moieties, such as a plurality of maleimide-containing moieties, various examples of which are also described above. Various examples of iodinated compounds comprising diene-containing moieties and various examples of multi-arm polymers comprising dienophile-containing moieties are described above.

[0058] In various embodiments, the radiopaque product of the present disclosure is visible under fluoroscopy. In various embodiments, such radiopaque product has greater than 250 Hounsfield units (HU), advantageously in the range of 250HU to 500HU to 750HU to 1000HU or higher (in other words, in the range between any two aforementioned numerical values) radiopacity. Such radiopaque product can be formed in vivo (e.g., using a delivery device as described below), or such radiopaque product can be formed in vitro and then applied to a subject. Such radiopaque product can be applied to various biomedical applications, including medical devices, implants and pharmaceutical compositions.

[0059] In addition to the residue comprising one or more iodinated compounds containing diene moieties and a multi-arm polymer containing a plurality of dienophile containing moieties, the radiopaque products of the present disclosure may further comprise one or more additives.

[0060] Examples of such additives include therapeutic agents such as anti-angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immunomodulatory cytokines, T cell agonists, and STING (stimulator of interferon genes) agonists. Examples of such additives include imaging agents other than iodine present in radiopaque products.

[0061] Examples of such additives also include imaging agents, for example, (a) fluorescent dyes such as fluorescein, indocyanine green or fluorescent proteins (e.g., green, blue, cyan fluorescent protein), (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd (III) , Mn (II) , Fe (III) and compounds containing them (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid, (c) contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that cause an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that cause a decrease in reflected ultrasound energy), (d) radiocontrast agents, such as those based on clinically important isotopes 99m Tc radiocontrast agents, as well as other gamma emitters, such as 123 I. 125 I. 131 I. 111 In, 57 Co. 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga 和75 Se, etc.; (e) positron emitters, such as 18 F. 11 C. 13 N. 15 O and 68 Ga, etc., which can be used to produce functionalized radiotracer coatings; and (f) contrast agents used in conjunction with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coating of the present disclosure, thereby allowing deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxylic acid groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles (such as dye-doped nanofibers and dye-encapsulated nanoparticles), and semiconductor quantum dots, etc. NIR-sensitive dyes include cyanine dyes, squarylium cyanines, phthalocyanines, porphyrin derivatives, and boron bipyrrolmethane (BODIPY) analogs, etc.

[0062] When combined, the diene-containing compound (such as a furan-containing compound) and the dienophile-containing compound (such as a maleimide-containing compound) will spontaneously and rapidly undergo a [4+2] Diels-Alder reaction, thereby connecting the diene-containing compound to the dienophile-containing compound. The reaction will proceed at room temperature and intensify as the temperature rises above room temperature (e.g., at 37° C.). In an embodiment of the present disclosure, an iodinated diene-containing compound (such as an iodinated furan-containing compound) and a multi-arm polymer containing a dienophile (such as a multi-arm polymer containing maleimide) are combined so that they undergo a [4+2] Diels-Alder reaction, thereby connecting the iodinated compound to the multi-arm polymer. Such a reaction can be performed in vivo or in vitro. The high reaction selectivity of the Diels-Alder reaction will only occur between furan and maleimide groups, which avoids non-target crosslinking or unintentional crosslinking in vivo.

[0063] As described above, when the iodinated compound contains two or more furan-containing moieties, the [4+2] Diels-Alder reaction of the iodinated compound with a multi-arm polymer containing maleimide moieties produces a furan-maleimide Diels-Alder adduct in the form of a crosslinked network, wherein the iodinated compound is bonded to the furan-maleimide Diels-Alder adduct via The bonds cross-link the arms of the multi-arm polymer.

[0064] This can be obtained from e.g. Figure 5 As can be seen from the schematic diagram, Figure 4 The maleimide-terminated multi-arm polymer 414 and Figure 1B The iodinated furan-containing product 118 is coupled via a Diels-Alder reaction to form the cross-linked radiopaque product 520 as shown.

[0065] Similarly, in Figure 6 In the schematic diagram, Figure 4 The maleimide-terminated multi-arm polymer 414 and Figure 2B The iodinated furan-containing product 218 was coupled via a Diels-Alder reaction to form Figure 6 A cross-linked radiopaque product 620 is shown.

[0066] On the other hand, in the case where the iodinated compound contains only a single furan-containing moiety, the [4+2] Diels-Alder reaction of the iodinated compound with the multi-arm polymer containing maleimide-containing moieties results in coupling of the iodinated compound to the multi-arm polymer without concomitant crosslinking.

[0067] This is in e.g. Figure 7 As shown in Figure 3B The iodinated furan-containing product 318 and Figure 4The maleimide-terminated multi-arm polymer 414 was coupled via a Diels-Alder reaction. Figure 3B The iodinated furan-containing product 318 contains only a single furan group, so this reaction is not a cross-linking reaction. However, the multi-arm polymer 414 is converted into a radiopaque product 720 by coupling with the iodinated furan-containing product 318.

[0068] In other aspects, the present disclosure relates to a system that can be used to form a cross-linked radiopaque product. The system may include: (a) a first composition comprising an iodinated multifunctional compound containing a plurality of diene-containing moieties, and (b) a second composition comprising a multifunctional multi-arm polymer containing a plurality of dienophile-containing moieties. Various examples of iodinated compounds containing diene moieties and various examples of multi-arm polymers containing dienophile moieties are described above. The first composition and the second composition may be provided in a first container and a second container, respectively. For example, the first container and the second container may be independently selected from vials and syringe tubes and other forms.

[0069] In some aspects of the present disclosure, the system is configured to dispense and combine the first composition and the second composition such that the iodinated multifunctional compound and the multifunctional multi-arm polymer are cross-linked to each other through a Diels-Alder reaction.

[0070] Such a system is advantageous, for example, because the Diels-Alder reaction is highly selective, thereby minimizing non-target cross-linking. Such a system is also advantageous, for example, because no buffer solution is needed to maintain the pH value at a specific value. Such a system is also advantageous, for example, because the iodinated multifunctional compound as the cross-linking agent of the multi-arm polymer provides the iodine function, thereby providing radiopacity. This allows providing reactive end groups on each polymer arm, thereby maximizing the cross-linking ability of the multi-arm polymer, without sacrificing radiopacity.

[0071] The first composition can be a first fluid composition comprising an iodinated multifunctional compound, or a first dry composition comprising an iodinated multifunctional compound, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a first fluid composition. In addition to the iodinated multifunctional compound, the first composition can also include additives, including those described above.

[0072] The second composition can be a second fluid composition comprising a multi-arm polymer, or a second dry composition comprising a multi-arm polymer, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a second fluid composition. In addition to the multi-arm polymer, the second composition can also include additives, including those described above.

[0073] In various embodiments, a system is provided that includes one or more delivery devices for delivering a first composition and a second composition to a subject.

[0074] In some embodiments, the system may include a delivery device comprising a first reservoir and a second reservoir, the first reservoir containing a first composition comprising an iodinated multifunctional compound as described above, and the second reservoir containing a second composition comprising a multi-arm polymer as described above. During operation, the first composition and the second composition are dispensed and combined from the first reservoir and the second reservoir, whereupon the iodinated multifunctional compound and the multi-arm polymer are cross-linked to form a hydrogel.

[0075] In certain embodiments, the system can include a delivery device comprising a double-barreled syringe comprising a first barrel having a first barrel outlet (the first barrel containing a first composition, a first plunger movable in the first barrel), a second barrel having a second barrel outlet (the second barrel containing a second composition and a second plunger movable in the second barrel).

[0076] In some embodiments, device can also include a mixing part, and this mixing part has a first mixing part inlet that is communicated with the first pipe outlet fluid, a second mixing part inlet that is communicated with the second pipe outlet fluid, and a mixing part outlet. In some embodiments, device can also include sleeve pipe or conduit, which is configured to receive the first fluid composition and the second fluid composition from the first pipe and the second pipe. For example, sleeve pipe or conduit can be configured to be connected with the outlet of mixing part by sleeve pipe or conduit being attached to the outlet (for example, via suitable fluid connector such as Luer connector) to form fluid with mixing part.

[0077] As another example, the catheter can be a multi-lumen catheter including a first lumen and a second lumen, the proximal end of the first lumen being configured to form a fluid connection with the first tube outlet, and the proximal end of the second lumen being configured to form a fluid connection with the second tube outlet. In some embodiments, the multi-lumen catheter can include a mixing section having a first mixing section inlet in fluid communication with the distal end of the first lumen, a second mixing section inlet in fluid communication with the distal end of the second lumen, and a mixing section outlet.

[0078] During operation, when depressing the first and second plungers, the first fluid composition and the second fluid composition are distributed from the first pipe and the second pipe, so the first fluid composition and the second fluid composition interact and finally crosslink to form a hydrogel, which is applied to the tissue of the experimenter or in the tissue. For example, the first fluid composition and the second fluid composition can enter the mixing part from the first pipe and the second pipe via the first mixing part entrance and the second mixing part entrance, so the first fluid composition and the second fluid composition mix to form a mixture, and the mixture leaves the mixing part via the mixing part outlet. In some embodiments, a sleeve tube or a catheter is attached to the mixing part outlet, thereby allowing the mixture to be applied to the experimenter after passing through a sleeve tube or a catheter.

[0079] As another example, the first fluid composition can enter the first lumen of the multi-lumen catheter from the first tube outlet, and the second fluid composition can enter the second lumen of the multi-lumen catheter from the second tube outlet. In some embodiments, the first fluid composition and the second fluid composition can enter the mixing part at the far end of the multi-lumen catheter from the first lumen and the second lumen via the first mixing part inlet and the second mixing part inlet, respectively, so that the first fluid composition and the second fluid composition are mixed in the mixing part to form a mixture, and the mixture leaves the mixing part via the mixing part outlet.

[0080] No matter how the type of the device for mixing the first fluid composition and the second fluid composition or the first fluid composition and the second fluid composition are mixed, after the mixture of the first fluid composition and the second fluid composition is formed, the mixture is initially a fluid state, and can be applied to a subject (for example, mammal, particularly people) by various technologies. Or, the first fluid composition and the second fluid composition can be applied to a subject independently, and the fluid mixture of the first fluid composition and the second fluid composition is formed in the subject or on the body surface. In either method, the fluid mixture of the first fluid composition and the second fluid composition is formed, and is used for various medical procedures.

[0081] For example, in the treatment of diseases and cancers, and in the repair and regeneration of tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide spacing between tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected (for example, in the form of blisters) to provide reference markers, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected for tissue augmentation or regeneration, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a filler or replacement for soft tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide mechanical support for damaged tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a scaffold, and / or the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a carrier for therapeutic agents.

[0082] Upon administration of the disclosed composition (either alone as a first fluid composition and a second fluid composition that are mixed in vivo, or as a fluid mixture of the first fluid composition and the second fluid composition), a cross-linked hydrogel is ultimately formed at the site of administration.

[0083] After administration, the compositions of the present disclosure can be imaged using a suitable imaging technique. Typically, the imaging technique is an X-ray based imaging technique, such as computed tomography or X-ray fluoroscopy.

[0084] As can be seen from the foregoing, the compositions of the present disclosure can be used in a variety of medical procedures, including the following: a procedure for implanting a fiducial marker comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue regeneration scaffold comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue support comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue expander comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a therapeutic agent-containing depot comprising a cross-linked product of a first fluid composition and a second fluid composition, a tissue augmentation procedure comprising implanting a cross-linked product of a first fluid composition and a second fluid composition, and a procedure for introducing a cross-linked product of a first fluid composition and a second fluid composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0085] The first fluid composition and the second fluid composition, the fluid mixture of the first fluid composition and the second fluid composition, or the cross-linked product of the first fluid composition and the second fluid composition can be injected in conjunction with various medical procedures including: injection for spacing between the prostate or vagina and rectum in radiation therapy for rectal cancer, injection for spacing between the rectum and prostate in radiation therapy for prostate cancer, subcutaneous injection for palliative treatment of prostate cancer, transurethral or submucosal injection for female stress urinary incontinence, intravesical injection for urinary incontinence, uterine cavity injection for Asherman's syndrome, submucosal injection for anal incontinence, percutaneous injection for heart failure, intramyocardial injection for heart failure and dilated cardiomyopathy, transendocardial injection for myocardial infarction, intra-articular injection for osteoarthritis, spinal injection for spinal fusion and spinal, oral maxillofacial and orthopedic trauma surgery, Spinal injections for posterolateral lumbar fusion, Intradiscal injections for degenerative disc disease, Injections between the pancreas and duodenum for pancreatic cancer imaging, Resection bed injections for oropharyngeal cancer imaging, Peritumoral bed injections for bladder cancer imaging, Submucosal injections for gastrointestinal tumors and polyps, Visceral pleural injections for lung biopsy, Renal injections for type 2 diabetes and chronic kidney disease, Renal cortical injections for chronic kidney disease from congenital anomalies of the kidney and urinary tract, Intravitreal injections for neovascular age-related macular degeneration, Intratympanic injections for sensorineural hearing loss, Dermal injections for correction of wrinkles, creases and folds, Facial fat loss, signs of volume loss, Contour defects from superficial to deep, Correction of depressed skin scars, Perioral wrinkles, Lip augmentation, Facial lipoatrophy, Stimulation of natural collagen production.

[0086] Cross-linked hydrogel compositions according to the present disclosure include lubricious compositions for medical applications, compositions for therapeutic agent release (e.g., by including one or more therapeutic agents in the matrix of the cross-linked hydrogel), and implants (which can be formed in vitro or in vivo) (e.g., compositions used as tissue markers, compositions that act as spacers to reduce side effects of off-target radiation therapy, cosmetic compositions, etc.).

Claims

1. A system for forming a radiopaque product, comprising (a) an iodinated compound and (b) a multi-arm polymer, wherein the iodinated compound comprises one or more diene-containing moieties, and the multi-arm polymer comprises a plurality of dienophile-containing moieties, wherein the diene-containing moieties of the iodinated compound are coupled with the dienophile-containing moieties of the multi-arm polymer by a Diels-Alder reaction.

2. The system of claim 1, wherein the iodinated compound comprises two or more diene moieties.

3. The system of claim 1, wherein the diene-containing moiety is a furan-containing moiety and the dienophile-containing moiety is a maleimide-containing moiety.

4. The system of claim 1, wherein the iodinated compound comprises a core, one or more furan-containing moieties attached to the core, and one or more iodine-containing moieties attached to the core.

5. The system of claim 4, wherein the one or more furan-containing moieties are attached to the core via an ester group and the one or more iodine-containing moieties are attached to the core via an amide group.

6. The system of claim 4, wherein the one or more iodine-containing moieties comprise an aromatic structure substituted with one or more iodine groups and one or more hydrophilic functional groups.

7. The system of claim 1, wherein the multi-arm polymer comprises a plurality of hydrophilic polymer arms.

8. The system of claim 7, wherein the hydrophilic polymer arms comprise one or more hydrophilic monomers selected from the group consisting of ethylene oxide, N-vinyl pyrrolidone, oxazoline, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or N-isopropylacrylamide.

9. The system of claim 7, wherein two or more of the plurality of hydrophilic polymer arms each comprise one or more dienophile end groups.

10. The system of claim 9, wherein the dienophile end groups are attached to the two or more hydrophilic polymer arms via hydrolyzable ester groups.

11. The system of claim 1 , comprising a first composition comprising the iodinated compound in a first container, and a second composition comprising the multi-arm polymer in a second container, wherein the iodinated compound comprises one or more diene-containing moieties and the multi-arm polymer comprises a plurality of dienophile-containing moieties.

12. The system of claim 11, wherein the first container and the second container are independently selected from a vial and a syringe tube.

13. The system of claim 11, further comprising a delivery device.

14. A crosslinked network formed by crosslinking an iodinated compound comprising one or more diene-containing moieties according to the system of claim 1 with a multi-arm polymer comprising a plurality of dienophile-containing moieties in a Diels-Alder reaction.

15. The cross-linked network of claim 14, wherein the cross-linked network has a radiopacity greater than 250 Hounsfield units.

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