Tissue-catalyzed growth of polymers as epithelial therapy

Abstract

The present disclosure provides compositions, methods, and kits that enable in situ growth of a polymer on or within a subject. In some aspects, the monomeric dopamine is polymerized in vivo to form a polymer on tissue. In additional aspects, the compositions, methods, and kits may be used to treat or prevent a disease or disorder.

Description

[0001] This application is a divisional application of the patent application for invention titled "Tissue Catalytic Growth of Polymers as Epithelial Layer Therapy" with the application date of December 10, 2020, application number 202080086502.4.

[0002] Cross - reference to related applications

[0003] This application claims the priority of U.S. Provisional Patent Application U.S.S.N. 62 / 947,582 filed on December 13, 2019, U.S. Provisional Patent Application U.S.S.N. 63 / 050,206 filed on July 10, 2020, and U.S. Provisional Patent Application U.S.S.N. 63 / 050,216 filed on July 10, 2020 under 35 U.S.C.§119(e). The content of each is incorporated herein by reference in its entirety.

[0004] Government support

[0005] This invention was made with government support under Grant No. R01 EB000244 awarded by the National Institutes of Health. The government has certain rights in the invention. Background of the invention

[0006] The small intestine is a multifunctional organ with a variety of physiological functions. The epithelium covering the gastrointestinal tract is a multifunctional tissue that plays an important role as a permeable barrier for selective transport (e.g., absorption) and a protective armor against various pathogens. Specifically, the epithelial tissue of the gastrointestinal tract (especially the small intestine epithelium) is not only a protective screen against physical abrasion, chemical stress, and pathogens, but also a dynamic lining for signal sensing, molecular transport, and immune coordination. Selective intervention in the small intestine mucosa is related to disease treatment and health management. At the same time, in response to the challenge of specifically and effectively restoring or enhancing small intestine epithelial function, a variety of elaborately designed biotechnologies have been developed. These specific techniques using exquisitely designed tissue adhesives (e.g., pH - dependent polymers, metal complexes, and targeted nanoparticles) or system - engineered tissue substitutes (e.g., epithelial grafts, autologous cell layers, and plastic epithelial sleeves) are effective tools for the restoration of epithelial dysfunction and the treatment of systemic diseases 1-7 . Despite these advances in research laboratories, the widespread adoption of these technologies in medical laboratories and healthcare clinics is limited, thus hindering their impact 8-10 . This limited implementation is the result of multiple factors such as invasive transplantation, potential immunogenicity, toxicity, and the imprecision, instability, and inconvenience of current tissue - targeting strategies, which limit selective small intestine access.

[0007] Similarly, the ability to intervene in digestive disorders and treat systemic diseases in the small intestine has spurred scientists to develop various targeted drugs. 31,32 . However, the challenges of small intestine-specific targeting have hindered widespread adoption. 9,10 . Alternative techniques that require surgical implantation (such as intestinal sleeves) are limited to therapies with complex procedures, low biocompatibility, risk of inflammation, and high costs. Therefore, it remains a challenge to develop the function of the epithelial layer through advanced biotechnology while maintaining the physiological characteristics of the tissue. SUMMARY OF THE INVENTION

[0008] Compositions, methods, and kits for in situ forming polymers in a subject are disclosed herein. This disclosure enables polymers to grow on the surface of epithelial tissue, thereby providing a transient coating layer with tunable functions. Polymer coating relies on dopamine polymerization catalyzed by an endogenous cellular enzyme (catalase), strong tissue adhesion generated by chemical crosslinking, and optionally functional agents introduced through facile conjugation. For example, catalase in epithelial tissue in the gastrointestinal tract catalyzes the growth of polydopamine on the small intestinal mucosa. In addition, the catalase expression level along tissues (such as the gastrointestinal tract) allows for effective and specific formation of polymer coatings.

[0009] The disclosed compositions, methods, and kits can be used, for example, to enhance lactose digestion by immobilizing galactosidase in the intestine, resulting in improved lactose digestion; to regulate nutrient uptake by hindering glucose absorption; and to control drug delivery by prolonging the residence time of an active pharmaceutical ingredient in a specific anatomical location.

[0010] In one aspect, a method for in situ forming a polymer in a subject is provided herein, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst of the subject and the catalyst polymerizes the monomer, wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

[0011] In one aspect, the present disclosure provides a composition comprising dopamine, an oxygen source, and optionally a buffer. In some aspects, the composition further comprises a digestive enzyme, a nutrient blocker, a nutritional preparation, a radiation protectant, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

[0012] In another aspect, the present disclosure provides a method for treating a disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a composition as described herein.

[0013] In one aspect, the present disclosure provides a method of preventing a disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a composition as described herein.

[0014] In another aspect, the present disclosure further provides a kit, the kit comprising a composition as described herein and instructions for administering the composition.

[0015] Details of particular embodiments of the present disclosure are set forth in the Detailed Description of Certain Embodiments below. Other features, objects, and advantages of the present disclosure will be apparent from the definitions, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A-1H. Endogenous enzyme-catalyzed polydopamine growth on small intestinal epithelium. Figure 1 A shows a schematic diagram of tissue-accelerated polymerization of the technology of the present disclosure. Dopamine monomers in the orally administered monomer solution are rapidly oxidized in the presence of hydrogen peroxide (H 2 O 2 ) under the catalysis of endogenous catalase and form a polydopamine coating on the small intestinal epithelium. Due to the uneven distribution of catalase along the digestive tract, this specific small intestinal coating and targeting are achieved. Figure 1 B shows a schematic diagram of catalase-accelerated polydopamine polymerization in a hypoxic environment. In an extremely hypoxic environment as depicted above the horizontal arrow, the oxidation of dopamine (colorless) (using oxygen as the oxidant) and the formation of polydopamine (dark brown) are inhibited and are even almost quenched in the presence of H 2 O 2 . In contrast, catalase can promote oxygen release (using H 2 O 2 as the oxygen source) and accelerate the polymerization of polydopamine by, for example, about 400-fold. Thus, as shown below the horizontal arrow, colorless dopamine rapidly polymerizes into polydopamine in the presence of hydrogen peroxide and catalase. TAPPE = tissue-accelerated polymerization on the external epithelium. Figure 1 C shows a visual observation of polydopamine polymerization at different time points under the conditions shown in Figure 1 B. Figure 1 D shows the extinction measured at 700 nm of the sample shown in Figure 1 C. The optical extinction generated within 20 seconds under the catalysis of catalase is the same as that generated within 2 hours under other conditions. Figure 1Panel E depicts an image showing polydopamine coating on the mucosal and serosal sides of porcine small intestine after in vitro coating treatment as disclosed herein, where the scale bar indicates 2 cm. Figure 1 Panel F shows the quantitative evaluation of in situ in vitro polymerization kinetics. The polydopamine signal reached completion within 12 minutes. Data are reported as mean ± SD of three porcine tissue samples. Figure 1 Panel G depicts images showing porcine tissue samples in different parts of the gastrointestinal tract before and after tissue-accelerated polymerization coating. Samples (6 mm in diameter) were collected at three random sites of the polydopamine-coated tissue. Figure 1 Panel H shows Figure 1 Quantitative measurement of the polydopamine signal intensity of the samples shown in G. The intensity difference between the small intestine and other tissues was statistically significant. ****P < 0.05, one-way ANOVA and post hoc Bonferroni. Data are reported as mean ± SD of three different tissue samples.

[0017] Figure 2 A - 2H. Biological mechanisms of tissue-accelerated polymerization. Figure 2 Panel A shows the evaluation of the relationship between tissue catalytic ability and polydopamine polymerization. Porcine tissue lysates were added individually to the tissue-accelerated polymerization solution, and the extinction of each solution was measured at 700 nm. When comparing small intestinal epithelium with other tissues and the control (no lysate), both visual assessment (upper panel) and quantitative measurement (lower panel) of the polydopamine solution showed differences in catalytic ability. *P < 0.05, one-way ANOVA and post hoc Bonferroni. Data are reported as mean ± SD of three parallel determinations. Figure 2 Panels B - 2C show the verification of the unique role of catalase in the reaction shown in Figure 2 A by treating the lysates with a catalase-specific inhibitor ( Figure 2 B) or an antibody that induces immunoprecipitation ( Figure 2 C). The relative catalytic ability difference between the treated and untreated groups was visually and statistically significant. ***P < 0.001 (by two-tailed t-test). Data are reported as mean ± SD of three different tissue samples. Figure 2 Panels D - 2F show the quantification of catalase expression (gene and protein levels) along the porcine gastrointestinal tract by catalase activity assay ( Figure 2 D), real-time PCR ( Figure 2 E), and Western blotting ( Figure 2 F). At Figure 2A similar distribution pattern was achieved in D-2F, indicating a higher level of catalase expression in the small intestinal epithelium compared to other tissues. The difference was statistically significant. ***P < 0.05, one-way ANOVA and post hoc Bonferroni. Data are reported as the mean ± SD of three parallel measurements. Figure 2 G shows a microscopic analysis of polydopamine-coated small intestinal epithelium, showing a thin polydopamine layer coated on the outer villi (indicated by arrows), but not on the control tissue (without coating). Scale bar, 150 μm. Figure 2 H shows bright-field imaging of uncoated tissue sections treated with specific peroxisome / catalase staining (left panel) and tissue-accelerated polymerization solution (right panel). Dark brown polydopamine spots were observed within the villus tips, and the staining pattern was consistent with conventional peroxisome / catalase staining. Scale bar, 150 μm.

[0018] Figure 3 A-3I. In Vivo Performance of Tissue-Accelerated Polymerization Coating in Pigs. Figure 3 A-3C shows a schematic diagram and photographs of real-time in vivo gastrointestinal endoscopy recordings of polydopamine formation during the tissue-accelerated polymerization process. Under endoscopic visual guidance, the tissue-accelerated polymerization solution was directly applied to the porcine small intestine of pigs through a catheter, and the endoscopic camera was placed both inside and outside the solution within the small intestine for observation. Figure 3 B-3C shows endoscopic images (bottom three panels) revealing the steps during polydopamine coating. Oxygen bubbles were generated at the epithelial-solution interface (indicated by white arrows). Figure 3 D shows a schematic diagram of small intestine ligation (upper panel) and direct polydopamine coating evaluation (lower panel). The tissue-accelerated polymerization solution filled the intestinal lumen up to the clamping site and could not be transmitted downward to the lower small intestine. The separated tissues showed different polydopamine coatings before and after the clamping site. Figure 3 E shows a schematic diagram of polydopamine-coated intestinal retention indicated by X-ray imaging of the polydopamine probe. X-ray images of two tests were taken: (I) short-term stability evaluation (rinsing the coated area) and (II) long-term retention assessment (liquid diet for 24 hours). PDA = polydopamine. Figure 3 F shows X-ray images of the polydopamine probe stably resident in the small intestine before and after rinsing the imaging area, as well as the polydopamine coating layer, as shown in test (I). The stomach and small intestine (SI) regions are separated by a white dashed line. The polydopamine coating is indicated by yellow arrows. Figure 3 G shows X-ray images of polydopamine-coated intestinal retention during the duration of test (II). Conventional probes were hardly detectable after food exposure. Figure 3 H shows Figure 3Quantitative signal intensity analysis of the small intestine region encapsulated in F, i.e., the region of interest (ROI). The enhancement and stability of the signals (before and after rinsing) of the polydopamine probe compared to the conventional (CON) probe indicated effective probe introduction and stable polydopamine coating. Data were reported as the mean ± SD of three different measurements. Figure 3 I shows Figure 3 Quantitative signal intensity analysis of the polydopamine coating in G over time. From 2 to 6 hours, there was only a 28% difference in signal intensity, indicating extended retention of the polydopamine coating. Data were reported as the mean ± SD of three different measurements.

[0019] Figure 4 A-4G. Therapeutic applications enabled by tissue-accelerated polymerization. Figure 4 A shows a schematic diagram of the tissue-accelerated polymerization treatment platform. Functional agents (including digestive enzymes, nutrient blockers, and anthelmintics) were introduced into the platform by co-oral administration with the tissue-accelerated polymerization solution to pigs. Figure 4 B shows a schematic diagram of introducing a digestive enzyme (β-galactosidase, β-gal) into the polydopamine coating layer on the porcine intestinal epithelium to enhance the digestion of the substrate (lactose). After in vivo coating, the β-gal activity of the coated epithelium was evaluated. Figure 4 C shows a quantitative comparison of β-gal activity, showing an increase in enzyme activity in the tissue with β-gal coating based on tissue-accelerated polymerization compared to the negative control. Data were reported as the mean ± SD of four animals. Figure 4 D shows a schematic diagram of introducing a nano-crosslinker (blocker) into the tissue-accelerated polymerization coating to make the polydopamine coating layer impermeable, thereby blocking glucose uptake in the small intestine. After in vivo coating, oral glucose was administered to pigs, and then blood glucose concentration was monitored. Figure 4 E shows a quantitative comparison of blood glucose changes, showing a decrease in the blood glucose response of pigs with tissue-accelerated polymerization coating compared to the control (without coating). Data were averaged between animals in each group (each animal represented by a gray line) (shown by the black line). Figure 4 F shows a schematic diagram of coated drug (praziquantel) particles on the intestinal epithelium for sustained release of the therapeutic agent in the small intestine. After oral administration of the praziquantel-tissue-accelerated polymerization solution, the blood drug concentration was analyzed after 48 hours. Figure 4 G shows a quantitative comparison of pharmacokinetics, showing an extended retention time of praziquantel (with the tissue-accelerated polymerization solution) compared to the control (without the tissue-accelerated polymerization solution). *Indicates p < 0.02, two-sample t-test comparing praziquantel-tissue-accelerated polymerization and the control group at matching time points. Data were reported as the mean ± SD of three animals.

[0020] Figure 5 A-5G. Compatibility of human tissue with tissue-accelerated polymerization.Figure 5 A shows images of freshly excised tissue specimens from the human small intestine before and after in vitro tissue-accelerated polymerization coating. A dark brown polydopamine coating was clearly observed on the surface of the human small intestine (lower panel). Scale bar, 1 cm. Figure 5 B depicts the coating kinetics showing the emergence of an ultrafast polydopamine signal in ex vivo human tissue. The polydopamine signal reached completion within 3 minutes. Figure 5 C shows the evaluation of tissue-accelerated polymerization consistency. Tissue specimens from donors of 3 different ages, ethnicities, and genders were tested. Five ex vivo evaluations were performed at random sites on the human small intestine. Quantitative measurements (right panel) of the polydopamine coating signal of samples (6 mm in diameter) before and after coating (left panel) confirmed consistent tissue-accelerated polymerization coating performance. Data are reported as the mean ± SD of five parallel determinations. Figure 5 D shows microscopic and histological analyses of cryosections (40 μm thick) and FFPE sections (5 μm thick) collected from polydopamine-coated human small intestine epithelium. A thin polydopamine layer was observed on the outer villi of the coated tissue. Uncoated tissue was used as a control. Histological studies (hematoxylin and eosin (H&E) staining) of adjacent cryosections and FFPE samples showed that the epithelial layer remained intact (where the staining pattern was similar to the control), indicating the absence of tissue toxicity. Scale bar, 150 μm. Figure 5 E depicts representative images showing no significant decrease in the polydopamine signal in the coated human small intestine after mechanical stirring and scratching. Figure 5 F shows the quantitative ex vivo evaluation of the polydopamine signal intensity of coated tissue under a series of physical conditions. The intensity differences between all conditions were not statistically significant (two-tailed t-test). Data are reported as the mean ± SD of three parallel determinations. Figure 5 G shows the quantitative ex vivo evaluation of the polydopamine signal intensity of coated tissue under a series of chemical conditions. The intensity differences between all conditions were not statistically significant (two-tailed t-test). Data are reported as the mean ± SD of three parallel determinations.

[0021] Figure 6 A-6B. Comparison of polydopamine polymerization kinetics under different reaction conditions. Figure 6 A shows the extinction measured at 700 nm of samples that underwent polydopamine polymerization in air (with and without H 2 O 2 (control)). Figure 6 B shows the extinction measured at 700 nm of samples that underwent polydopamine polymerization under extremely low oxygen levels (hypoxic environment) (with and without H 2 O 2 (control)). Compared with conventional conditions (without H 2 O 2Compared with the reaction under 2 O 2 ) conditions, polydopamine polymerization was inhibited by 65% at extremely low oxygen levels without H 2 O 2 . The addition of H

[0022] Figure 7 A-7D. Fourier transform infrared (FTIR) spectra of dopamine, polydopamine standards, and polymerization products. The FTIR spectra of dopamine ( Figure 7 A) and polydopamine ( Figure 7 B) prepared under conventional conditions were measured and used as standards. The FTIR spectra confirmed the formation of polydopamine in the polymerization products catalyzed by catalase (commercially purified) ( Figure 7 C) and catalase (from tissue lysates) ( Figure 7 D). The indole (or dihydroindole) peaks (1515 and 1605 cm -1 ) and the broad peak spanning 3200 - 3500 cm -1 (hydroxyl structure) in the catalase-catalyzed polymerization products were almost the same as those in the polydopamine standards.

[0023] Figure 8 A-8C. Normalized extinction spectra of polydopamine standards and polymerization products. The UV-Vis spectra of the polydopamine standard ( Figure 8 A), the polymerization product catalyzed by catalase (commercially purified) ( Figure 8 B), and the polymerization product catalyzed by catalase (from tissue lysates) ( Figure 8 C) were almost the same, confirming the formation of polydopamine in Figure 8 B and Figure 8 C.

[0024] Figure 9 . Tissue-accelerated polymerization coating evaluation using porcine tissue specimens. The mucosa and serosa of the small intestine (schematic diagram, left figure) were separately exposed to the tissue-accelerated polymerization solution, and a dark brown polydopamine coating was observed only on the mucosal side of the tissue (middle figure), but not on the serosal side of the tissue (right figure). To confirm the coating specificity, the two ends of the small intestine tissue were tied with sutures, and only the segment between the sutures was exposed to the tissue-accelerated polymerization solution.

[0025] Figure 10.Analysis of catalytic ability of tissue lysates by native gel electrophoresis. Tissue lysates from different parts of the porcine gastrointestinal tract were loaded onto native polyacrylamide gels, electrophoresed to allow protein separation, and stained for catalytic ability analysis. After staining with the tissue-accelerated polymerization solution, dark brown polydopamine signals were visualized on the gels. Only one clear band (indicated by an arrow) was observed in each lane, supporting the expected role of catalase as the sole enzyme responsible for polydopamine polymerization.

[0026] Figure 11 A-11B. Quantification of catalase mRNA levels in tissues using real-time PCR. Housekeeping genes, including β-actin ( Figure 11 A) and 18S ( Figure 11 B), were used as controls for quantifying catalase mRNA levels. Tissue specimens from 4 pigs were tested. The small intestine catalase mRNA expression levels had similar distribution characteristics in Figure 11 A and Figure 11 B. Data were reported as the mean ± SD of 4 animals.

[0027] Figure 12 A-12E. Ct values of gene expression levels. For mRNA level quantification, catalase ( Figure 12 A), β-actin ( Figure 12 B), 18S ( Figure 12 C), GUS ( Figure 12 D), and GAPDH ( Figure 12 E) genes were included in the test. Tissue specimens from 4 pigs were tested. Data were reported as the mean ± SD of 4 animals.

[0028] Figure 13 . Bright-field images of polydopamine-coated small intestinal epithelium. Porcine small intestinal tissues were ex vivo exposed to the tissue-accelerated polymerization solution for 3 and 15 minutes and examined under a bright-field microscope. Polydopamine was first deposited at the tips of intestinal villi (indicated by yellow arrows, upper panel), and then coated the entire villi and the surrounding area (lower panel). Scale bar, 500 μm.

[0029] Figure 14 A-14C. Evaluation of in vivo tissue-accelerated polymerization coating performance in the stomach. Figure 14 A shows a schematic diagram of real-time recording of the stomach by gastrointestinal endoscopy after oral administration of the tissue-accelerated polymerization solution to the stomach. The pig was in a moderately sedated state throughout the process. The endoscope camera was placed outside the solution for observation, and images were recorded at the same position over time. Figure 14 B shows the endoscopic image, revealing that no dark brown polydopamine was seen in the stomach. The tissue-accelerated polymerization solution in the stomach remained clear for 20 minutes. Figure 14 C shows fromFigure 14 Images of the isolated stomach of the animal in B confirmed the absence of polydopamine coating on the epithelial surface.

[0030] Figure 15 A-15C. Evaluation of in vitro polydopamine probe tissue coating performance by X-ray imaging. Figure 15 A shows images displaying the conventional (CON) probe solution and the polydopamine probe solution. The polydopamine probe was prepared by encapsulating the conventional probe with a thin layer of polydopamine. The dark brown color of the polydopamine probe solution comes from the chromogenic polydopamine on the probe surface. Figure 15 B shows a schematic diagram of the in vitro tissue coating process. The porcine small intestine was placed in a Franz cell, and the tissue accelerating polymerization solution (with or without the probe) was added to the chamber. After coating, the coated tissue was rinsed with water and imaged by an X-ray system. Figure 15 C shows X-ray images of the tissue coated with the tissue accelerating polymerization solution with the polydopamine probe (left panel), the conventional (CON) probe (middle panel), and the tissue accelerating polymerization solution without the probe (right panel). Strong X-ray signals were observed only in the coated area (indicated by the red circle) of the tissue coated with the polydopamine probe. No obvious X-ray signals were detected in the controls where either the conventional probe alone or polydopamine was applied for coating.

[0031] Figure 16 A-16B. In vivo X-ray imaging of intestinal retention of the polydopamine coating layer. Figure 16 A shows X-ray images revealing the stability of the polydopamine coating. The tissue accelerating polymerization solution suspended with the polydopamine probe (upper panel) and the conventional probe (lower panel) were orally administered to healthy pigs, respectively, and imaged by an X-ray system. The solution was directly administered to the small intestine through a catheter under endoscopic visual guidance. The same pigs without probe administration were imaged and used as a control. The imaging area was rinsed with water to test the stability of the polydopamine coating. Figure 16 B shows X-ray images revealing the intestinal retention of polydopamine over time. A series of X-ray images were taken regularly at the same position at 2, 6, and 24 hours. The animals consumed a liquid diet throughout the imaging period to simulate real conditions and test the stability of the polydopamine coating in the presence of food.

[0032] Figure 17 A-17B. Characterization of the nanocrosslinker. Figure 17 A shows TEM images with different magnifications, showing uniform polydopamine nanocrosslinkers. Figure 17 B depicts dynamic light scattering (DLS) analysis, showing the hydrodynamic size of the nanocrosslinker at 527 nm.

[0033] Figure 18A-18B. Evaluation of tissue-accelerated polymerization coating performance across different animal species. Samples (6 mm in diameter) were collected at 3-5 random sites of polydopamine-coated tissues, and the images of the samples were analyzed to quantify the polydopamine coating. ImageJ was used to identify the region of interest that included the polydopamine-coated tissue and excluded the "blank" tissue-free area. The same analysis was performed on all samples in each group to obtain the total average polydopamine signal intensity and evaluate the signal variation. This is an ex vivo study. Figure 18 A shows the quantitative evaluation of polydopamine coating density on the small intestines from pigs, humans, and rats. The polydopamine signal intensity was measured after tissue-accelerated polymerization coating, which represents the polydopamine coating density. The data were reported as the mean ± SD of three parallel determinations. Figure 18 B shows the quantification of catalase expression by measuring the catalase activity in the small intestines from pigs, humans, and rats. Tissue specimens were collected from the same animals as in Figure 18 A. The data were reported as the mean ± SD of three parallel determinations.

[0034] Figure 19 . Dose-dependent cytotoxicity of polydopamine in HeLa, COLO320DM, Caco-2, Hep3B, and HS 895.T cells. Cells were treated with different concentrations of polydopamine, and the cytotoxicity was analyzed at different time points. After 24 hours of polydopamine exposure, for all cell lines, polydopamine was of low toxicity (>80% viability) in the concentration range of 0 - 2000 μg / ml. -1

[0035] Figure 20 A-20C. Body weight changes in rats during the 28-day oral toxicity evaluation. During a 4-week period, rats were exposed to water (control) ( Figure 20 A), polydopamine as prepared ( Figure 20 B), and the tissue-accelerated polymerization solution ( Figure 20 C). No significant differences in body weight were observed among the rats exposed to the tissue-accelerated polymerization solution, polydopamine, and water. The data were averaged among the animals in each group (each animal is represented by a gray line) (shown by a black line). The data were reported as the mean ± SD of four animals.

[0036] Figure 21 . Hematological measurements of rat blood after the 28-day oral toxicity evaluation. Blood samples were collected from rats exposed to water (control), polydopamine as prepared, and the tissue-accelerated polymerization solution. No significant differences in hematological parameters were observed among the rats exposed to the tissue-accelerated polymerization solution, polydopamine, and water (four parallel determinations).

[0037] Figure 22. Blood biochemical tests of rat blood after 28-day oral toxicity evaluation. Blood samples were collected from rats exposed to water (control), as-prepared polydopamine, and tissue acceleration polymerization solution. No significant differences in blood biochemical parameters were observed among rats exposed to tissue acceleration polymerization solution, polydopamine, and water (four parallel determinations).

[0038] Figure 23 . Histology of major organs collected from rats after 28-day oral toxicity evaluation. Tissues were collected from rats exposed to water (control), as-prepared polydopamine, and tissue acceleration polymerization solution, respectively. No obvious organ damage was observed in rats treated with polydopamine and tissue acceleration polymerization solution compared with the control. Scale bar, 300 μm.

[0039] Figure 24 A-24B. Evaluation of tissue acceleration polymerization performance on epithelium after removing bacteria present in small intestinal mucus. Samples (6 mm in diameter) were collected at 3-5 random sites of polydopamine-coated tissue, and the images of the samples were analyzed to quantify the polydopamine coating. Regions of interest including polydopamine-coated tissue and excluding "blank" tissue-free areas were identified using ImageJ. The same analysis was performed on all samples in each group to obtain the total average polydopamine signal intensity and evaluate the signal variation. This is an ex vivo study. Figure 24 A depicts images showing tissue samples (with and without bacteria removal) after ex vivo tissue acceleration polymerization. Samples (6 mm in diameter) were collected at three random sites of polydopamine-coated tissue. Bacteria were removed from the luminal surface of the epithelium by incubation with antibiotic-antifungal solution and repeated washing. Figure 24 B shows Figure 24 Quantitative measurement of the polydopamine signal intensity of the samples shown in A. The intensity difference was not statistically significant. P > 0.05 (by two-tailed t-test). Data were reported as the mean ± SD of three different tissue samples.

[0040] Figure 25 . Comparison of catalase catalytic ability between epithelium and mucus (bacteria). First, a solution (180 μl) was prepared and added to a 96-well plate, and then 10 μl of tissue lysate (villi or mucus) was added. The reaction mixture was maintained at 37 °C for 20 minutes. The extinction of the solution at 700 nm was measured using a microplate reader (Tecan). This is an ex vivo study. The relative catalytic ability of intestinal villi (without bacteria) was higher than that of bacteria in mucus. Mucus was collected at the top of the epithelium (3 cm 2 ) and epithelial villi were collected from the same tissue region. The samples were diluted to the same volume for measurement. The ability difference was statistically significant. ***P < 0.001 (by two-tailed t-test). Data were reported as the mean ± SD of three different parallel determinations.

[0041] Figure 26 A-26C. Microscopic Analysis of Polydopamine Epithelial Deposition. Expose the tissue (12 cm 2 ) to the tissue-accelerated polymerization solution (10 ml) for 20 minutes and wash it 3 times with PBS buffer (1X) to remove the excess polydopamine. Freeze the polydopamine-coated small intestine rapidly and embed it in the optimal cutting temperature (OCT) compound. Cut the fixed tissue into 40-μm-thick sections using a cryostat (Leica Biosystems). This is an ex vivo study. Figure 26 A shows the bright-field imaging of the tissue section coated with tissue-accelerated polymerization. The dark brown polydopamine layer is deposited only on the luminal surface of the epithelial cells (indicated by arrows), but not intracellularly. Figure 26 B shows the bright-field imaging of the uncoated tissue section. The light yellow background signal comes from blood vessels. Figure 26 C shows the bright-field imaging of intracellular polydopamine deposition on the control tissue section of the section, where both dopamine and hydrogen peroxide molecules can diffuse freely and rapidly into the epithelial cells. Dark brown polydopamine deposition (indicated by arrows) is observed inside the epithelial cells, but not on the cell surface, and the deposition pattern is significantly different from that of the tissue section coated with tissue-accelerated polymerization. Scale bar, 150 μm.

[0042] Figure 27 . Polydopamine Polymerization Kinetics in the Luminal Solution. Through ex vivo studies, evaluate the polydopamine polymerization kinetics in the luminal solution located on the top of the porcine epithelium. Measure the extinction of the samples undergoing polydopamine polymerization at 700 nm. Use the polydopamine polymerization kinetics in tissue-accelerated polymerization (without epithelial catalysis) as a control. The optical extinction generated within 45 seconds under epithelial catalysis is the same as that generated within 1 hour under control conditions.

[0043] Figure 28 . Evaluation of Polydopamine Signals in Different Cell Fractionations. Perform cell fractionation on the villi coated with tissue-accelerated polymerization. Strip the villi from the luminal surface of the small intestine tissue (opened longitudinally) placed on an ice-cold substrate. Evaluate the polydopamine signal by measuring the extinction of each cell fraction at 700 nm. No polydopamine signal is detected in the cytoplasmic fraction, but clear polydopamine signals are detected in the membrane and other fractions. The intensity difference is statistically significant. **P < 0.01 (by two-tailed t-test). Data are reported as the mean ± SD of three parallel determinations.

[0044] Figure 29 . Evaluation of the Stability of Tissue-Accelerated Polymerization in the Stomach. To evaluate the stability, add the tissue-accelerated polymerization solution (containing dopamine (500 mg) and H 2 O 2(1 M, 1 mL) was rapidly added to Tris buffer (50 mM, 50 mL) at pH 8.5 and used freshly) was applied to pigs (in vivo, applying non-invasive forceps at the pylorus), recovered from the stomach at different time points, and characterized by ex vivo coating studies. The relative coating performance showed that the recovered solution (10 - 30 minutes) showed consistent coating performance, and the relative coating efficiency only decreased by 30% after 60 minutes, indicating that neither dopamine nor hydrogen peroxide in tissue-accelerated polymerization was absorbed or consumed in significant amounts in the stomach. Data were reported as the mean ± SD of three parallel determinations.

[0045] Figure 30 . Evaluation of polydopamine signal in the submucosa. After in vivo tissue-accelerated polymerization, no detectable increase in polydopamine signal was observed in the porcine submucosa. The solution consisted of dopamine (500 mg) and H 2 O 2 (1 M, 1 mL). Both were rapidly added to Tris buffer (50 mM, 50 mL) at pH 8.5 and used freshly. Epithelial tissue (uncoated) was used as a control. The signal difference was not statistically significant. P > 0.05 (by two-tailed t-test). Data were reported as the mean ± SD of three parallel determinations.

[0046] Figure 31 A - 31B. Evaluation of dopamine concentration in blood and submucosa by liquid chromatography - tandem mass spectrometry. Figure 31 A shows that after in vivo application of the tissue-accelerated polymerization solution (dopamine (500 mg) and H 2 O 2 (1 M, 1 mL) was rapidly added to Tris buffer (50 mM, 50 mL) at pH 8.5 and used freshly), no obvious change in dopamine concentration was observed in the blood. P > 0.05, two-sample t-test comparing tissue-accelerated polymerization and control group (without tissue-accelerated polymerization) at matching time points. Data were reported as the mean ± SD of three animals. Figure 31 B shows that no detectable increase in dopamine concentration was observed in the submucosa after application of the tissue-accelerated polymerization solution (3 hours later). The concentration difference was not statistically significant. P > 0.05 (by two-tailed t-test). Data were reported as the mean ± SD of three parallel determinations.

[0047] Figure 32 A - 32D. Evaluation of the blocking efficiency of the tissue-accelerated polymerization layer by ex vivo studies. The tissue was exposed to the solution (dopamine (500 mg) and H 2 O 2(1M, 1 ml) was quickly added to Tris buffer (50 mM, 50 ml) at pH 8.5, and the mixed solution was used freshly), and washed three times with PBS buffer (1X) to remove the excess polydopamine. Polydopamine nanocrosslinkers at different concentrations (25 mg / ml, 12.5 mg / ml, and 0 mg / ml) were suspended in the tissue acceleration polymerization solution. This is an in vitro study. Figure 32 A-32C shows the relative barrier function (tissue permeability) of the tissue acceleration polymerization layer to Ca 2+ ( Figure 32 A), glutamate ( Figure 32 B), and glucose ( Figure 32 C). All three nutrients showed reduced tissue penetration, and three separate experiments showed that the tissue acceleration polymerization barrier blocked approximately 49% of Ca 2+ , approximately 71% of glutamate, and approximately 78% of glucose. Figure 32 D shows the relative barrier function (glucose tissue penetration) of the tissue acceleration polymerization layer (with different crosslinking densities). When less nanocrosslinker was introduced into the coating layer, glucose had a normal tissue penetration level, indicating that the polydopamine coating layer itself does not affect cellular glucose uptake, but the crosslinking density of the coating layer regulates the glucose uptake efficiency. Porcine small intestine tissue (uncoated) was used as a control. *P < 0.05 (relative to the control), one-way analysis of variance (ANOVA) and post hoc Bonferroni. Data were reported as the mean ± SD of three parallel determinations.

[0048] Figure 33 . Evaluation of glucose absorption recovery in tissue acceleration polymerization animals. First, the polydopamine nanocrosslinker (25 mg / ml) was suspended in the tissue acceleration polymerization solution. The nanocrosslinker-suspended tissue acceleration polymerization solution (10 ml / kg) was orally administered to pigs and introduced into the small intestine. The solution was directly administered to the small intestine through a catheter under endoscopic visual guidance. This is an in vitro study. An oral glucose tolerance test was performed 24 hours after the pigs received the tissue acceleration polymerization coating. Pigs with the tissue acceleration polymerization coating recovered normal glucose absorption 24 hours later, indicating that the tissue acceleration polymerization coating layer is transient. The data were averaged between the animals (each animal is represented by a gray line) in each group (shown by a black line).

[0049] Figure 34 . Evaluation of CYP450 activity in the epithelium with and without the polydopamine coating layer. Tissue (12 cm 2) Exposed to the tissue accelerated polymerization solution (10 ml) for 20 minutes and washed 3 times with PBS buffer (1x) to remove the excess polydopamine. This is an in vitro study. After tissue accelerated polymerization, no change in CYP3A4 activity was observed in the epithelium. Epithelial tissue (uncoated) was used as a control. The difference in activity was not statistically significant. P > 0.05 (by two-tailed t-test). Data were reported as the mean ± SD of five parallel determinations.

[0050] Figure 35 A-35B. Tissue accelerated polymerization pattern in the human GI tract. Exposed the tissue (12 cm 2 ) to the tissue accelerated polymerization solution (10 ml) for 20 minutes and washed 3 times with PBS buffer (1X) to remove the excess polydopamine. This is an in vitro study. Figure 35 A depicts images showing human tissue samples in different parts of the GI tract before and after in vitro application of the tissue accelerated polymerization coating. Samples (6 mm in diameter) were collected at three random sites of the polydopamine-coated tissue. Figure 35 B shows Figure 35 the quantitative measurement of the polydopamine signal intensity of the samples shown in A. The intensity difference between the small intestine and other tissues was statistically significant. *P < 0.05, one-way ANOVA and post hoc Bonferroni. Data were reported as the mean ± SD of three different tissue samples.

[0051] Figure 36 A-36C. Stability of the surface-based polydopamine coating. Applied the polydopamine coating to the surface of an impermeable polycarbonate substrate. Exposed the polycarbonate sheet to the tissue accelerated polymerization solution (without H 2 O 2 ) for 36 hours and washed with water to remove the excess polydopamine. The white polycarbonate (left) turned dark brown after polydopamine coating (right). Evaluated the stability of the polydopamine coating under a series of physical conditions. Figure 36 A-36C shows that no obvious decrease in the polydopamine signal was observed under mild and severe scratching, and the polydopamine coating was only removed under extremely severe scratching with sandpaper. These results indicate that the stability of the surface-based polydopamine coating is due to strong surface-based adhesion rather than penetration into the substrate surface.

[0052] Figure 37 . Conversion of the tissue accelerated polymerization platform to a capsule. The porcine small intestine tissue isolated in vivo showed different polydopamine coatings before and after the clamping site, indicating the coating performance of the tissue accelerated polymerization capsule. The capsule was composed of dopamine hydrochloride powder (500 mg), Tris powder (30 - 300 mg; 300 mg), solid urea H 2 O 2Composed of powder (10 - 50 mg; 50 mg). The mixed powder is filled into (000 - size) capsules. An opening is made surgically on the intestine, and the capsules are directly administered into the intestine for capsule delivery. Due to small intestine ligation, the capsules cannot be passed down to the lower small intestine. After releasing the tissue - accelerating polymerization components, the capsules collapse, dissolve, and break into smaller pieces.

[0053] Definitions

[0054] Unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular.

[0055] The phrases “in some embodiments” and “in certain embodiments” are used interchangeably.

[0056] The following definitions are for more general terms used throughout this application:

[0057] The singular terms “a”, “an”, and “the” include plural referents unless the context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise.

[0058] Except in the examples, or where otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term “about”. “About” and “approximately” generally mean an acceptable degree of error for the quantity being measured in light of the nature or precision of the measurement. Exemplary degrees of error are within 20% (percent) of the given value or value range, typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1%.

[0059] When a range of values (“range”) is listed, it is intended to cover every value and sub - range within that range. The range includes the values at both ends of the range unless otherwise provided.

[0060] The terms “composition” and “formulation” are used interchangeably.

[0061] The “subject” to be administered is intended to mean a human (i.e., male or female of any age, such as a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young, middle - aged, or elderly)) or a non - human animal. In certain embodiments, the non - human animal is a mammal (e.g., a primate (e.g., cynomolgus monkey or rhesus monkey), a commercially relevant mammal (e.g., cow, pig, horse, sheep, goat, cat, or dog) or a bird (e.g., a commercially relevant bird such as chicken, duck, goose, or turkey)). In certain embodiments, the non - human animal is a fish, reptile, or amphibian. The non - human animal can be male or female at any stage of development. The non - human animal can be a transgenic or genetically engineered animal. The term “patient” refers to a human subject in need of treatment for a disease.

[0062] The terms "administer", "administering", or "administration" mean implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into or onto a subject the compositions described herein.

[0063] The terms "treatment", "treat", and "treating" mean reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment may also continue after symptoms have subsided, e.g., to delay or prevent recurrence.

[0064] The terms "condition", "disease", and "disorder" are used interchangeably.

[0065] An "effective amount" of a polymer or composition described herein means an amount sufficient to elicit a desired biological response. The effective amount of a polymer or composition described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the polymer or composition, the condition being treated, the mode of administration, and the age and health status of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a single dose of a compound, polymer, or composition described herein. In certain embodiments, the effective amount is the combined amount of multiple doses of a compound, polymer, or composition described herein.

[0066] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th Edition; Hensyl, Ed.; Williams & Wilkins: Philadelphia, 1990.

[0067] "Autoimmune disease" refers to a disease in which the subject's body mounts an inappropriate immune response against substances and tissues that are normally present in the body. In other words, the immune system mistakes certain parts of the body for pathogens and attacks its own cells. This can be limited to certain organs (e.g., in autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membrane in both the lungs and the kidneys). Treatment of autoimmune diseases typically involves immunosuppression, such as drugs that reduce the immune response.

[0068] The term "inflammatory disease" refers to a disease caused by, resulting from, or causing inflammation. The term "inflammatory disease" can also refer to a dysregulated inflammatory response that causes an overreaction of macrophages, granulocytes, and / or T lymphocytes, leading to abnormal tissue damage and / or cell death. Inflammatory diseases can be acute or chronic inflammatory conditions and can be caused by infectious or non-infectious etiologies.

[0069] The term "polymer" refers to a compound that contains eleven or more covalently linked repeating units. In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring).

[0070] The term "nanoparticle" refers to a particle having an average (e.g., mean) size (e.g., diameter) of from about 1 nanometer (nm) to about 1 micrometer (μm), including the end values (e.g., about 1 nm to about 300 nm, about 1 nm to about 100 nm, about 1 nm to about 30 nm, about 1 nm to about 10 nm, or about 1 nm to about 3 nm).

[0071] As used herein, the term "reagent" refers to a molecule, group of molecules, complex, or substance that is administered to an organism for diagnostic, therapeutic, prophylactic medical, or veterinary purposes. In certain embodiments, the reagent is an active pharmaceutical ingredient reagent, a diagnostic agent, or a prophylactic agent. In certain embodiments, the polymers and compositions disclosed herein contain one or more reagents, such as a first reagent (e.g., at least one (including, for example, at least two, at least three)). In some embodiments, the polymers and compositions may also contain a second reagent. In some embodiments, the reagent is an enzyme (e.g., a digestive enzyme), a nutrient blocker (e.g., a crosslinking agent), a diagnostic agent, a nutritional preparation, a radiation protection agent, an active pharmaceutical ingredient, or a combination thereof.

[0072] As used herein, the term "radiation protection agent" refers to a reagent that protects a biological system that is naturally or through radiation leakage exposed to radiation. In certain embodiments, the radiation protection agent protects normal cells of cancer patients undergoing radiotherapy from radiation damage.

[0073] As used herein, the term "diagnostic agent" means an imaging agent or a contrast agent. The terms "imaging agent" and "contrast agent" refer to substances used in medical imaging to enhance the contrast of structures or fluids within the body. It is typically used to enhance the visibility of blood vessels and the gastrointestinal tract in medical imaging.

[0074] As used herein, the term "active pharmaceutical ingredient" includes agents capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is administered. For example, an active pharmaceutical ingredient can be used for functions such as controlling tumor growth, controlling infection or inflammation, acting as an analgesic, promoting anti-cell adhesion, and enhancing bone growth. Other suitable active pharmaceutical ingredients can include antiviral agents, hormones, antibodies, or therapeutic proteins. Other active pharmaceutical ingredients include prodrugs, i.e., agents that are not biologically active upon administration but are converted to a biologically active agent upon administration to a subject through metabolism or some other mechanism.

[0075] The active pharmaceutical ingredient can be a compound, such as an organic or inorganic small molecule; saccharin; oligosaccharide; polysaccharide; biological macromolecule, such as a peptide, protein, and peptide analogs and derivatives; peptidomimetic; antibody and its antigen-binding fragment; nucleic acid; nucleic acid analogs and derivatives; extracts made from biological materials such as bacteria, plants, fungi, or animal cells; animal tissues; naturally occurring or synthetic compositions; and any combination thereof.

[0076] Examples of active pharmaceutical ingredients include, but are not limited to, antimicrobials, analgesics, anti - inflammatory agents, counter - irritants, coagulation regulators, diuretics, sympathomimetics, anorectics, antacids and other gastrointestinal agents; antiparasitics, antidepressants, antihypertensives, anticholinergics, stimulants, anti - hormones, central and respiratory stimulants, drug antagonists, blood lipid regulators, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergics, antiemetics, muscle relaxants, parasympathomimetics, antispasmodics, antihistamines, beta - blockers, laxatives, anti - arrhythmic agents, contrast agents, radiopharmaceuticals, anti - allergics, tranquillizers, vasodilators, antivirals, and anti - tumor agents or cytostatics or other agents with anti - cancer properties, or combinations thereof. Other suitable active pharmaceutical ingredients include contraceptives and vitamins as well as micronutrients and macronutrients. Still other examples include anti - infective agents such as antibiotics and antivirals; analgesics and analgesic combinations; anorectics; antihelmintics; anti - arthritics; anti - asthmatics; antispasmodics; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti - inflammatory agents; anti - migraine preparations; anti - nausea agents; anti - tumor agents; anti - parkinsonian agents; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta - blockers such as pindolol and anti - arrhythmic agents; antihypertensives; diuretics; vasodilators (including general coronary, peripheral, and cerebral); central nervous system stimulants; cough and cold preparations including decongestants; hormones such as estradiol and other steroids including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic blockers; psychostimulants; sedatives; and tranquilizers; and proteins, polysaccharides, glycoproteins, or lipoproteins of natural origin or genetically engineered.

[0077] Detailed Description of Specific Embodiments

[0078] Before describing the disclosed systems, compositions, methods, uses, and kits in more detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, devices, or configurations and may, therefore, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein.

[0079] Generally speaking, polydopamine polymerization is a slow process, and under normal dopamine oxidation conditions, its reaction rate is limited by low oxygen levels. 11However, the present inventors unexpectedly found that the decomposition of hydrogen peroxide by endogenous catalase to produce defensive oxygen (termed the cellular antioxidant effect) promoted the release of oxygen for dopamine oxidation and significantly increased the rate of dopamine polymerization. Figure 1 A shows a schematic of an embodiment of the present disclosure, in which an oral monomer solution containing dopamine monomers and hydrogen peroxide is administered to a subject. The solution flows uninhibited on the gastrointestinal mucosal surface, and hydrogen peroxide molecules freely diffuse between the epithelial tissue and the dopamine solution. However, dopamine remains in the solution due to its slow diffusion and transport. Hydrogen peroxide diffuses into the epithelial cells and is rapidly decomposed by intracellular catalase into oxygen, which is released from the cells and mixed with the extracellular monomers. These monomers near the epithelial surface are rapidly oxidized into oligomers and further oxidized into polymers, which crosslink with biomolecules exposed outside the epithelium, thereby forming a thin and strong polydopamine coating layer on the tissue. The unreacted monomers and unbound polydopamine in the solution are washed away from the epithelium. This type of tissue surface-initiated polymer coating avoids potential intestinal adhesions and obstructions, which are often induced by bulk-crosslinking-based sealants or other conventional tissue adhesives. 13 Catalytic polydopamine polymerization mainly occurs in the small intestine because the expression level of catalase in the small intestine is higher than that in other parts of the gastrointestinal tract (including the esophagus, stomach, and large intestine). Therefore, due to the non-uniform distribution of the natural enzyme along the digestive tract, specific small intestine targeting can be achieved spontaneously.

[0080] The inventors performed a series of studies involving the compositions, methods, and kits disclosed herein. The present inventors used various techniques, including endoscopy, intestinal ligation, and X-ray imaging, which consistently demonstrated the robustness of the subject matter, indicating the characteristics of the in-situ formed polymers (prolonged but transient intestinal retention). In addition, the present inventors did not observe any clinical, endoscopic, or radiological imaging evidence of gastrointestinal perforation, inflammation, or obstruction associated with the use of the disclosed compositions, methods, and kits. The biocompatibility of certain compositions of the present disclosure was carefully characterized by following the guidelines issued by the Organization for Economic Co-operation and Development (OECD) and confirming the absence of oral toxicity.

[0081] Methods and Uses

[0082] In one aspect, the present disclosure provides a method for in situ forming a polymer in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject and the catalyst polymerizes the monomer, wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

[0083] In some embodiments, the endogenous catalyst is peroxidase. In certain embodiments, the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

[0084] In some embodiments, the endogenous catalyst is catalase. In some embodiments, the catalase is bacterial catalase. In some embodiments, the catalase is human catalase.

[0085] In some embodiments, the endogenous catalyst is located in the gastrointestinal (GI) tract of the subject. In some embodiments, the endogenous catalyst is located in the upper GI tract of the subject. In some embodiments, the endogenous catalyst is located in the intestine of the subject. In some embodiments, the endogenous catalyst is located in the stomach of the subject.

[0086] In some embodiments, the endogenous catalyst is located in cells. In some embodiments, the endogenous catalyst is located in blood cells. In some embodiments, the endogenous catalyst is located on cells. In some embodiments, the endogenous catalyst is located on blood cells. In some embodiments, the endogenous catalyst is located in cells. In some embodiments, the endogenous catalyst is secreted by blood cells. In some embodiments, the endogenous catalyst is located on cells. In some embodiments, the endogenous catalyst is secreted by blood cells.

[0087] In some embodiments, the composition further comprises an enzyme, a nutrient blocker, a radiation protectant, a nutritional preparation, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof. In some embodiments, the composition further comprises an enzyme. In some embodiments, the composition further comprises a nutrient blocker. In some embodiments, the composition further comprises a radiation protectant. In some embodiments, the composition further comprises an active pharmaceutical ingredient. In some embodiments, the composition further comprises a diagnostic agent. In some embodiments, the composition further comprises a combination of two or more of an enzyme, a nutrient blocker, a nutritional preparation, a radiation protectant, an active pharmaceutical ingredient, and a diagnostic agent.

[0088] In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the oxygen source is urea hydrogen peroxide.

[0089] In some embodiments, at least one of the monomer and the oxygen source is stable in the subject's stomach. In some embodiments, at least one of the monomer and the oxygen source is stable in the subject's stomach for at least 30 minutes. In some embodiments, at least one of the monomer and the oxygen source is stable in the subject's stomach for at least 60 minutes.

[0090] In some embodiments, the composition is stable in the subject's stomach. In some embodiments, the composition is stable in the subject's stomach for at least 30 minutes. In some embodiments, the composition is stable in the subject's stomach for at least 60 minutes.

[0091] In some embodiments, at least one of the monomer and the oxygen source is stable because it does not decompose in the subject's stomach. In some embodiments, at least 95% of at least one of the monomer and the oxygen source remains after the composition has passed out of the subject's stomach. In some embodiments, at least 90% of at least one of the monomer and the oxygen source remains after the composition has passed out of the subject's stomach. In some embodiments, at least 80% of at least one of the monomer and the oxygen source remains after the composition has passed out of the subject's stomach.

[0092] In some embodiments, the composition comprises from about 0.001 to about 1000 mg / mL of dopamine. In some embodiments, the composition comprises from about 0.01 to about 100 mg / mL of dopamine. In some embodiments, the composition comprises from about 0.01 to about 50 mg / mL of dopamine. In some embodiments, the composition comprises from about 1 to about 20 mg / mL of dopamine. In some embodiments, the composition comprises 10 mg / mL of dopamine. In some embodiments, the composition comprises 9.8 mg / mL of dopamine.

[0093] In some embodiments, the composition comprises from about 0.01 to about 100 mM of an oxygen source. In some embodiments, the composition comprises from about 0.1 to about 50 mM of an oxygen source. In some embodiments, the composition comprises from about 1 to about 30 mM of an oxygen source. In some embodiments, the composition comprises about 20 mM of an oxygen source.

[0094] In some embodiments, the composition comprises an oxygen source at a concentration compatible with the subject's uptake.

[0095] In certain embodiments, the composition further comprises a buffer.

[0096] In some embodiments, the composition has a pH of from about 7 to about 10. In some embodiments, the composition has a pH of from about 7 to about 9. In some embodiments, the composition has a pH of about 8.5. In some embodiments, the composition has a pH of about 7.4.

[0097] In some embodiments, the composition is administered by a route selected from oral, rectal, injection, sublingual, buccal, vaginal, ocular, otic, inhalation, or transdermal. In some embodiments, the composition is administered orally. In certain embodiments, the composition is administered by intra-articular injection. In certain embodiments, the composition is administered topically. In certain embodiments, the composition is administered dermally. In certain embodiments, the composition is administered ocularly.

[0098] In some embodiments, the composition is administered via an observation instrument. In certain embodiments, the composition is administered via an endoscope, arthroscope, cystoscope, colposcope, colonoscope, bronchoscope, ureteroscope, anoscope, esophagoscope, gastroscope, laparoscope, laryngoscope, neuroendoscope, proctoscope, sigmoidoscope, or thoracoscope.

[0099] In some embodiments, the composition is in liquid or solid dosage form.

[0100] In some embodiments, the composition is in the form of a solution, gel, tablet, powder, capsule, eye drop, or transdermal patch. In some embodiments, the composition is in the form of a solution, gel, tablet, or capsule. In some embodiments, the composition is in the form of a solution. In some embodiments, the composition is in the form of an eye drop. In some embodiments, the composition is in the form of a powder. In some embodiments, the composition is in the form of a transdermal patch.

[0101] In certain embodiments, the polymer forms and adheres to tissue upon contact with tissue in a subject. In some embodiments, the polymer adheres to tissue of a subject. In certain embodiments, the tissue is epithelial. In some embodiments, the epithelium is intestinal epithelium.

[0102] In some embodiments, the location where the polymer forms is based on the expression level of a catalyst. In certain embodiments, the polymer forms substantially on a specific tissue based on a high expression level of the catalyst. In some embodiments, the polymer does not form substantially on a specific tissue due to a low expression level of the catalyst. In some embodiments, the location where the polymer forms is based on the expression level of catalase. In certain embodiments, the polymer forms substantially on a specific tissue based on the expression level of catalase. In some embodiments, the polymer does not form substantially on a specific tissue due to a low expression level of catalase.

[0103] In certain embodiments, the tissue is epithelium. In some embodiments, the polymer forms on and adheres to the epithelium of a subject. In some embodiments, the polymer forms upon contact with the epithelium of a subject. In some embodiments, the epithelium is intestinal epithelium. In some embodiments, the polymer forms on the small intestine. In certain embodiments, the polymer forms in the lumen of the small intestine. In certain embodiments, the polymer forms on the duodenal epithelium of a subject.

[0104] In some embodiments, the polymer binds to amine moieties exposed on the luminal surface of the epithelium of a subject. In some embodiments, the polymer crosslinks to amine moieties exposed on the luminal surface of the epithelium of a subject.

[0105] In some embodiments, the polymer forms rapidly. In some embodiments, the polymer forms in less than about 20 minutes. In some embodiments, the polymer forms in less than about 15 minutes. In some embodiments, the polymer forms in less than about 12 minutes. In some embodiments, the polymer forms in less than about 10 minutes. In some embodiments, the polymer forms in less than about 5 minutes. In some embodiments, the polymer forms in less than about 3 minutes. In some embodiments, the polymer forms in less than about 2 minutes. In some embodiments, the polymer forms in less than about 1 minute. In some embodiments, the polymer forms almost instantaneously.

[0106] In some embodiments, the polymerization rate is increased by at least 10-fold compared to polymer formation in the absence of endogenous catalase. In some embodiments, the polymerization rate is increased by at least 50-fold compared to polymer formation in the absence of endogenous catalase. In some embodiments, the polymerization rate is increased by at least 100-fold compared to polymer formation in the absence of endogenous catalase. In some embodiments, the polymerization rate is increased by at least 150-fold compared to polymer formation in the absence of endogenous catalase. In some embodiments, the polymerization rate is increased by at least 200-fold compared to polymer formation in the absence of endogenous catalase.

[0107] In some embodiments, the polymer forms on the gastrointestinal epithelium of a subject. In some embodiments, the polymer forms on the small intestinal epithelium of a subject.

[0108] In some embodiments, the polymer does not form on the gastrointestinal epithelium outside of the small intestine of a subject.

[0109] In some embodiments, the polymer forms on the epithelium of one or more of the duodenum, jejunum, ileum, colon, esophagus, or stomach of a subject. In some embodiments, the polymer forms on the duodenal epithelium of a subject. In some embodiments, the polymer forms on the jejunal epithelium of a subject. In some embodiments, the polymer forms on the ileal epithelium of a subject. In some embodiments, the polymer forms on the colonic epithelium of a subject.

[0110] In some embodiments, the polymer substantially does not form on the epithelium of one or more of the esophagus or stomach of a subject. In some embodiments, substantially no polymer forms on the stomach and esophagus of a subject. In some embodiments, the polymer does not form on the stomach and esophagus of a subject.

[0111] In some embodiments, less polymer forms on the ileum and colon of a subject compared to the duodenum and jejunum of the subject.

[0112] In some embodiments, the polymer forms on the epithelial villi of a subject.

[0113] In some embodiments, the polymer forms a temporary barrier in vivo. In some embodiments, the polymer forms a transient barrier in vivo.

[0114] In some embodiments, the polymer persists for about 30 minutes. In some embodiments, the polymer persists for about 1 hour. In some embodiments, the polymer persists for about 6 hours. In some embodiments, the polymer persists for about 12 hours. In some embodiments, the polymer persists for about 24 hours.

[0115] In some embodiments, about 20% to about 70% of the transient barrier remains after 12 hours. In some embodiments, about 30% to about 50% of the transient barrier remains after 12 hours. In some embodiments, about 20% of the transient barrier remains after 12 hours. In some embodiments, about 20% to about 70% of the transient barrier remains after 6 hours. In some embodiments, about 30% to about 50% of the transient barrier remains after 6 hours. In some embodiments, about 20% of the transient barrier remains after 6 hours. In some embodiments, about 20% to about 70% of the transient barrier remains after 3 hours. In some embodiments, about 30% to about 50% of the transient barrier remains after 3 hours. In some embodiments, about 20% of the transient barrier remains after 3 hours.

[0116] In some embodiments, the polymer is cleared from the subject after about 3 hours. In some embodiments, the polymer is cleared from the subject after about 6 hours. In some embodiments, the polymer is cleared from the subject after about 12 hours. In some embodiments, the polymer is cleared from the subject after about 24 hours. In some embodiments, the polymer is cleared from the subject after about 48 hours.

[0117] In some embodiments, the polymer barrier provides selective molecular transport across the patient's epithelium.

[0118] In some embodiments, the method is a method of modulating intestinal diffusion in a subject. In some embodiments, the method modulates the diffusion of one or more of salts, ions, water, oxygen, carbon dioxide, carbonate anions, acids, bases, carbohydrates, lipids, proteins, nucleic acids, nutrients, or active pharmaceutical ingredients in the subject.

[0119] In some embodiments, the polymer modulates the absorption of one or more nutrients or active pharmaceutical ingredients in the small intestine.

[0120] In some embodiments, the polymer substantially impedes the absorption of one or more nutrients into the epithelium on which the polymer is formed, the intestinal wall of the subject, or the bloodstream of the subject.

[0121] In some embodiments, the method is a method of delivering a reagent to a subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent. In some embodiments, the reagent is delivered to the intestine.

[0122] In some embodiments, the method enables sustained release of the reagent in the subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent. In some embodiments, the sustained release occurs in the GI tract.

[0123] In some embodiments, the method is a method of immobilizing a reagent in a subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent. In some embodiments, the reagent is immobilized within the GI tract.

[0124] In some embodiments, the method is a method of locally delivering a reagent to a subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent. In some embodiments, the local delivery occurs in the GI tract.

[0125] In some embodiments, the method is a method of reducing the dosing frequency of a reagent. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent.

[0126] In some embodiments, the method is a method of increasing the half-life of a reagent in a subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent.

[0127] In some embodiments, the method is a method of increasing the residence time of a reagent in a subject. In some embodiments, the reagent is an active pharmaceutical ingredient. In some embodiments, the reagent is an enzyme. In some embodiments, the reagent is a radioprotective agent. In some embodiments, the method is a method of increasing the residence time of a reagent in the GI tract.

[0128] In some embodiments, the method is a method of treating or preventing a disease in a subject. In some embodiments, the method is a method of treating a disease in a subject. In some embodiments, the method is a method of preventing a disease in a subject.

[0129] In some embodiments, the method is a method of facilitating tissue restoration and regeneration at a polymerization site in a subject. In some embodiments, the method is a method of facilitating tissue restoration at a polymerization site in a subject. In some embodiments, the method is a method of facilitating tissue regeneration at a polymerization site in a subject.

[0130] In some embodiments, the method keeps the intestinal lumen of the subject dilated.

[0131] In some embodiments, the method is a method of preventing intestinal adhesions in a subject.

[0132] In some embodiments, the method is a method of preventing intestinal obstruction in a subject.

[0133] In some embodiments, the method is a method of treating bleeding in a subject. In some embodiments, the bleeding is in the upper GI tract.

[0134] In some embodiments, the polymer and the composition further comprise an enzyme. In some embodiments, the enzyme is a digestive enzyme. In some embodiments, the digestive enzyme is lactase, peptidase, sucrase, maltase, amylase, lipase, or protease. In some embodiments, the digestive enzyme is β-galactosidase.

[0135] In some embodiments, the method is a method of improving the digestive efficiency of a subject.

[0136] In some embodiments, the method is a method of enhancing a subject's digestion of sugar. In some embodiments, the method is a method of enhancing a subject's digestion of lactose.

[0137] In some embodiments, the method is a method of treating lactose intolerance in a subject.

[0138] In some embodiments, the enzyme increases the subject's digestion efficiency of sugar by about 5-fold. In some embodiments, the enzyme increases the subject's digestion efficiency of sugar by about 10-fold. In some embodiments, the enzyme increases the subject's digestion efficiency of sugar by about 20-fold. In some embodiments, the enzyme increases the subject's digestion efficiency of lactose by about 40-fold. In some embodiments, the enzyme increases the subject's digestion efficiency of sugar by about 50-fold.

[0139] In some embodiments, β-galactosidase increases the subject's digestion efficiency of lactose by about 5-fold. In some embodiments, β-galactosidase increases the subject's digestion efficiency of lactose by about 10-fold. In some embodiments, β-galactosidase increases the subject's digestion efficiency of lactose by about 20-fold. In some embodiments, β-galactosidase increases the subject's digestion efficiency of lactose by about 40-fold. In some embodiments, β-galactosidase increases the subject's digestion efficiency of lactose by about 50-fold.

[0140] In some embodiments, the polymer barrier does not inhibit the inherent digestive enzyme activity of the subject's epithelium.

[0141] In some embodiments, the polymer and the composition further comprise a nutrient blocker.

[0142] In some embodiments, the method is a method of blocking nutrient absorption in a subject.

[0143] In some embodiments, the method is a method of regulating or controlling a subject's sugar absorption. In some embodiments, the sugar is selected from glucose, lactose, fructose, maltose, dextrose, galactose, sucrose, and isomaltose. In some embodiments, the method is a method of regulating or controlling a subject's glucose absorption.

[0144] In some embodiments, the method blocks absorption for less than about 48 hours. In some embodiments, the method blocks absorption for less than about 24 hours. In some embodiments, the method blocks absorption for less than about 12 hours. In some embodiments, the method blocks absorption for less than about 6 hours. In some embodiments, the method blocks absorption for less than about 3 hours.

[0145] In some embodiments, the method is a method of treating obesity in a subject.

[0146] In some embodiments, the method is a method of treating hyperinsulinemia in a subject.

[0147] In some embodiments, the method is a method of treating diabetes in a subject. In some embodiments, the diabetes is type 2 diabetes.

[0148] In some embodiments, the composition further comprises a crosslinking agent.

[0149] In some embodiments, the crosslinking agent comprises nanoparticles. In some embodiments, the crosslinking agent comprises polydopamine. In some embodiments, the crosslinking agent is a nutrient blocker. In some embodiments, the crosslinking agent enhances the nutrient blocking ability of the polymer.

[0150] In some embodiments, glucose absorption is regulated by adjusting the crosslinking density of the polymer. In some embodiments, the method decreases glucose absorption in the subject by at least about 50%, at least about 60%, or at least about 70% over a three-hour period after administration of the composition. In some embodiments, the method decreases glucose absorption in the subject by at least about 70% over a three-hour period after administration of the composition. In some embodiments, the method decreases glucose absorption in the subject by at least about 50%, at least about 60%, or at least about 70% over a two-hour period after administration of the composition. In some embodiments, the method decreases glucose absorption in the subject by at least about 50%, at least about 60%, or at least about 70% over a one-hour period after administration of the composition.

[0151] In some embodiments, the method is a method of modulating or regulating nutrient uptake in a subject.

[0152] In some embodiments, the composition further comprises an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is an antiparasitic agent. In some embodiments, the active pharmaceutical ingredient is an anthelmintic agent. In some embodiments, the active pharmaceutical ingredient is praziquantel.

[0153] In some embodiments, the composition further comprises an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is a reagent for treating infectious diseases. In some embodiments, the active pharmaceutical ingredient is an antiparasitic agent. In some embodiments, the active pharmaceutical ingredient is an anthelmintic. In some embodiments, the active agent is an antiparasitic agent. In some embodiments, the active pharmaceutical ingredient is praziquantel. In some embodiments, the active agent is an antiviral agent. In some embodiments, the active agent treats influenza. In some embodiments, the active agent treats type 2 diabetes. In some embodiments, the active agent treats eye diseases. In some embodiments, the active agent treats Crohn's disease. In some embodiments, the active agent treats osteoarthritis. In some embodiments, the active agent treats Alzheimer's disease.

[0154] In some embodiments, the active pharmaceutical ingredient treats mental disorders, Alzheimer's disease, infectious diseases, or transplant rejection. In certain embodiments, the active pharmaceutical ingredient is a contraceptive, a statin, an antihypertensive agent, or an antibiotic.

[0155] In some embodiments, the active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is an anti-cancer agent. Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapies, immunostimulants and / or immunomodulators (e.g., IL-1, 2, 4, 6, or 12), immunocyte growth factors (e.g., GM-CSF), and antibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypericin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (e.g., busulfan and mannomustine), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxanes (e.g., paclitaxel or paclitaxel equivalents such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate-bound paclitaxel (PG-paclitaxel, novel paclitaxel (paclitaxelpoliglumex), CT-2103, XYOTAX), tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 conjugated with three paclitaxel molecules), paclitaxel-EC-1 (paclitaxel conjugated with erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, such as 2-pyranosyl succinate 2'-paclitaxel methyl ester;Docetaxel (Taxotere), etoposide (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, Camptosar (irinotecan), irinotecan, crisnatol, mitomycin C), antimetabolites DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB1093 and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunomycin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca2+ ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib; BMS-354825), erlotinib gefitinib imatinib ( CGP57148B, STI-571), lapatinib lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib semaxinib (SU5416), sunitinib ( SU11248), toceranib vandetanib ( ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab bevacizumab rituximab cetuximab panitumumab ranibizumab nilotinib Sorafenib Everolimus Alemtuzumab Gemtuzumab Temsirolimus ENMD-2076, PCI-32765, AC220, Dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, sirolimus (CCI-779), everolimus (RAD-001), deforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methotrexate, porfiromycin, melphalan, vinblastine, vindesine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin and hexamethylmelamine.

[0156] In certain embodiments, the active pharmaceutical ingredient is selected from the group consisting of, but not limited to: anti-proliferatives, anti-cancer agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antibacterial agents, antiviral agents, cardiovascular agents, decholesterylating agents, anti-diabetic agents, anti-allergic agents, contraceptives and analgesics. In certain embodiments, the active pharmaceutical ingredient is an anti-proliferative. In certain embodiments, the active pharmaceutical ingredient is an anti-cancer agent. In certain embodiments, the active pharmaceutical ingredient is an antiviral agent.

[0157] Exemplary active pharmaceutical ingredients include, but are not limited to, antibiotics, antiviral agents, anesthetics, anticoagulants, enzyme inhibitors, steroid agents, steroid or non-steroidal anti-inflammatory agents, antihistamines, immunosuppressants, antigens, vaccines, antibodies, decongestants, sedatives, analgesics, painkillers, antipyretics, hormones, and prostaglandins, etc. Active pharmaceutical ingredients include organic small molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration, as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0158] In certain embodiments, the active pharmaceutical ingredient is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithromycin, azithromycin, oleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., co-trimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline)), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclitols (e.g., spectinomycin), chloramphenicol, sparamycin, quinupristin / dalfopristin (Syndercid TM ). In certain embodiments, the antibiotic is a ribosome-targeting antibiotic.

[0159] In some embodiments, the active pharmaceutical ingredient is retained or encapsulated in a polymer. In some embodiments, the active pharmaceutical ingredient is retained or encapsulated on a polymer.

[0160] In some embodiments, the method is a method of prolonging the residence time of the active pharmaceutical ingredient in a subject compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method is a method of prolonging the residence time of the active pharmaceutical ingredient at the polymerization site in a subject compared to administering the active pharmaceutical ingredient in the absence of a polymer.

[0161] In some embodiments, the method is a method of providing sustained release of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer.

[0162] In some embodiments, the method is a method of reducing the dosing frequency of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the dosing frequency is once daily. In some embodiments, the dosing frequency is twice daily.

[0163] In some embodiments, the method is a method of increasing the half-life of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the half-life of the active pharmaceutical ingredient by at least about 2-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the half-life of the active pharmaceutical ingredient by at least about 4-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the half-life of the active pharmaceutical ingredient by at least about 6-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the half-life of the active pharmaceutical ingredient by at least about 10-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer.

[0164] In some embodiments, the method is a method of increasing the AUC of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 2-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 3-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 4-fold as compared to administering the active pharmaceutical ingredient in the absence of a polymer.

[0165] In some embodiments, the method is a method of modulating the C of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer. max In certain embodiments, the method of modulation is to increase. In certain embodiments, the method of modulation is to decrease.

[0166] In some embodiments, the method is a method of modulating the T of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of a polymer. max In certain embodiments, the method of modulation is to increase. In certain embodiments, the method of modulation is to decrease.

[0167] In some embodiments, once the active pharmaceutical ingredient is absorbed by the small intestine, the method does not affect drug metabolism.

[0168] In some embodiments, the method is a method for treating schistosomiasis in a subject.

[0169] In some embodiments, the composition further comprises a radioprotectant. In certain embodiments, the radioprotectant is an antioxidant, a thiol compound, or a nitrogen oxide. In certain embodiments, the radioprotectant is thalidomide, cysteine, amifostine, palifermin, or L-carnitine. In certain embodiments, the radioprotectant is thalidomide.

[0170] In some embodiments, the nutritional preparation is vitamin D or iron.

[0171] In some embodiments, the method provides targeting to the small intestine.

[0172] In some embodiments, the method is a method for reducing small intestine uptake. In some embodiments, the method is a method for reducing the uptake of one or more nutrients and active pharmaceutical ingredients by the small intestine. In some embodiments, the method is a method for reducing the uptake of one or more nutrients by the small intestine. In some embodiments, the method is a method for reducing the uptake of one or more active pharmaceutical ingredients by the small intestine.

[0173] In some embodiments, the method is a method for increasing the residence time in the small intestine. In some embodiments, the method is a method for increasing the residence time of one or more nutrients and active pharmaceutical ingredients in the small intestine. In some embodiments, the method is a method for increasing the residence time of one or more nutrients in the small intestine. In some embodiments, the method is a method for increasing the residence time of one or more active pharmaceutical ingredients in the small intestine.

[0174] In some embodiments, the method keeps the intestinal lumen dilated.

[0175] In some embodiments, the method is a method for treating or preventing intestinal adhesions in a subject. In some embodiments, the method is a method for preventing intestinal adhesions in a subject.

[0176] In some embodiments, the method is a method for treating or preventing intestinal obstruction in a subject. In some embodiments, the method is a method for preventing intestinal obstruction in a subject.

[0177] In some embodiments, the method is a method for treating bleeding in a subject. In some embodiments, the method is a method for treating small intestine bleeding in a subject. In some embodiments, the bleeding is in the upper GI tract. In some embodiments, the bleeding is in the stomach. In some embodiments, the method for treating bleeding is a method for treating hemostasis.

[0178] In some embodiments, the polymer modulates absorption in the small intestine. In some embodiments, the polymer modulates the absorption of one or more nutrients or active pharmaceutical ingredients, or combinations thereof, in the small intestine. In some embodiments, the polymer modulates the absorption of one or more nutrients and active pharmaceutical ingredients in the small intestine. In some embodiments, the polymer modulates the absorption of one or more nutrients in the small intestine. In some embodiments, the polymer modulates the absorption of one or more active pharmaceutical ingredients in the small intestine.

[0179] In some embodiments, the polymer modulates digestion in the small intestine. In some embodiments, the polymer modulates the digestion of one or more nutrients in the small intestine.

[0180] In certain embodiments, the polymer substantially impedes absorption in the small intestine. In some embodiments, the polymer substantially impedes the absorption of one or more nutrients or active pharmaceutical ingredients, or combinations thereof, into the epithelium on which the polymer is formed. In some embodiments, the polymer substantially impedes the absorption of one or more nutrients into the epithelium on which the polymer is formed. In some embodiments, the polymer substantially impedes the absorption of one or more active pharmaceutical ingredients into the epithelium on which the polymer is formed.

[0181] In some embodiments, the polymer substantially impedes the absorption of one or more nutrients or active pharmaceutical ingredients, or combinations thereof, into the intestinal wall of a subject. In some embodiments, the polymer substantially impedes the absorption of one or more nutrients into the intestinal wall of a subject. In some embodiments, the polymer substantially impedes the absorption of one or more active pharmaceutical ingredients into the intestinal wall of a subject.

[0182] In some embodiments, the polymer substantially impedes the absorption of one or more nutrients or active pharmaceutical ingredients, or combinations thereof, into the bloodstream of a subject. In some embodiments, the polymer substantially impedes the absorption of one or more nutrients into the bloodstream of a subject. In some embodiments, the polymer substantially impedes the absorption of one or more active pharmaceutical ingredients into the bloodstream of a subject.

[0183] In some embodiments, the method is a method of immobilizing an enzyme in a subject.

[0184] In some embodiments, the method is a method of delivering an active pharmaceutical ingredient to a subject.

[0185] In some embodiments, the method is a method of supplementing digestion in a subject.

[0186] In some embodiments, the polymer induces blood gelation. In certain embodiments, the polymer induces blood clotting. In some embodiments, the composition is in the form of a powder. In certain embodiments, the method includes spraying the powder onto the affected area on or within the subject.

[0187] In some embodiments, the polymer is non-toxic. In some embodiments, the composition is non-toxic. In some embodiments, the composition and its components are non-toxic.

[0188] In some embodiments, the polymer is stable to physical and chemical forces. In some embodiments, the polymer is stable to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, and saline. In some embodiments, the polymer decomposes less than about 25% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes less than about 20% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes less than about 10% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the polymer decomposes less than about 5% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline. In some embodiments, the physical forces are selected from one or more of peristalsis and segmentation.

[0189] In another aspect, the present disclosure provides a method of treating a disease or disorder, the method including administering to a subject in need thereof an effective amount of a composition as described herein.

[0190] The present disclosure also provides a method of preventing a disease or disorder, the method including administering to a subject in need thereof an effective amount of a composition as described herein.

[0191] In some embodiments, the disease or disorder is a metabolic disorder, an eye disease, a systemic disease, a digestive disorder, an infectious disease, cancer, bleeding, an ulcer, an intestinal obstruction, mesenteric ischemia, obesity, a mental disorder, Alzheimer's disease, or transplant rejection. In some embodiments, the disease or disorder is a metabolic disorder, a systemic disease, a digestive disorder, an infectious disease, cancer, bleeding, an ulcer, an intestinal obstruction, mesenteric ischemia, obesity, a mental disorder, Alzheimer's disease, or transplant rejection.

[0192] In some embodiments, the disease is cancer. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendiceal cancer; benign monoclonal gammopathy; cholangiocarcinoma (e.g., hepatocholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, mammary carcinoma, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett adenocarcinoma); Ewing sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); common eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemia such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, B-precursor lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as T-precursor lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixed states of one or more of the leukemias / lymphomas described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocyte amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative diseases (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis type 1 or 2 (NF), schwannomatosis); neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasmacytosis; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland carcinoma; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; hidradenoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma);Thyroid cancer (e.g., papillary thyroid cancer, papillary carcinoma of the thyroid (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).;

[0193] In some embodiments, the metabolic disorder is hyperinsulinemia.

[0194] In some embodiments, the digestive disease is Crohn's disease, ulcerative colitis, malabsorption, inflammatory bowel disease, irritable bowel syndrome, lactose intolerance, or celiac disease. In some embodiments, the disease is Crohn's disease.

[0195] In some embodiments, the disease is a mental disorder.

[0196] In some embodiments, the disease is Alzheimer's disease.

[0197] In some embodiments, the disorder is transplant rejection.

[0198] In some embodiments, the systemic disease is an autoimmune disease. Exemplary autoimmune diseases include but are not limited to glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn's disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0199] In some embodiments, the systemic disease is mastocytosis, chronic fatigue syndrome, systemic vasculitis, sarcoidosis, hypothyroidism, diabetes, fibromyalgia, adrenal insufficiency, celiac disease, ulcerative colitis, Crohn's disease, hypertension, metabolic syndrome, AIDS, Graves’ disease, systemic lupus erythematosus, arthritis, atherosclerosis, sickle cell disease, myasthenia gravis, systemic sclerosis, inflammatory disease, or sinusitis.

[0200] In some embodiments, the disease is an inflammatory disease. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed type hypersensitivity (e.g., poison ivy dermatitis), pneumonia, respiratory inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergies, acute allergic reactions, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host versus graft reaction, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis and necrotizing enterocolitis. Ocular inflammatory diseases include, but are not limited to, postoperative inflammation. In some embodiments, the disease is an inflammatory joint disease. In some embodiments, the disease is arthritis. In certain embodiments, the disease is osteoarthritis. In some embodiments, the disease is rheumatoid arthritis.

[0201] In some embodiments, the disease is obesity, hyperinsulinemia, or diabetes. In some embodiments, the disease is obesity. In some embodiments, the disease is hyperinsulinemia. In some embodiments, the disease is diabetes. In some embodiments, the disease is type 2 diabetes.

[0202] In some embodiments, the disease is an infectious disease. In some embodiments, the disease is a bacterial, viral, fungal, or parasitic infection. In some embodiments, the disease is a parasitic disease. In some embodiments, the disease is giardiasis, ascariasis, or tapeworm infection. In some embodiments, the disease is schistosomiasis. In some embodiments, the disease is a viral infection. In some embodiments, the disease is influenza.

[0203] In some embodiments, the disease is lactose intolerance.

[0204] In some embodiments, the disorder is intestinal obstruction. In some embodiments, the disorder is intestinal adhesion. In certain embodiments, the methods and compositions described herein prevent re - adhesion and / or re - obstruction of the intestine.

[0205] In certain embodiments, the methods and compositions provided herein are contraceptives.

[0206] In certain embodiments, the disease is trauma.

[0207] In one aspect, the present disclosure provides the use of a composition for forming a polymer in vivo, the use comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject in vivo and the catalyst causes in - situ polymerization of the monomer, wherein the monomer is dopamine or a salt thereof.

[0208] In another aspect, the present disclosure provides the use of a composition for forming a polymer in vivo, the use comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject in vivo and the catalyst causes in - situ polymerization of the monomer, and wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

[0209] In one aspect, the present disclosure provides the use of an effective amount of a composition as described herein for treating a disease or disorder in a subject in need thereof.

[0210] In another aspect, the present disclosure provides the use of an effective amount of a composition as described herein for preventing a disease or disorder in a subject in need thereof.

[0211] Composition

[0212] In some aspects, the present disclosure also provides a composition comprising dopamine, an oxygen source, and optionally a buffer.

[0213] In some embodiments, the composition comprises from about 0.001 to about 1000 mg / mL of dopamine, from about 0.01 to about 100 mM of an oxygen source, and optionally a buffer.

[0214] In some embodiments, the composition comprises from about 0.001 to about 1000 mg / mL of dopamine. In some embodiments, the composition comprises from about 0.001 to about 500 mg / mL of dopamine. In some embodiments, the composition comprises from about 0.01 to about 100 mg / mL of dopamine. In some embodiments, the composition comprises from about 1 to about 20 mg / mL of dopamine. In some embodiments, the composition comprises about 10 mg / mL of dopamine. In some embodiments, the composition comprises about 9.8 mg / mL of dopamine.

[0215] In some embodiments, the composition comprises from about 0.01 to about 100 mM of an oxygen source. In some embodiments, the composition comprises from about 0.1 to about 50 mM of an oxygen source. In some embodiments, the composition comprises from about 1 to about 30 mM of an oxygen source. In some embodiments, the composition comprises about 20 mM of an oxygen source. In some embodiments, the composition comprises an oxygen source at a concentration compatible with uptake by a subject.

[0216] In some embodiments, the composition has a pH of from about 7 to about 10. In some embodiments, the composition has a pH of from about 7 to about 9. In some embodiments, the composition has a pH of about 8.5. In some embodiments, the composition has a pH of about 7.4.

[0217] In some embodiments, the composition comprises about 10 mg / mL of dopamine, about 20 mM of hydrogen peroxide or urea hydrogen peroxide, and optionally a buffer. In some embodiments, the composition comprises about 9.8 mg / mL of dopamine, about 20 mM of hydrogen peroxide or urea hydrogen peroxide, and optionally a buffer.

[0218] In some embodiments, the buffer includes phosphate, acetate, citrate, N-[tris(hydroxymethyl)methyl]glycine), (tris(hydroxymethyl)aminomethane), or (2-(bis(2-hydroxyethyl)amino)acetic acid). In some embodiments, the buffer includes tris(hydroxymethyl)aminomethane.

[0219] In some embodiments, the composition further comprises a digestive enzyme, a nutrient blocker, a radiation protectant, a nutritional preparation, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

[0220] In some embodiments, the composition is in a liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, gel, tablet, or capsule.

[0221] Kit

[0222] The present disclosure also encompasses kits (such as pharmaceutical packages). The provided kits may contain the compositions described herein and containers (e.g., vials, ampoules, bottles, syringes, and / or dispenser packages, or other suitable containers).

[0223] The present disclosure also provides kits. In one aspect, the present disclosure provides a kit that includes: a composition as described herein, and instructions for administering the composition to a subject. In some embodiments, the composition includes: dopamine; hydrogen peroxide or urea hydrogen peroxide; a buffer; and optionally an enzyme, a nutrient blocker, a radiation protectant, a nutritional preparation, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof. In some embodiments, the buffer is tris(hydroxymethyl)aminomethane. In certain embodiments, the kit further includes an endoscope, arthroscope, cystoscope, colposcope, colonoscope, bronchoscope, ureteroscope, proctoscope, esophagoscope, gastroscope, laparoscope, laryngoscope, neuroendoscope, sigmoidoscope, or thoracoscope. In certain embodiments, the composition is in the form of a capsule.

[0224] In some embodiments, the provided kit may optionally further include a second container that contains a pharmaceutical excipient for diluting or suspending the composition described herein. In some embodiments, the compositions described herein provided in the first container and the second container are combined to form a unit dosage form.

[0225] Thus, in one aspect, a kit is provided that includes a first container containing the composition described herein. In certain embodiments, the kit can be used to treat a disease in a subject in need thereof. In certain embodiments, the kit can be used to prevent a disease in a subject in need thereof. In certain embodiments, the kit can be used to reduce the risk of developing a disease in a subject in need thereof.

[0226] In certain embodiments, the kits described herein further include instructions for using the kits. The kits described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescription information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. The kits described herein may include one or more of the additional reagents described herein as separate compositions.

[0227] Administration

[0228] The methods and uses described herein include administering to a subject an effective amount of a composition comprising a monomer and an oxygen source (i.e., to form a polymer in situ (e.g., for treating or preventing a disease)).

[0229] In some embodiments, the composition is administered orally. In some embodiments, the composition is in liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, gel, tablet, or capsule.

[0230] In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an amount effective to treat an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective to treat a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a blood disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a blood disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a neurological disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a neurological disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a pain condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a pain condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a mental disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a mental disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to treat a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to prevent a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount that reduces the risk of developing a disease (e.g., an infectious disease, a proliferative disease, a blood disease, a neurological disorder, a pain condition, a mental disorder, or a metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective to inhibit the activity of an organism (e.g., abnormal activity, such as increased activity) in a subject or cell.

[0231] In certain embodiments, the subject is an animal. The animal can be of either sex and can be at any stage of development. In certain embodiments, the subject described herein is a human. In some embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or a cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or a reptile.

[0232] The compositions can be prepared, packaged, and / or sold singly as a unit dose and / or as multiple single unit doses. A "unit dose" is a discrete amount of the composition that contains a predetermined quantity of the reagent or active ingredient. The quantity of the reagent or active ingredient is typically equal to the dose of the reagent or active ingredient to be administered to a subject and / or a convenient fraction of such a dose, such as one-half or one-third of such a dose.

[0233] Although the description of the compositions provided herein primarily relates to compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all kinds of animals. Modifying a composition suitable for administration to humans so that the composition is suitable for administration to various animals is well known, and an ordinary skilled veterinary pharmacologist can design and / or perform such modifications with ordinary experimentation.

[0234] The compositions provided herein are typically formulated in unit dosage forms for ease of administration and uniformity of dosage. However, it should be understood that the total daily usage of the compositions described herein will be decided by a physician within the scope of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the disease and the severity of the disorder being treated; the activity of the specific reagent or active ingredient employed; the specific composition employed; the age, weight, general health, sex, and diet of the subject; the time of administration, the route of administration, and the excretion rate of the specific reagent or active ingredient employed; the duration of the treatment; drugs used in combination with or concurrently with the specific reagent or active ingredient employed; and like factors well known in the medical arts.

[0235] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, ocular, intravaginal, intraperitoneal, topical, mucosal, nasal, buccal, sublingual; by tracheal instillation, bronchial instillation and / or inhalation; and / or as an oral spray, nasal spray and / or aerosol. Additionally, the desired route is direct administration to the affected site. Generally, the most appropriate route of administration will depend on a variety of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the route of administration is topical (to the skin, eye, ear, mouth, or affected site).

[0236] The precise amount of the agent or active ingredient required to achieve an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of side effects or disorders, the identification of the specific agent or active ingredient, the mode of administration, etc. The effective amount can be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses in the multiple doses comprise different or substantially the same amount of the agent or active ingredient described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering multiple doses to the subject or applying multiple doses to the tissue or cell is three doses per day, two doses per day, one dose per day, one dose every other day, one dose every three days, one dose per week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering multiple doses to the subject or applying multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering multiple doses to the subject or applying multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering multiple doses to the subject or applying multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first and last doses of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifespan of the subject, tissue, or cell. In certain embodiments, the duration between the first and last doses of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first and last doses of the multiple doses is the lifespan of the subject, tissue, or cell.

[0237] The compositions described herein can be administered in combination with one or more additional agents (e.g., therapeutic and / or prophylactic active agents). The compositions can be administered in combination with additional agents that improve their activity (e.g., treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, reducing the risk of developing a disease in a subject in need thereof, and / or activity in inhibiting the activity of an organism in a subject or cell (e.g., potency and / or efficacy)), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It should also be understood that the therapies employed can achieve the desired effect for the same disorder and / or they can achieve different effects.

[0238] The compositions can be administered simultaneously with, prior to, or after one or more additional agents, which can be used, for example, in combination therapies. Examples

[0239] In order to more fully understand the invention described herein, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0240] Abbreviations

[0241] PDA: Polydopamine

[0242] CAT: Catalase

[0243] GSEL: Gastrointestinal synthetic epithelial layer

[0244] PBS: Phosphate buffered saline

[0245] TBS: Tris buffered saline

[0246] TBST: Tris buffered saline containing Triton X 100

[0247] IgG: Immunoglobulin G

[0248] mRNA: Messenger ribonucleic acid

[0249] cDNA: Complementary deoxyribonucleic acid

[0250] FTIR: Fourier transform infrared

[0251] Chemicals and Materials

[0252] Dopamine hydrochloride (1225204), simulated gastric fluid (18818), urea H 2 O 2(289132), catalase (C3556 & C1345), Triton X-100 (T8787), 3-amino-1,2,4-triazole (A8056), RIPA buffer (R0278), protease inhibitor cocktail (P8340), phosphatase inhibitor cocktail 3 (P0044), Trizma base, o-nitrophenyl-β-D-galactopyranoside (N1127), β-galactosidase (1356698), glucose (G8270) and lactose (17814) were purchased from Sigma-Aldrich. Formalin (10%, phosphate buffered) (SF100), Tissue-Plus O.C.T (23-730-571), BD GasPak EZ Gas Generation System incubation container (B260002) and SouthernBiotech Fluoromount-G slide mounting medium (OB100) were purchased from Fisher Scientific. Pierce BCA Protein Assay (23225), Pierce DAB Substrate (34002), Pierce 16% formaldehyde (w / v) (28908), rabbit anti-goat immunoglobulin G (IgG) (H+L) secondary antibody-HRP (31402), goat anti-rabbit IgG (H+L) secondary antibody-HRP (65-6120), Vybrant MTT Cell Viability Assay (V13154), Dynabeads M-280 (tosylactivated) (14203), SeeBlue Plus2 Prestained Protein Standard (LC5925), SuperSignal West Femto Maximum Sensitivity Substrate (34094), Pierce ECL Western Blotting Substrate (32109), NuPAGE 4-12% Bis-Tris Protein Gel (NP0321BOX), NE-PER Nuclear and Cytoplasmic Extraction Reagents (78835), Mem-PER Plus Membrane Protein Extraction Kit (89842), Antibiotic-Antimycotic (100X) (15240062), SuperScript IV Reverse Transcriptase (18090050), PCR Master Mix and all primers were purchased from ThermoFisher. Total RNA isolation kit was purchased from ZYMO RESEARCH. Precision Plus Protein Dual Color Standards (#1610374) was purchased from Bio-Rad. Barium sulfate (13989) was purchased from Alfa Aesar. Simulated intestinal fluid was purchased from VWR.The CYP3A4 Activity Assay Kit (ab211076), Calcium Assay Kit (ab102505), Glutamate Assay Kit (ab138883), anti-catalase and anti-β-actin antibodies were purchased from Abcam. The Catalase (CAT) Assay Kit (E-BC-K031) was purchased from Elabscience. Praziquantel was purchased from ArkPharm. Screens (150 and 300 μm mesh sizes) were purchased from McMaster-Carr. Glo-Tip spray tubes (G24892) were purchased from COOK Medical. All other chemicals and biochemicals (unless otherwise stated) were purchased from Sigma-Aldrich and used without further purification.

[0253] Methods

[0254] General principles. In vivo tissue accelerated polymerization coating performance was evaluated in the GI tract of a large animal (pig) model through multiple techniques, including endoscopy, intestinal ligation, and X-ray imaging. Yorkshire pigs (45 - 55 kg) were selected as the model in view of the anatomical and genomic similarities of the Yorkshire pig to the human digestive system. Biocompatibility was characterized according to OECD guidelines. All animal experiments were approved by the Committee on Animal Care of the Massachusetts Institute of Technology and conducted in accordance with it. 19,28 . The groups and sample sizes for each experiment are indicated in the figure descriptions. Independent experiments for each sample were performed on different animals. All rats were randomly divided into different experimental groups, but since pigs were only utilized as needed, there was no pre-established randomization plan for in vivo pig studies.

[0255] Preparation of tissue accelerated polymerization solution. Dopamine hydrochloride powder (500 mg) was rapidly dissolved in Tris buffer (50 mM, 50 ml) at pH 8.5, and then H 2 O 2 (1 M, 1 ml) was rapidly added. The freshly mixed Tris-buffered tissue accelerated polymerization solution was used immediately. Unless otherwise stated, this mixed solution was freshly used in all experiments and referred to as the tissue accelerated polymerization solution, etc., as well as the gastrointestinal synthetic epithelial layer (GSEL). Solid urea H 2 O 2 (as a replacement for the H 2 O 2 solution) was used to prepare the tissue accelerated polymerization capsules. The capsules were made with dopamine hydrochloride powder (500 mg), Tris powder (30 - 300 mg; e.g., 300 mg), and solid urea H 2 O 2Preparation of powder (10 - 50 mg; e.g., 50 mg). The mixed powder is filled into (000 - size) capsules (see Figure 37 ).

[0256] In vitro evaluation of catalase - catalyzed polydopamine polymerization. First, prepare a tissue - accelerating polymerization solution (200 μl) and add it to a 96 - well plate, then add catalase (1 mg / mL, 5 μl in 1X phosphate - buffered saline (PBS) buffer). Place all solutions in a container with a low oxygen partial pressure (BD GasPak EZ). Keep the reaction mixture at 37 °C for 10 - 130 minutes. Measure the extinction of the solution at 700 nm using an Infinite M200 microplate reader (Tecan). Compare the results with those obtained from solutions that never added catalase and H 2 O 2 and those obtained from reactions under conventional conditions (in air). See Figure 1 C to 1D and 6A to 6B.

[0257] Characterization of polydopamine using FTIR and UV - Vis spectroscopy. Prepare a polydopamine standard by polymerizing a dopamine solution (10 mg / mL) under conventional conditions (in air) for 24 hours (H. Lee, S. M. Dellatore, W. M. Miller, P. B. Messersmith, Mussel - inspired surface chemistry for multifunctional coatings., Science 318, 426 - 30 (2007)). For catalase - catalyzed polydopamine, place catalase (1 mg / mL) in a dialysis device (5 ml), which is incorporated into a tissue - accelerating polymerization solution (100 ml) and kept for 24 hours. After the reaction, measure the polydopamine solution by FTIR (Nicolet) and UV - Vis spectroscopy (Varian Cary 100). See Figure 7 A to 7D and 8A to 8C.

[0258] Ex vivo evaluation of tissue - accelerating polymerization coating performance. Obtain porcine tissues from Blood Farm Slaughterhouse (West Groton, USA). Euthanize the pigs, excise the fresh tissues and store them on ice. Obtain human tissue specimens from 4 donors of different ages, ethnicities and genders (National Disease Research Interchange (NDRI), USA). Place the tissues (12 cm 2)Expose to the tissue accelerating polymerization solution (10 mL), and wash 3 times with PBS buffer (1X) to remove the excessive polydopamine. Collect samples (diameter 6 mm) at 3 - 5 random sites of the polydopamine-coated tissue, and analyze the images of the samples to quantify the polydopamine coating. Use ImageJ to identify the region of interest that includes the polydopamine-coated tissue and excludes the "blank" tissue-free area. Perform the same analysis on all samples in each group to obtain the total average polydopamine signal intensity and evaluate the signal variation. Expose the tissue to the antibiotic-antimycotic solution (10X, Gibco) and wash 3 times with PBS buffer (1X) to remove bacteria in the mucus. Strip the villi from the luminal surface of the small intestine tissue (longitudinally opened) placed on the ice-cold substrate. Based on the kit protocol, perform cell fractionation on the villi using the cytoplasmic and membrane extraction kit (NE-PER, Mem-PER). Based on the assay protocol, measure the CYP3A4 activity by CYP3A4 activity assay (Abcam). See Figure 1 E to 1H, 5A to 5G, 9, 13, 15, 24, 25, 27, 28, 32, 34, and 35.

[0259] Tissue lysate preparation. Dissect the epithelial tissue of the porcine gastrointestinal tract on ice. Remove the outer mucus layer by aspiration, and then freeze the rinsed tissue in liquid nitrogen [(with 1X phosphate-buffered saline (PBS)]. Incubate and homogenize the tissue (10 mg) in ice-cold lysis buffer (600 μl, RIPA buffer mixed with protease and phosphatase inhibitor cocktail, Sigma-Aldrich) to form the tissue lysate. Use the bicinchoninic acid (BCA) assay to measure the total protein concentration of the tissue lysate.

[0260] Analysis of the catalytic ability of tissue lysate. Perform a non-denaturing gel-based catalytic activity assay. Separate the proteins in the tissue lysate on a 7.5% non-denaturing polyacrylamide gel, and stain the gel with the gastrointestinal synthetic epithelial layer (tissue accelerating polymerization) solution (50 ml) for 10 minutes. After staining, wash the gel 3 times with PBS buffer (1X) and image it. See Figure 2 A and 10.

[0261] In vitro inhibition of catalase activity. Use 3-amino-1,2,4-triazole as the inhibitor. Incubate the tissue lysate (10 mg / ml, 100 μl) in the inhibitor solution (20 mM) at 4 °C for 6 hours. See Figure 2 B.

[0262] Immunoprecipitation of catalase in tissue lysates. First, based on the immunomagnetic bead (Dynabeads) protocol, catalase antibody was conjugated to tosyl-activated magnetic beads (Dynabeads M-280). The conjugated beads (60 mg) were further added to the tissue lysate solution (10 mg / ml, 100 μl), incubated for 2 hours to capture catalase in the solution, and placed on a magnet for 2 minutes to remove the beads. See Figure 2 C.

[0263] Evaluation of catalase expression in tissues. Fresh porcine tissues were collected for real-time PCR and Western blotting. Total RNA was isolated and reverse transcribed into cDNA using a standard protocol. mRNA expression was measured using the LightCycler480II system (Roche). The catalase mRNA expression level was normalized to housekeeping genes (β-actin, 18S, GUS, and GAPDH) and expressed as a percentage of the negative control. For Western blotting, tissue lysates were separated on SDS-PAGE gels using a standard protocol. Anti-catalase (diluted 1:500 in Tris-buffered saline (TBST) buffer containing Triton X 100) and anti-β-actin (diluted 1:1000 in TBST buffer) were used as primary antibodies. A secondary antibody (diluted 1:2000 in TBST buffer) was used for specific detection. Catalase signals were generated using SuperSignal TM West Femto Maximum Sensitivity substrate, and β-actin signals were generated using Pierce TM ECL Western blotting substrate. Western blots were imaged on a ChemiDoc TM XRS+ system (Bio-Rad) and analyzed using Image Lab 3.0. See Figure 2 D to 2F, 10, 11, and 12.

[0264] Microscopic analysis of polydopamine-coated tissues. The polydopamine-coated small intestine was snap-frozen and embedded in optimal cutting temperature (O.C.T) compound. The fixed tissues were sectioned into 40-μm-thick slices using a cryostat (Leica Biosystems). Specific peroxidase / catalase staining was performed as previously reported (M. Connock, W. Pover, Catalase particles in the epithelial cells of the guinea-pig small intestine, Histochem. J. 2, 371-380 (1970)). Uncoated tissue sections were stained with 3,3'-diaminobenzidine (DAB) substrate or tissue accelerator polymerization solution (1 mL) for 10 minutes. The slides were scanned using an Aperio digital pathology slide scanner (Leica Biosystems) and analyzed using Aperio ImageScope (Leica Biosystems). See Figure 2 G to 2H, 5D, and 26.

[0265] In vivo evaluation of tissue accelerator polymerization coating performance. All animal experiments were approved by and conducted in accordance with the Committee on Animal Care of the Massachusetts Institute of Technology. A large animal model, namely 45-55 kg Yorkshire pigs (Tufts, Medford, USA), was selected to test the in vivo performance of tissue accelerator polymerization coating. The pigs were fed a diet consisting of pellets (LabDiet Mini-Pig Grower 5081) in the morning and evening, in addition to a lunch snack consisting of various fruits and vegetables. The pellets consisted of ground oats, alfalfa meal, wheat middlings, soybean meal, dried beet pulp, salt, and other micronutrient supplements. Before oral administration of the tissue accelerator polymerization solution, the gastric juice was removed from the stomach. Under endoscopic visual guidance, the tissue accelerator polymerization solution (1 ml / kg -1 IM), xylazine (2 mg / kg -1 IM), and atropine (0.05 mg / kg -1 IM) were used to sedate the pigs, intubated, and maintained with isoflurane (1 to 3%, by inhalation). Additionally, before administration of the Tris-buffered tissue accelerator polymerization solution (pH 8.5), the gastric juice was removed from the stomach. Under endoscopic visual guidance, the tissue accelerator polymerization solution (1 ml / kg -1)Transcatheter oral administration to the intestine or stomach. After delivering the tissue-accelerated polymerization solution, the formation of polydopamine was recorded in real time using a gastrointestinal endoscope camera, and the endoscopic camera was placed inside and outside the tissue-accelerated polymerization solution. To directly evaluate the polydopamine coating, laparotomy was performed on pigs. Before applying the tissue-accelerated polymerization solution to the intestine, non-invasive forceps were applied at the small intestine. The tissue-accelerated polymerization solution filled the intestinal lumen up to the clamped site and could not be passed down to the lower small intestine. After 20 minutes of application, the pigs were euthanized, and the tissue near the clamp was dissected, washed, and opened. All animals were euthanized before tissue harvest. Macroscopic images of the tissue were taken to evaluate the polydopamine coating performance. During the procedure, a Cardell multiparameter monitor (Midmark) was used to monitor the blood pressure and heart rate of the pigs. Additionally, no clinical or endoscopic evidence of gastrointestinal perforation, inflammation, or obstruction was observed during the study. See Figure 3 , 4 , 14, 16, 29, 30, 31, 33, and 37.

[0266] Preparation of polydopamine probe. Barium sulfate particles (20 g) were added to Tris buffer (50 mM, 1000 mL, pH 8.5), and then dopamine (10 g) was added rapidly. The reaction mixture was kept at room temperature and stirred (600 rpm) for 3 hours. The synthesized polydopamine probe was purified by centrifugation (4000 rpm × 10 minutes). The purified polydopamine probe was redispersed in 100 ml of water and sonicated. The purified polydopamine probe was lyophilized for 3 days and stored at -20 °C. Before application, the polydopamine probe was resuspended in the tissue-accelerated polymerization solution, and the polydopamine probe tissue-accelerated polymerization solution was used freshly. See Figure 3 E and 15.

[0267] In vivo evaluation of intestinal retention of polydopamine coating by X-ray imaging. The pigs were sedated, intubated, and maintained with isoflurane as described above. Before application, gastric juice was removed from the stomach. First, the polydopamine probe (20 mg -1 mL -1 ) was suspended in the tissue-accelerated polymerization solution. The polydopamine probe-suspended tissue-accelerated polymerization solution (3 ml / kg -1) and introduced into the small intestine. An aqueous solution of a conventional radio-opaque probe (unmodified barium sulfate particles) suspended at the same concentration was administered as a control. Radiography was performed to monitor the probe and polydopamine-coated intestinal retention. For short-term stability evaluation, X-ray images were taken before and after flushing the coated area with 500 ml of water. For long-term retention assessment, a series of X-ray images were taken regularly at specified time points at the same location, during which the pigs were constantly consuming a liquid diet. Additionally, clinical and radiological imaging evaluated the evidence of gastrointestinal perforation and obstruction in the pigs (e.g., loss of appetite, abdominal distension, insufficient feces, or vomiting). No clinical or radiological evidence of gastrointestinal perforation and obstruction was observed during the study. See Figure 3 E to 3I, and 16.

[0268] In vivo coating of exogenous β-galactosidase on intestinal epithelium. The pigs were sedated, intubated, and maintained with isoflurane as described above. Before administration, gastric juice was removed from the stomach. The pigs were subjected to laparotomy to open the small intestine. A chamber was placed on top of the intestinal epithelium, and then a tissue accelerating polymerization solution (3 ml) suspended with β-galactosidase (5 μg -1 mL -1 ) was added. Three control chambers with and without the reagents (β-galactosidase and tissue accelerating polymerization solution) were also placed in the same pigs. After 20 minutes of coating, the epithelium inside the chamber was washed 3 times with water, and the β-gal activity of the tissue was evaluated using o-nitrophenyl-β-D-galactoside (ONPG) as a substrate. See Figure 4 A to 4C.

[0269] Preparation and characterization of polydopamine nanocrosslinker. Ammonium hydroxide (10 ml, 28 - 30% w / w) was diluted into a 650 ml ethanol-water (4:9 ratio v / v) mixed solution. The mixed solution was stirred at 30 °C for 1 hour, and then 50 ml of dopamine solution (50 mg -1 mL -1 in water) was added. The reaction mixture was kept at 30 °C for 24 hours. The synthesized polydopamine nanocrosslinker was purified by centrifugation (6000 rpm × 15 minutes). The purified polydopamine nanocrosslinker was redispersed in 500 ml of water and sonicated. The dry size and hydrodynamic size were measured using a transmission electron microscope (TEM, JEOL 2100F, JEOL.Ltd) and a Zetasizer Nano ZS90 instrument (Malvern Panalytical), respectively. See Figure 4 D to 4E and 17A to 17B.

[0270] Ex vivo evaluation of the blocking efficiency of tissue-accelerated polymerization. The tissue was exposed to the tissue-accelerated polymer and washed three times with PBS buffer (1X) to remove excess polydopamine. Polydopamine nanocrosslinkers at different concentrations (25 mg -1 mL -1 、12.5 mg -1 mL -1 and 0 mg -1 mL -1 ) were suspended in the tissue-accelerated polymer. The coated tissue was placed in a Franz cell, and 100 mM nutrients (CaCl 2 , glutamate, and glucose) were added to the chambers (sealed with paraffin film) separately, and samples were taken from the receptor compartment (with a stir bar) after 3 hours for measurement. See Figure 32 A to 32D.

[0271] In vivo evolution of impermeable polydopamine coating for blocking glucose uptake. Pigs (fasted overnight) were sedated, intubated, and maintained with isoflurane as described above. Before administration, gastric juice was removed from the stomach. First, the polydopamine nanocrosslinker (25 mg -1 mL -1 ) was suspended in the tissue-accelerated polymerization solution. The nanocrosslinker-suspended tissue-accelerated polymerization composition (10 ml kg -1 ) was orally administered to the pigs and introduced into the small intestine. The solution was directly administered to the small intestine through a catheter under endoscopic visual guidance. For the control, 500 ml of aqueous solution was administered in the same manner. Twenty minutes after the solution administration, a standard oral glucose tolerance test (OGTT) was performed on the pigs (Y. Lee, T. E. Deelman, K. Chen, D. S. Y. Lin, A. Tavakkoli, J. M. Karp, Therapeutic luminal coating of the intestine, Nat. Mater. 17, 834 - 842 (2018); E. Manell, P. Hedenqvist, A. Svensson, M. Jensen-Waern, E. Xu, Ed. Establishment of a refined oral glucose tolerance test in pigs, and assessment of insulin, glucagon and glucagon-like peptide-1 responses, PLoS One 11, e0148896 (2016)). An aqueous glucose solution (3 ml kg -1 , 500 mg -1 mL -1), and introduced into the small intestine. Blood samples were collected from the central venous catheter at the specified time points and immediately used OneTouch glucose monitor (LifeScan Inc) to test the glucose level. Each data point (blood glucose change) over time was plotted, and the area under the curve was calculated for quantitative evaluation. See Figure 4 A, 4D to 4E, and 33.

[0272] Praziquantel - tissue accelerating polymerization preparation. Praziquantel particles were encapsulated in polydopamine, allowing reactive groups (such as catechol and amine groups) on the surface of polydopamine to chemically crosslink and incorporate the praziquantel particles into the polydopamine coating layer. Additionally, the hydrophilic polydopamine layer on the particle surface significantly improved the stability and dispersion characteristics of the hydrophobic drug particles. Praziquantel particles (powder) (8 g) were sieved (150 - 300 μm mesh size) and added to Tris buffer (50 mM, 400 ml, pH 8.5), followed by rapid addition of dopamine (4 g) (J. Park, T. F. Brust, H. J. Lee, S. C. Lee, V. J. Watts, Y. Yeo, Polydopamine - based simple and versatile surface modification of polymeric nano drug carriers, ACS Nano 8, 3347 - 3356 (2014)). The reaction mixture was kept at room temperature and stirred (600 rpm) for 3 hours. The synthesized praziquantel particles were purified by centrifugation (4000 rpm × 10 minutes). The purified praziquantel particles were lyophilized for 3 days and stored at -20 °C. Before administration, the praziquantel particles were resuspended in the tissue accelerating polymerization solution, and the praziquantel particle tissue accelerator was used freshly. See Figure 4 A, 4F and 4G.

[0273] Praziquantel concentration assessment. Using the high - performance liquid chromatography Agilent 1260 Infinity II HPLC system (Agilent Technologies, Inc.), which is equipped with a 1260 - type quaternary pump, a 1260 - type Hip ALS autosampler, a 1290 - type thermostat, a 1260 - type TCC control module, and using a 1260 - type diode array detector. Using OpenLab software (Agilent Technologies, Inc.) to perform data processing and analysis. For praziquantel, chromatographic isocratic separation was carried out on an Agilent Zorbax Eclipse XDB C with 5 μm particles -1Performed on an 8 × 4.6 × 150 mm analytical column, maintained at 40 °C. The optimized mobile phase consisted of MilliQ-grade water and acetonitrile, with a flow rate of 1 ml per minute -1 , and the run time was 5 minutes. Separation was achieved using a gradient elution curve starting at 50% water and 50% acetonitrile at 0 minutes and ending at 30% water and 70% acetonitrile at 3 minutes. The injection volume was 5 μl, and the selected ultraviolet (UV) detection wavelength was 217 nm. See Figure 4 Figures 4F and 4G.

[0274] In vivo evolution of the pharmacokinetics of praziquantel-tissue accelerating polymerization. The pigs were sedated, intubated, and maintained with isoflurane as described above. Before administration, gastric juice was removed from the stomach. The praziquantel-tissue accelerating polymer (20 mg -1 mL -1 , 1 ml kg -1 ) was delivered into the small intestine. Praziquantel without tissue accelerating polymerization was used as a control. Blood samples were collected from the marginal ear vein at the designated time points. Serum samples were separated from the blood by centrifugation (1800 G × 10 minutes, at 4 °C) and stored at -80 °C for further analysis. See Figure 4 Figures 4F and 4G.

[0275] Serum praziquantel concentration assessment. The concentration of praziquantel in serum from in vivo experiments was analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS). The analysis was performed on a Waters ACQUITY UPLC-I-Class system coupled with a Waters Xevo TQ-S mass spectrometer (Waters Corporation, Milford MA). Liquid chromatography separation was performed at 50 °C on an Acquity UPLC BEH C18 column (50 mm × 2.1 mm, 1.7-μm particle size). The mobile phase consisted of 0.1% formic acid aqueous solution, 10 mM ammonium formate solution (mobile phase A) and acetonitrile: 10 mM ammonium formate, 0.1% formic acid solution (95:5 v / v) (mobile phase B). Using a certain time and solvent gradient composition, the mobile phase had a continuous flow rate of 0.6 ml / min. For the analysis of praziquantel, the initial composition of 80% mobile phase A was held for 0.50 min and then linearly changed to 0% mobile phase A over the next 2.00 min. The composition of 0% mobile phase A and 100% mobile phase B was held constant until 3.50 min. At 3.51 min, the composition returned to 80% mobile phase A and was held at this composition until the run was completed, ending at 5.00 min, where it was held for column equilibration. The total run time was 5.00 min. The mass-to-charge ratio transitions (m / z) used for the quantification of praziquantel were 313.22>203.09 and 313.22>83.01 (for quantification and confirmation, respectively). As the internal standard, mebendazole, the 296.06>264.03 and 296.06>76.99 m / z transitions were used for quantification and confirmation, respectively. Sample introduction and ionization were performed by electrospray ionization (ESI) in positive ionization mode. Waters MassLynx 4.1 software was used for data acquisition and analysis. A stock solution of praziquantel was prepared at a concentration of 500 μg / ml in methanol. In analyte-free blank serum in the range of 1.25 - 5000 ng / ml, a twelve-point calibration curve was made. Each 100 μl serum sample was spiked with 200 μl of 250 ng / ml mebendazole in acetonitrile to cause protein precipitation. The samples were vortexed, sonicated for 10 min, and centrifuged at 13,000 rpm for 10 min. 200 μl of the supernatant was pipetted into a 96-well plate containing 200 μl of water. Finally, 1.00 μl was injected onto the UPLC-ESI-MS system for analysis. See Figure 4 F and 4G.

[0276] Serum and tissue dopamine concentration assessment. The dopamine concentrations in serum and tissues from in vivo experiments were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS). The analysis was performed on a Waters ACQUITY UPLC-I-Class system coupled with a Waters Xevo TQ-S mass spectrometer (Waters Corporation, Milford MA). Liquid chromatography separation was carried out at 50 °C on an Acquity UPLC BEH C18 column (50 mm × 2.1 mm, 1.7-μm particle size). The mobile phase consisted of 0.1% formic acid aqueous solution, 10 mM ammonium formate solution (mobile phase A), and acetonitrile: 10 mM ammonium formate, 0.1% formic acid solution (95:5 v / v) (mobile phase B). With a certain time and solvent gradient composition, the mobile phase had a continuous flow rate of 0.45 ml / min. Sample introduction and ionization were carried out by electrospray ionization (ESI) in the positive ionization mode. Waters MassLynx 4.1 software was used for data acquisition and analysis. A stock solution was prepared at a concentration of 500 μg / ml in methanol. A twelve-point calibration curve was made in analyte-free blank porcine serum in the range of 1.25 - 10000 ng / ml. Each 100 μl serum sample was spiked with 100 μl of 500 ng / ml methyldopamine (internal standard) in acetonitrile to cause protein precipitation. Then, 200 μl of 5 mg / ml fluorescamine in acetonitrile was added to each sample as a derivatization reagent for both dopamine and methyldopamine to facilitate detection. The samples were vortexed, sonicated for 10 minutes, and centrifuged at 13,000 rpm for 10 minutes. 300 μl of the supernatant was incubated at 37 °C for 60 minutes. Then 200 μl of the incubation solution was added to 200 μl of water in a 96-well plate. Finally, 10 μl was injected onto the UPLC-ESI-MS system for analysis. See Figure 31 .

[0277] The tissue samples were divided into chunks of approximately 300 mg. 3% bovine serum albumin in PBS buffer was added at a volume-to-mass ratio of 2:1. The samples were homogenized at 4 °C. 100 μl of each homogenate was admixed with 100 μl of 500 ng / ml methyldopamine in acetonitrile, and 200 μl of 5 mg / ml fluorescamine in acetonitrile (for derivatization). 1.00 ml of ethyl acetate was also added to the homogenized samples for extraction. The samples were vortexed, sonicated for 10 minutes, and centrifuged at 13,000 rpm for 10 minutes. After centrifugation, 300 μl of the supernatant was incubated at 37 °C for 60 minutes. The samples were allowed to evaporate overnight. The evaporated samples were reconstituted with 300 μl of acetonitrile and centrifuged at 6,000 rpm for 5 minutes. 200 μl of the supernatant was pipetted into a 96-well plate containing 200 μl of water. Finally, 10 μl was injected onto a UPLC-ESI-MS system for analysis. See Figure 31 .

[0278] For the analysis of dopamine fluorescamine, the initial composition of 95% mobile phase A was held for 0.75 minutes. Thereafter, the composition was linearly changed to 5% mobile phase A and 95% mobile phase B until 1.00 minute. The composition was held constant at 95% mobile phase B until 3.00 minutes. At 3.25 minutes, the composition returned to 95% mobile phase A, where it was held to equilibrate the column during the run duration, ending at 4.00 minutes. The mass-to-charge ratio transitions (m / z) used for quantifying dopamine were 414.223>137.125 and 414.223>119.115 (for quantification and confirmation, respectively). For the internal standard methyldopamine fluorescamine, the 472.223>139.139 and 472.223>278.094 m / z transitions were used for quantification and confirmation, respectively. See Figure 31 A and 31B.

[0279] Cytotoxicity assay. The Vybrant MTT cell proliferation assay was used to test the cytotoxicity of polydopamine (PDA) in living cells. Polydopamine as prepared was added to cell culture media at various concentrations (0, 10, 50, 250, 500, 1000, 1500, and 2000 μg / ml). Cytotoxicity was tested on multiple cell lines: HeLa (ATCC), COLO320DM (ATCC), Caco-2 (ATCC), Hep3B (ATCC), and HS 895.T (ATCC) by inoculating them at a density of 10,000 cells each in 96-well plates and allowing them to remain in culture for 24 hours, then replacing the media with 100 μl of the polydopamine solution. The cells were incubated at 37 °C in a cell culture incubator for different amounts of time (6, 12, 24 hours). The cells were washed 3 times with PBS buffer, then MTT solution (10 μl) and cell culture media (100 μl) were added to each well and incubated at 37 °C for 4 hours. After 4 hours, 100 μl of SDS-HCl solution was added to each well and incubated for an additional 4 hours (at 37 °C). Absorbance at 570 nm was recorded on a 96-well plate reader (Tecan Infinite M200). See Figure 19 。

[0280] Oral toxicity test. By following a slightly modified version of the guidelines published by OECD (OECD, test number 407: repeated dose 28-day oral toxicity study in rodents OECD Guideline. Test. Chem. Sect. 4, OECD Publ. Paris, 1–10 (2008)), over a 4-week period, three groups (4 animals per group) of rats (Sprague Dawley, 150 - 200 g, Charles River Labs) were exposed to water (5 ml kg -1 ), polydopamine as prepared (15 mg mL -1 , 5 ml kg -1 ), and tissue accelerating polymerization solution (5 ml kg -1 ). The solutions were administered directly to the rats via gavage needle rather than an endoscopic catheter. Body weight was measured daily for 28 days. Blood samples were collected on day 27 for hematological and blood biochemical measurements, and food was withheld for 24 hours. On day 28, all 12 rats were euthanized and necropsied. Samples of the heart, lungs, liver, kidneys, spleen, stomach, small intestine, and large intestine were collected for histological analysis. See Figure 20 、 21 、22 and 23.

[0281] Histological analysis of tissues. First, the tissues were fixed in PBS buffer (1X) containing 4% paraformaldehyde for 6 hours, and then placed in PBS buffer containing 30% sucrose overnight at 4°C. The fixed tissues were embedded in paraffin and sectioned into 5-μm thick slices using a cryostat (Leica Biosystems). The sections were stained with hematoxylin and eosin for histopathological analysis. See Figure 5 D and 23.

[0282] Polydopamine coating of impermeable polycarbonate sheets. The polycarbonate sheets were exposed to tissue-accelerated polymerization solution (without H 2 O 2 ) for 36 hours and washed with water to remove excess polydopamine. See Figure 36 A to 36C.

[0283] Statistical analysis. All data were reported as mean ± SD, with n ≥ 3 measurements per group. Two-sample t-tests, one-way ANOVA, and post hoc Bonferroni multiple comparison tests were used to determine significance.

[0284] Overview of selected examples

[0285] The therapeutic value of the compositions, methods, and kits described in the present disclosure has been evaluated in many clinical settings. Tissue-accelerated polymerization was applied to address lactose intolerance by coating digestive enzymes on the small intestinal epithelium. The results showed that β-galactosidase coated on the tissue increased the digestion efficiency of lactose by approximately 20-fold, indicating the therapeutic utility of the present disclosure in digestive disorders and diseases. In addition, the ability of tissue-accelerated polymerization technology in the regulation of intestinal glucose absorption, which is urgently needed for type 2 diabetes patients, was evaluated. An impermeable coating layer acting as a glucose-blocking barrier was developed to block postprandial glucose intake (a decrease in glucose response by approximately 70%). The application of tissue-accelerated polymerization was extended to improve the administration efficiency of drugs under inconvenient regimens, demonstrating its ability to sustainably release therapeutic agents. The disclosed method for administering praziquantel (an anthelmintic drug) achieved a persistent (over 24 hours) drug level in the systemic circulation (a 10-fold increase in the half-life value), with the potential to revolutionize the drug options for patients with schistosomiasis and other regimen-dependent diseases. Coupled with the outstanding performance of tissue-accelerated polymerization technology in human tissue specimens, these clinical applications are suitable for in vivo human testing. The tissue-accelerated polymerization technology is applicable to a wide range of technological adoption and applications in disease treatment and health management.

[0286] Example 1

[0287] Endogenous enzyme-catalyzed polydopamine growth on epithelium

[0288] To demonstrate that catalase accelerates polydopamine polymerization in a hypoxic environment, the hypoxic partial pressure in the gastrointestinal tract was simulated, and the polydopamine polymerization rate was quantitatively evaluated under different reaction conditions, where dopamine was maintained at the same concentration ( Figure 1 B-D and Figure 6 A-6B). In an extremely hypoxic environment, the conventional slow polydopamine polymerization was inhibited by 65% ( Figure 6 A-6B). The addition of trace amounts of hydrogen peroxide (H 2 O 2 ), which acts as a strong reducing agent, prevented dopamine oxidation and almost quenched the reaction. As Figure 1 shown in 2 C, the slow color change of the dopamine solution from clear to light gray over two hours indicated minimal polydopamine polymerization, and the clear dopamine-H 2 O 2 solution indicated negligible polydopamine polymerization. In contrast, the color of the dopamine solution quickly turned dark brown in the presence of both catalase and H 2 O Figure 7 A-7D and 8A-8C), indicating accelerated polydopamine polymerization. In this study, using both Fourier transform infrared (FTIR) and ultraviolet-visible (UV-Vis) spectroscopy, it was confirmed that the polymerization products catalyzed by catalase from both commercially purified enzymes and crude tissue lysates were polydopamine ( Figure 1 D). To further quantitatively evaluate the effect of catalase on the polydopamine polymerization rate, reaction kinetics were compared by measuring the optical extinction of the solution at 700 nm, where polydopamine has an absorbance characteristic (

[0289] D). The signal of the catalase-polydopamine combination grew rapidly within 10 minutes of the reaction and reached a steady state. However, the extinction intensity under other conditions was relatively low even after 2 hours, where the same intensity level was reached within 20 seconds under catalase-catalyzed conditions, showing an approximately 400-fold increase in the polymerization rate. Figure 1 E and Figure 9 shown, when the mucosal side of the small intestine was exposed to the tissue-accelerated polymerization solution, a clear dark brown polydopamine coating was observed on the epithelial surface, indicating that polydopamine was formed in situ and deposited at the anchoring points of the tissue due to the high reactivity between polydopamine and primary amines in nearby biomolecules 14. In contrast, after the same incubation, little polydopamine was found on the serosal side of the tissue, indicating that polydopamine polymerization is an enzyme-dependent reaction ( Figure 1 E). Due to the colorimetric properties of polydopamine, these polydopamine coating processes are visualized. To further quantify the growth rate of polydopamine, the amount of polydopamine coated on the small intestine was analyzed over a series of reaction times. The coating kinetics showed a rapid appearance of the polydopamine signal, reaching completion within 12 minutes ( Figure 1 F), indicating a rapid polydopamine coating process. In addition to efficiency, the specificity of tissue-accelerated polymerization was evaluated by comparing the tissue-accelerated polymerization coatings in different parts of the gastrointestinal tract, including the esophagus, stomach, duodenum, jejunum, ileum, and colon. As Figure 1 shown in G, tissue images (6 mm in diameter) revealed significant polydopamine coating on the duodenum and jejunum, relatively less polydopamine coating on the ileum and colon, and negligible polydopamine coating on the stomach and esophagus. This coating pattern was additionally demonstrated by Figure 1 quantitative polydopamine signal analysis in H. This particular efficiency and specificity of tissue-accelerated polymerization pave the way for downstream in vivo applications.

[0290] Example 2

[0291] Tissue-Accelerated Polymerization Mechanisms at the Molecular, Cellular, and Tissue Levels

[0292] Before exploring the applications of tissue-accelerated polymerization technology, its biological mechanisms were systematically and thoroughly studied. First, it was tested whether endogenous catalase is a component that determines catalytic polydopamine polymerization on the epithelium. The epithelial tissues of the porcine gastrointestinal tract were dissected and washed, and the outer mucus layer was removed by aspiration. Then, the rinsed tissues were homogenized to prepare tissue lysates, which were further diluted relative to the total protein concentration. These tissue lysates were individually added to the tissue-accelerated polymerization solution, and the extinction of each solution was measured after the reaction. As Figure 2 shown in A, the signal of the polydopamine solution with small intestine epithelial lysate was higher than that of the others, consistent with the tissue coating results ( Figure 1 G). In addition, a similar trend was observed in the analysis of the catalytic ability of these lysates by non-denaturing gel electrophoresis and polydopamine staining ( Figure 10 ). Only one clear band was seen in each lane, supporting the expected role of catalase as the sole enzyme responsible for polydopamine polymerization. To further confirm the unique role of catalase, the small intestine lysates were treated with a catalase-specific inhibitor to reduce catalase activity, or with magnetic beads coated with catalase antibody to remove immunoprecipitated catalase. As Figure 2As shown in B, the catalytic ability of the lysate decreased by approximately 80% after the addition of the inhibitor and by approximately 90% when catalase was removed from the sample ( Figure 2 C), indicating that tissue-accelerated polymerization is only catalase-dependent. Additionally, it was confirmed that catalase present due to bacteria in the small intestinal mucus does not affect tissue-accelerated polymerization coating ( Figure 24 A-24B and 25), showing that most H 2 O 2 is not degraded or consumed in the intestinal lumen and that the amount of H 2 O 2 is sufficient to activate oxygen release and polydopamine polymerization. In addition, catalytic polydopamine polymerization was observed to occur mainly in the small intestine, as catalase is more highly expressed in the small intestine compared to other segments of the GI tract.

[0293] It has previously been shown that human catalase is expressed at higher mRNA and protein levels in the small intestine than in other organs of the digestive tract, such as the esophagus, stomach, and large intestine 15 , playing a role in the coating specificity of tissue-accelerated polymerization technology. To further confirm this distinguishable catalase expression profile in the gastrointestinal epithelium, quantitative evaluation of catalase expression along the porcine gastrointestinal tract was performed by both gene and protein analysis. As Figure 2 shown in D, high levels of catalase activity were detected in the duodenum and jejunum, while relatively low levels of catalase activity were observed in the esophagus, stomach, ileum, and colon, indicating stronger catalase activity in the small intestine relative to the rest of the gastrointestinal tissue. Additionally, quantitative real-time polymerase chain reaction (PCR) was used to measure the catalase mRNA levels in the tissue. The catalase mRNA expression level in the small intestine was approximately 10-fold higher than that in other epithelial tissues ( Figure 2 E and Figure 11 A-11B), yet no such difference was present in the mRNA levels of control genes (housekeeping genes) between the small intestine and other organs ( Figure 12 A-12E). As predicted, the small intestine catalase protein expression level had a similar distribution profile compared to the mRNA expression levels in the gastrointestinal tract (western blot analysis, Figure 2 F).

[0294] Then, efforts were made to characterize the interface between the polydopamine layer and the epithelium under the microscope. The chromogenic polydopamine was visualized not only by the naked eye but also by the microscope 16 . Interestingly, it was found that during the tissue-accelerated polymerization process, polydopamine was first deposited on the tips of the intestinal villi and then coated the entire villus and the surrounding area ( Figure 13 ). Microscopic analysis showed a thin polydopamine layer tightly coating the outer villi ( Figure 2G), but not on the control tissue (without tissue acceleration polymerization treatment). Polydopamine was completely restricted to the outer layer of the epithelium, the luminal surface, rather than inside the epithelial cells, indicating that polydopamine polymerization occurred only at the epithelial surface and that dopamine remained outside the cells throughout the reaction ( Figure 26 A-26C, 27, and 28). Specific peroxisome / catalase staining studies showed that catalase was located inside peroxisomes, which had a high density distribution in the villi rather than in the submucosa and other inner layers ( Figure 2 H, left panel). Similar studies confirmed the presence of catalase "granules" in the peroxisomes of intestinal epithelial cells 17 . To further confirm that peroxisomal catalase could catalyze the formation of polydopamine, dopamine was used instead of the typical peroxisome / catalase substrate for staining. As Figure 2 shown in H (right panel), dark brown polydopamine spots were observed inside the epithelial cells, and the staining pattern was consistent with the conventional peroxisome / catalase staining, confirming the catalytic ability of peroxisomal catalase for polydopamine polymerization in the sectioned tissue segments. No peroxisomal polydopamine pattern was observed in the tissue acceleration polymerization-coated samples that were subjected to in-lumen tissue acceleration polymerization and then sectioned for microscopy without peroxisome / catalase staining ( Figure 2 G, left panel).

[0295] Example 3

[0296] Evaluation of the in vivo performance of tissue coating based on tissue acceleration polymerization

[0297] The biological mechanism of tissue acceleration polymerization has been elucidated, and the in vivo performance of this tissue coating technology was tested in Yorkshire pigs. It is also worth mentioning that the advantages of using pigs as a large animal model include their high homology with the human genome, anatomical similarity to the human gastrointestinal tract, and physiological similarity to the human digestive system 18,19 . Under moderate sedation, the tissue acceleration polymerization solution was orally administered to the pigs under endoscopic monitoring and introduced into the small intestine through the esophagus ( Figure 3 A). After delivering the tissue acceleration polymerization solution, the formation of polydopamine was recorded in real time using a gastrointestinal endoscope, and the endoscopic camera was placed inside and outside the tissue acceleration polymerization solution ( Figure 3 B and 3C). The in vivo observations were consistent with those of the ex vivo tissue coating studies. As Figure 3 shown in C, a dark brown polydopamine layer was observed on the small intestinal wall 20 minutes after administration, while no such polydopamine coating was seen in the stomach after the same gavage ( Figure 14A-14C). The tissue-accelerated polymerization solution remained overall stable in the stomach for 30 - 60 minutes ( Figure 29 ), confirming the durability of the solution. It should be noted that all animals were fasted overnight and gastric juice was removed from the stomach before administering the Tris-buffered tissue-accelerated polymerization solution (pH 8.5), thus minimizing the possible effect of pH on the stability of the tissue-accelerated polymerization solution and polydopamine polymerization. Additionally, no detectable increase in polydopamine and dopamine signals in the submucosa and blood was observed after tissue-accelerated polymerization coating, where microscopy ( Figure 26 A-26C), UV-visible spectroscopy ( Figure 30 ), and liquid chromatography-tandem mass spectrometry ( Figure 31 A-31B) were used for signal measurement. Furthermore, no significant increase in blood pressure or heart rate was detected in any of the animals throughout the procedure, indicating no dopamine absorption and supporting the early safety of the tissue-accelerated polymerization technique 40 . Consistent with Figure 1 the schematic of the tissue-accelerated polymerization technique depicted in Figure 1 A, endoscopic video revealed that the polydopamine coating process consisted of three main steps. When the clear dopamine-H 2 O 2 solution was first introduced into the small intestine lumen, oxygen bubbles formed and the intestinal wall rapidly turned light yellow-brown, indicating rapid diffusion of hydrogen peroxide and initiation of polydopamine polymerization. Second, an increased amount of oxygen bubbles were generated at the epithelial-solution interface (view with camera inside) and released into the solution (view with camera outside), confirming rapid decomposition of hydrogen peroxide and providing evidence of the oxygen release mechanism. Third, interfacial oxygen catalyzed polydopamine polymerization and adhered to the intestinal epithelium, while the tissue-accelerated polymerization solution remained liquid and the intestinal lumen remained dilated, alleviating concerns about intestinal adhesion and obstruction. The results showed that after coating, the solution in the lumen also turned dark brown, which might be due to diffusion of unbound polydopamine into the solution.

[0298] To directly evaluate coating formation, laparotomy was performed on pigs. Before endoscopically administering the tissue-accelerated polymerization solution into the intestine, non-traumatic forceps were applied to the small intestine. As Figure 3 shown in

[0299] D, the tissue-accelerated polymerization solution filled the intestinal lumen up to the forceps site and could not be passed down to the lower small intestine. The tissue near the forceps was separated, washed, and opened. Different polydopamine coating results were observed before and after the forceps site. Compared with the control section after the forceps site, the tissue immersed in the tissue-accelerated polymerization solution showed enhanced polydopamine coating density, confirming the significant tissue coating performance of in vivo tissue-accelerated polymerization.Next, the research organization accelerated the polymerization technology to see if it could achieve safe and extended intestinal retention. After 24 hours, polydopamine detached from the epithelium could be seen through endoscopy, indicating that the coating was transient. However, considering the inconvenience of the endoscopic procedure, the incompatibility of frequent sedation, and the uncertainty of the remaining solution in the endoscopic imaging field of view, a more ergonomic method was needed to monitor the intestinal retention of polydopamine. X-ray imaging is a convenient and effective tool commonly used for the examination of the digestive tract 19 . To apply X-ray imaging to this study, a conventional X-ray contrast agent modified by encapsulating radiopaque particles in polydopamine was used ( Figure 15 A). These polydopamine probes suspended in the tissue-accelerated polymerization solution were co-coated on the intestinal epithelium with polydopamine and introduced into the polydopamine coating layer, which could be achieved through chemical cross-linking between the reactive polydopamine on the probe surface and the dopamine monomers or oligomers in the tissue-accelerated polymerization solution ( Figure 3 E) 14 . This co-coating performance was first characterized by ex vivo studies ( Figure 15 B and 15C), where the coated polydopamine probes were easily visualized by X-ray imaging, and no signal attenuation was observed after rinsing the epithelial surface with water, indicating the stability of the polydopamine probe coating. In contrast, in the control experiments using separate conventional probes or polydopamine for coating, no obvious X-ray signal was detected. The polydopamine probes showed their potential use for in vivo imaging of the intestinal retention of the polydopamine coating layer. When a tissue-accelerated polymerization solution suspended with polydopamine probes was administered to healthy pigs, an enhanced X-ray signal was observed in the small intestine after the clinical procedure of a barium meal test ( Figure 16 A), revealing the shape of the intestine. However, when an equal concentration of conventional probes was administered to pigs, the resulting X-ray signal in the small intestine was relatively weak. It is also worth mentioning that after rinsing the imaging area, the signal of the conventional probes was hardly detectable, while the polydopamine probes were still clearly visible ( Figure 3 G), and the difference in signal intensity between the two types of probes was 8.9 times ( Figure 3 H), indicating the effective introduction of the polydopamine probes and the stable coating of polydopamine on the tissue. To monitor the intestinal retention of polydopamine over time, a series of X-ray images were taken regularly at the same location ( Figure 3 G and Figure 16 B). The animals consumed a liquid diet throughout the imaging period to simulate real conditions and test the stability of the polydopamine coating in the presence of food. Quantitative signal intensity analysis was performed on the small intestine and surrounding tissues ( Figure 3I). When a conventional probe is administered to pigs, after flushing and exposure to food for 2 - 24 hours, X-ray signals in the small intestine are difficult to detect due to relatively weak tissue adhesion, resulting in rapid probe elimination. However, when a polydopamine probe is administered for imaging, distinct X-ray signals are observed in the small intestine 2 hours after food exposure, with only a 28% decrease at the sixth hour, indicating extended intestinal retention of the polydopamine coating. The decline in the polydopamine signal may be due to the rapid regeneration of intestinal mucus secreted by goblet cells (about 12 - 24 hours) and the frequent renewal of epithelial cells through stem cell proliferation (about 1 - 5 days) 20 , where the polymer coating layer and the epithelium beneath the polydopamine slough off into the lumen. Notably, the intestinal X-ray signal returns to the pre-administration level 24 hours later, indicating complete elimination of the polydopamine coating layer and transient retention. Confirmation of this transient property of the polydopamine coating indicates the safety of the tissue acceleration polymerization technique.

[0300] Example 4

[0301] Tissue Acceleration Polymerization for Regulating Enzymatic Digestion

[0302] To demonstrate the broad utility of the tissue acceleration polymerization technique, the therapeutic value of this technique in regulating enzymatic digestion was evaluated( Figure 4 A). Polydopamine is highly reactive with many chemical groups (such as amines, phenols, and thiols), enabling easy introduction of functional agents into the polydopamine coating layer 14 . Therefore, digestive enzymes were introduced into the tissue acceleration polymerization system.

[0303] By introducing digestive enzymes into the polydopamine coating layer on the small intestinal epithelium, the tissue acceleration polymerization technique was used to improve digestion efficiency( Figure 4 B). According to recent research, approximately 70% of the world's population has intestinal lactase deficiency (referring to low levels or absence of lactase), resulting in lactose intolerance 21,22 . If exogenous β-galactosidase is coated on the intestinal epithelium using the tissue acceleration polymerization technique, it will enhance the digestion of lactose in the small intestine. The restored function of brush border enzymes (especially β-galactosidase) enables the treatment of digestive disorders and diseases, improving patient prognosis and quality of life 23,24 .

[0304] To demonstrate the ability of tissue-accelerated polymerization technology to enhance lactose digestion, a tissue-accelerated polymerization solution suspended with β-galactosidase was used to coat the small intestine of anesthetized pigs, and laparotomy was performed on the anesthetized pigs to provide access to the small intestine mucosa. Then, the β-galactosidase activity of the coated epithelium was evaluated after rinsing. The coating efficiency was confirmed by analyzing β-galactosidase activity with and without the reagents (β-galactosidase and tissue-accelerated polymerization solution). As Figure 4 shown in C, the quantitative comparison of β-galactosidase activity indicated that after adding tissue-accelerated polymerization-based β-galactosidase coating to the pig small intestine, the digestion efficiency increased by approximately 20-fold. In contrast, no enhancement of β-galactosidase activity was detected in the control group (without β-galactosidase, without tissue-accelerated polymerization solution, or without both), confirming that the increase in β-galactosidase activity was due to its pairing with tissue-accelerated polymerization technology. Additionally, when only the tissue-accelerated polymerization solution was applied, no decrease in digestive enzyme activity was observed compared to the uncoated tissue. This consistent baseline enzyme activity indicates that neither the coating chemistry (the cross-linking between polydopamine and epithelial biomolecules) nor the coated polydopamine itself inhibits the intrinsic digestive enzyme activity of the epithelium, suggesting that the permeability of the polydopamine coating in the small intestine allows molecular diffusion through. Tissue-accelerated polymerization technology opens up new avenues for enhancing digestion efficiency in the small intestine and promising mechanisms for treating digestive disorders and diseases.

[0305] Example 5

[0306] Tissue-Accelerated Polymerization for Regulating Nutrient Absorption

[0307] The therapeutic value of this technology in regulating nutrient absorption was also evaluated ( Figure 4 A). Polydopamine is highly reactive with many chemical groups (such as amines, phenols, and thiols), enabling the easy introduction of functional agents into the polydopamine coating layer 14 . Therefore, nutrient blockers were introduced into the tissue-accelerated polymerization system to create an impermeable barrier for regulating nutrient absorption.

[0308] Glucose absorption in the small intestine plays a role in regulating plasma glucose levels, which are often associated with metabolic disorders and systemic diseases (such as obesity, hyperinsulinemia, and diabetes) 25 . To prevent excessive glucose intake in patients with these diseases and disorders, treatments such as gastric bypass surgery, intestinal sleeve placement, surgical adhesives, and gastrointestinal electrical stimulation have been tested 3,7,26,27 . However, these procedures are invasive and target the entire gastrointestinal tract, imposing limitations on widespread adoption. Tissue-accelerated polymerization technology provides a non-invasive tissue-targeted method for regulating glucose absorption. The ability of tissue-accelerated polymerization technology to isolate nutrient exposure (especially glucose absorption) in the small intestine was demonstrated.

[0309] To provide a barrier against glucose uptake, the small intestinal epithelium was coated with an impermeable polydopamine coating layer using this technique ( Figure 4 D). A nano-crosslinker was added to the tissue-accelerated polymerization solution to produce a highly cross-linked polydopamine coating layer with ultra-low permeability. As Figure 17 shown in A-17B, the additional nano-crosslinker had a diameter of approximately 527 nm and a uniform size distribution. These hydrophilic nano-crosslinkers suspended in the tissue-accelerated polymerization solution were thus introduced into the polydopamine coating layer, which could be achieved by chemical cross-linking between the reactive catechol and amine groups exposed on the surface of the nano-crosslinker and dopamine monomers or oligomers in the tissue-accelerated polymerization solution. Therefore, the introduction of the crosslinker increased the number of covalent bonds inside the polydopamine coating, enabling the achievement of a highly dense polydopamine coating with low permeability. To verify the nutrient regulation function, the tissue-accelerated polymerization solution with suspended nano-crosslinkers was administered to pigs via endoscopy. After tissue-accelerated polymerization coating, oral glucose was administered to the pigs, and then a standard oral glucose tolerance test (OGTT) was performed. Blood glucose levels were monitored to quantify intestinal glucose absorption. As Figure 4 shown in E, the blood glucose levels of control pigs without tissue-accelerated polymerization coating increased significantly after oral glucose administration. However, the animals treated with the tissue-accelerated polymerization solution showed a reduced blood glucose response. Quantitative comparison of blood glucose levels from samples of pigs with and without tissue-accelerated polymerization coating showed that the glucose level in the tissue-accelerated polymerization coating was reduced by an average of 73.3% compared to the control, where six separate experiments were performed on six different pigs and analyzed. This reduction in glucose response demonstrated the ability of the tissue-accelerated polymerization technique to effectively block postprandial glucose uptake. Additionally, the tissue-accelerated polymerization barrier showed effective blocking ability against different nutrients, and the blocking efficiency was regulated by adjusting the cross-linking density of the tissue-accelerated polymerization coating layer ( Figure 32 A-32D). Furthermore, it was confirmed that the glucose absorption barrier was transient, and normal glucose absorption was restored after 24 hours ( Figure 33 ). These results addressed the clinical need for non-invasive blocking of glucose absorption in the small intestine and demonstrated the feasibility of the tissue-accelerated polymerization technique as a treatment method for type 2 diabetes patients.

[0310] Example 6

[0311] Tissue-Accelerated Polymerization for Drug Release Regulation

[0312] The therapeutic value of this technique in drug release regulation was also evaluated ( Figure 4 A). Polydopamine is highly reactive with many chemical groups (such as amines, phenols, and thiols), enabling the easy introduction of functional agents into the polydopamine coating layer 14Thus, introducing anthelmintics into tissue-accelerated polymerization systems to evaluate systems such as those for oral drug delivery demonstrated its ability to sustain the release of therapeutic agents in the small intestine.

[0313] The development of orally sustained-release drugs is limited by the rapid transit time of therapeutic agents in the gastrointestinal tract. Attempts have been made to prolong gastrointestinal retention of drugs, especially in the small intestine (i.e., an environment more compatible with sensitive drugs compared to the harsh acidity of the stomach), but with little success. 19,28 Praziquantel was selected as a model drug to test the ability of tissue-accelerated polymerization technology to prolong intestinal retention. Praziquantel is the only anthelmintic commonly used to treat schistosomiasis, a major neglected tropical disease caused by intestinal parasitic worms that affects over 200 million people worldwide. 29,30 Praziquantel, which has a half-life of 1 to 1.5 hours in humans, is recommended to be taken orally 3 times a day, with a 5-hour interval, which is a difficult-to-adhere-to regimen. There is an urgent need for alternative technologies that can prolong intestinal retention to reduce the frequency of drug administration.

[0314] As Figure 4 shown in F, praziquantel particles (powder) were coated on the small intestinal epithelium using tissue-accelerated polymerization technology, enabling it to prolong intestinal retention and sustain release. The praziquantel particles (powder) were encapsulated in polydopamine to introduce the drug into the polydopamine coating layer. Pharmacokinetic studies were conducted on praziquantel-tissue-accelerated polymerization solutions administered orally once in pigs to investigate the release kinetics of the praziquantel-tissue-accelerated polymerization solutions. After administration, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 24, and 48 hours, and their serum praziquantel concentrations were further analyzed by liquid chromatography-tandem mass spectrometry. As Figure 4 shown in G, the quantitative comparison of pharmacokinetics revealed an extended retention time of praziquantel with the tissue-accelerated polymerization solution relative to conventional administration. When praziquantel control (without tissue-accelerated polymerization solution) was administered conventionally, the drug was rapidly cleared from the blood with an elimination period of 2 - 6 hours, and no drug was detectable at or after 24 hours. However, the blood levels of praziquantel administered by tissue-accelerated polymerization technology persisted for more than 6 hours, and an average concentration of 20.0 ng / mL was still detectable at 24 hours, even higher than the average control drug concentration (15.1 ng / mL) at 6 hours. -1 The quantitative analysis of pharmacokinetic parameters (including area under the curve (AUC) and half-life) was performed using a non-compartmental pharmacokinetic model. The results of the 3 large animal studies showed that praziquantel (905.8 ng h / mL, with tissue-accelerated polymerization solution) and praziquantel control (222.4 ng h / mL) -1 ) -1 with tissue-accelerated polymerization solution) and praziquantel control (222.4 ng h / mL -1) The AUC value increased by 4-fold. Additionally, when administered using the tissue-accelerated polymerization technique, the half-life of praziquantel increased by 10-fold (from 1.3 hours to 13 hours), indicating an extended intestinal retention of the drug. Notably, praziquantel is mainly metabolized by cytochrome P450 enzymes (especially CYP3A4 present in the small intestine and liver). 30,38 . To confirm that the tissue-accelerated polymerization coating does not affect drug metabolism, the CYP3A4 activity of the epithelium with and without the polydopamine coating layer was measured and compared ( Figure 34 ), and no change in CYP3A4 activity was observed after the tissue-accelerated polymerization coating. The sustained release of praziquantel through the tissue-accelerated polymerization technique extends the effectiveness of treatment options for schistosomiasis and is also applicable to diseases where regimen compliance is important for efficacy.

[0315] Example 7

[0316] Ultra-fast and stable coating of human tissues using tissue-accelerated polymerization

[0317] The tissue-accelerated polymerization technique is applicable to human tissues and suitable for clinical translation. Freshly excised tissue specimens from the human small intestine were coated to test their compatibility with the tissue-accelerated polymerization technique. Similar to the porcine tissue coating results ( Figure 1 E), a polydopamine coating was clearly observed on the surface of the human small intestine ( Figure 5 A). However, compared to porcine tissues, the polydopamine signal was generated faster in human tissues, with the coating completion time reduced from 12 minutes to 3 minutes ( Figure 5 B), which may be due to a higher level of catalase in the human small intestine. The relationship between small intestine catalase activity and the tissue-accelerated polymerization coating density was analyzed using human, porcine, and murine tissue specimens, resulting in an obvious correlation between the tissue-accelerated polymerization coating density and the enzyme activity level ( Figure 18 A-18B). Compared to murine small intestine, human and porcine small intestines showed 60% more polydopamine production due to their strong enzyme activity. Similar tissue-accelerated polymerization efficiency (between humans and pigs) may be due to their genomic and proteomic similarities. To further demonstrate the robustness of the tissue-accelerated polymerization technique for human tissue coating, tissue specimens from 3 donors with polydopamine coating were tested. Additionally, five evaluations were performed on random sites of the small intestine (from donors of different ages, ethnicities, and genders) to confirm consistent polydopamine coating performance. Additionally, it was confirmed that the human and porcine GI tracts exhibited similar tissue-accelerated polymerization patterns ( Figure 35 A-35B), which is due to a higher expression of catalase in the small intestines of these two species compared to other segments of the GI tract 15 . As Figure 5As shown in C, 30 tissue images (6 mm in diameter) revealed highly consistent polydopamine coating and signal enhancement. These tissue specimens coated by tissue-accelerated polymerization technology were further examined with a microscope. Consistent with the porcine results ( Figure 2 G), microscopic and histological analysis of cryopreserved and formalin-fixed paraffin-embedded (FFPE) specimens showed a thin layer of polydopamine coating on the outer villi of the human small intestine ( Figure 5 D). After exposure to the tissue-accelerated polymerization solution, the epithelial layer remained intact (where the staining pattern was similar to that of the unexposed control), indicating the absence of tissue toxicity.

[0318] To further evaluate the biocompatibility of the tissue-accelerated polymerization technology, the cytotoxicity of polydopamine to various cell lines: HeLa, COLO320DM, Caco-2, Hep3B, and HS 895.T ( Figure 19 ) was characterized, and no significant cytotoxicity was observed after 6 - 48 hours of in vitro incubation. In addition, the oral toxicity of the tissue-accelerated polymerization solution was systematically evaluated by following the guidelines published by the OECD with slight modifications. Therefore, based on the repeated-dose 28-day toxicity study method recommended by Good Laboratory Practice (GLP), rats were exposed to the tissue-accelerated polymerization solution over a 4-week period. During the 28-day exposure period, no significant difference in body weight was observed between rats exposed to the tissue-accelerated polymerization solution and the control ( Figure 20 A-20C). Additional hematological measurements, blood biochemical tests ( Figure 21 and 22 ) and histopathological examinations further confirmed the absence of oral toxicity ( Figure 23 ), supporting the favorable biocompatibility of the tissue-accelerated polymerization technology and indicating minimized risks for upcoming preclinical and clinical trials.

[0319] The stability of human tissue coating is a factor in the clinical translation of the tissue-accelerated polymerization technology. The small intestine provides a dynamic environment where physical forces (peristalsis and segmentation) and chemical exposures (chyme, gastric acid, and intestinal fluid) have the potential to damage the polydopamine coating ( Figure 36 A-36C). The stability of tissue coating was evaluated under a series of physical and chemical conditions. As Figure 5 shown in E, no decrease in polydopamine signal was observed under mechanical stirring and scratching. Quantitative signal intensity analysis showed that even after vigorously scratching the small intestine with the back of a scalpel, approximately 80% of the polydopamine still remained strongly attached ( Figure 5 F). In addition, the stability of the polydopamine coating was further confirmed by incubating the polydopamine-coated human tissue in different solutions for 24 hours. As Figure 5As shown by G, the polydopamine coating layer is highly stable under simulated intestinal fluid, gastric fluid, and other extreme conditions (ethanol and concentrated brine). These results confirm the coating stability of the tissue-accelerated polymerization technique in the human small intestine and demonstrate the feasibility of broad applicability.

[0320] This application also relates to the following embodiments:

[0321] 1. A method for in situ forming a polymer in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject and the catalyst polymerizes the monomer, wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

[0322] 2. The method according to any of the preceding embodiments, wherein the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

[0323] 3. The method according to any of the preceding embodiments, wherein the endogenous catalyst is catalase.

[0324] 4. The method according to any of the preceding embodiments, wherein the catalase is bacterial catalase.

[0325] 5. The method according to any of the preceding embodiments, wherein the endogenous catalyst is located in the gastrointestinal (GI) tract of the subject.

[0326] 6. The method according to any of the preceding embodiments, wherein the endogenous catalyst is located in the upper GI tract of the subject.

[0327] 7. The method according to any of the preceding embodiments, wherein the endogenous catalyst is located in the stomach of the subject.

[0328] 8. The method according to any of the preceding embodiments, wherein the composition further comprises an enzyme, a nutrient blocker, a nutritional preparation, a radiation protectant, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

[0329] 9. The method according to any of the preceding embodiments, wherein the composition is administered orally.

[0330] 10. The method according to any of the preceding embodiments, wherein at least one of the monomer and the oxygen source is stable in the stomach of the subject.

[0331] 11. The method according to any one of the foregoing embodiments, wherein at least one of the monomer and the oxygen source is stable in the stomach of the subject for at least 30 minutes.

[0332] 12. The method according to any one of the foregoing embodiments, wherein at least one of the monomer and the oxygen source is stable in the stomach of the subject for at least 60 minutes.

[0333] 13. The method according to any one of the foregoing embodiments, wherein at least one of the monomer and the oxygen source is stable because it does not decompose in the stomach of the subject.

[0334] 14. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 0.001 to about 1000 mg / mL of dopamine.

[0335] 15. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 0.01 to about 100 mg / mL of dopamine.

[0336] 16. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 0.01 to about 50 mg / mL of dopamine.

[0337] 17. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 1 to about 20 mg / mL of dopamine.

[0338] 18. The method according to any one of the foregoing embodiments, wherein the composition comprises about 10 mg / mL of dopamine.

[0339] 19. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 0.01 to about 100 mM of the oxygen source.

[0340] 20. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 0.1 to about 50 mM of the oxygen source.

[0341] 21. The method according to any one of the foregoing embodiments, wherein the composition comprises from about 1 to about 30 mM of the oxygen source.

[0342] 22. The method according to any one of the foregoing embodiments, wherein the composition comprises about 20 mM of the oxygen source.

[0343] 23. The method according to any one of the foregoing embodiments, wherein the composition has a pH of from about 7 to about 10.

[0344] 24. The method according to any one of the foregoing embodiments, wherein the composition has a pH of from about 7 to about 9.

[0345] 25. The method according to any one of the foregoing embodiments, wherein the composition has a pH of about 8.5.

[0346] 26. The method according to any one of the foregoing embodiments, wherein the composition has a pH of about 7.4.

[0347] 27. The method according to any one of the foregoing embodiments, wherein the composition is in a liquid or solid dosage form.

[0348] 28. The method according to any one of the foregoing embodiments, wherein the composition is in the form of a solution, gel, tablet, or capsule.

[0349] 29. The method according to any one of the foregoing embodiments, wherein the polymer is formed upon contact with the epithelium of the subject.

[0350] 30. The method according to any one of the foregoing embodiments, wherein the polymer adheres to the tissue of the subject.

[0351] 31. The method according to embodiment 30, wherein the tissue is epithelium.

[0352] 32. The method according to embodiment 31, wherein the epithelium is intestinal epithelium.

[0353] 33. The method according to any one of the foregoing embodiments, wherein the polymer binds to amine moieties exposed on the luminal surface of the epithelium of the subject.

[0354] 34. The method according to any one of the foregoing embodiments, wherein the polymer is formed in less than about 20 minutes.

[0355] 35. The method according to any one of the foregoing embodiments, wherein the polymer is not formed on the gastrointestinal epithelium outside the small intestine of the subject.

[0356] 36. The method according to any one of the foregoing embodiments, wherein the polymer is formed on the epithelium of one or more of the duodenum, jejunum, ileum, colon, esophagus, or stomach of the subject.

[0357] 37. The method according to any one of the foregoing embodiments, wherein the polymer is formed on the epithelium of the duodenum of the subject.

[0358] 38. The method according to any one of the foregoing embodiments, wherein the polymer is substantially not formed on the epithelium of one or more of the esophagus or stomach of the subject.

[0359] 39. The method according to any one of the foregoing embodiments, wherein less polymer is formed on the ileum and colon of the subject compared to the duodenum and jejunum of the subject.

[0360] 40. The method according to any one of the foregoing embodiments, wherein substantially no polymer is formed on the stomach and esophagus of the subject.

[0361] 41. The method according to any one of the foregoing embodiments, wherein the polymer is not formed on the stomach and esophagus of the subject.

[0362] 42. The method according to any one of the foregoing embodiments, wherein the polymer forms a temporary barrier in vivo.

[0363] 43. The method according to any one of the foregoing embodiments, wherein about 20% to about 70% of the transient barrier remains after 6 hours.

[0364] 44. The method according to any one of the foregoing embodiments, wherein the polymer is cleared from the subject after about 24 hours.

[0365] 45. The method according to any one of the foregoing embodiments, wherein the polymer and the composition further comprise an enzyme.

[0366] 46. The method according to any one of the foregoing embodiments, wherein the enzyme is a digestive enzyme.

[0367] 47. The method according to any one of the foregoing embodiments, wherein the digestive enzyme is lactase, peptidase, sucrase, maltase, amylase, lipase, or protease.

[0368] 48. The method according to any one of the foregoing embodiments, wherein the method is a method of improving the digestion efficiency of the subject.

[0369] 49. The method according to any one of the foregoing embodiments, wherein the method is a method of enhancing the digestion of lactose by the subject.

[0370] 50. The method according to any one of the foregoing embodiments, wherein the method is a method of treating lactose intolerance in the subject.

[0371] 51. The method according to any one of the foregoing embodiments, wherein the digestive enzyme is β-galactosidase.

[0372] 52. The method according to any one of the foregoing embodiments, wherein the β-galactosidase increases the digestion efficiency of lactose in the subject by about 20-fold.

[0373] 53. The method according to any one of the foregoing embodiments, wherein the polymeric barrier does not inhibit the activity of the native digestive enzymes of the epithelium of the subject.

[0374] 54. The method according to any one of the foregoing embodiments, wherein the polymer and the composition further comprise a nutrient blocker.

[0375] 55. The method according to any one of the foregoing embodiments, wherein the method is a method for preventing nutrient absorption in the subject.

[0376] 56. The method according to any one of the foregoing embodiments, wherein the method is a method for regulating or controlling glucose absorption in the subject.

[0377] 57. The method according to any one of the foregoing embodiments, wherein the method is a method for regulating or controlling sugar absorption in the subject.

[0378] 58. The method according to embodiment 57, wherein the sugar is selected from glucose, lactose, fructose, maltose, dextrose, galactose, sucrose, and isomaltose.

[0379] 59. The method according to any one of the foregoing embodiments, wherein the method prevents absorption for less than about 24 hours.

[0380] 60. The method according to any one of the foregoing embodiments, wherein the method prevents absorption for less than about 6 hours.

[0381] 61. The method according to any one of the foregoing embodiments, wherein the method is a method for treating obesity in the subject.

[0382] 62. The method according to any one of the foregoing embodiments, wherein the method is a method for treating hyperinsulinemia in the subject.

[0383] 63. The method according to any one of the foregoing embodiments, wherein the method is a method for treating diabetes in the subject.

[0384] 64. The method according to any one of the foregoing embodiments, wherein the diabetes is type 2 diabetes.

[0385] 65. The method according to any one of the foregoing embodiments, wherein the composition further comprises a crosslinking agent.

[0386] 66. The method according to any one of the foregoing embodiments, wherein the crosslinking agent comprises nanoparticles.

[0387] 67. The method according to any one of the foregoing embodiments, wherein the crosslinking agent comprises polydopamine.

[0388] 68. The method according to any one of the foregoing embodiments, wherein the crosslinking agent is a nutrient blocker.

[0389] 69. The method according to any one of the foregoing embodiments, wherein the crosslinking agent enhances the nutrient blocking ability of the polymer.

[0390] 70. The method according to any one of the foregoing embodiments, wherein the absorption is adjusted by modulating the crosslink density of the polymer.

[0391] 71. The method according to any one of the foregoing embodiments, wherein the method reduces the glucose absorption of the subject by at least about 50%, at least about 60%, or at least about 70% within a period of 3 hours after administration of the composition.

[0392] 72. The method according to any one of the foregoing embodiments, wherein the method reduces the glucose absorption of the subject by at least about 50%, at least about 60%, or at least about 70% within a period of 2 hours after administration of the composition.

[0393] 73. The method according to any one of the foregoing embodiments, wherein the method reduces the glucose absorption of the subject by at least about 50%, at least about 60%, or at least about 70% within a period of 1 hour after administration of the composition.

[0394] 74. The method according to any one of the foregoing embodiments, wherein the composition further comprises an active pharmaceutical ingredient.

[0395] 75. The method according to any one of the foregoing embodiments, wherein the active pharmaceutical ingredient is retained or encapsulated in the polymer.

[0396] 76. The method according to any one of the foregoing embodiments, wherein the method is a method of prolonging the residence time of the active pharmaceutical ingredient at the polymerization site in the subject as compared to administering the active pharmaceutical ingredient in the absence of the polymer.

[0397] 77. The method according to any one of the foregoing embodiments, wherein the method is a method of providing sustained release of the active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer.

[0398] 78. A method according to any one of the foregoing embodiments, wherein the method is a method of reducing the dosing frequency of an active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer.

[0399] 79. A method according to any one of the foregoing embodiments, wherein the method is a method of increasing the half-life of the active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer.

[0400] 80. A method according to any one of the foregoing embodiments, wherein the method is a method of increasing the AUC of the active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer.

[0401] 81. A method according to any one of the foregoing embodiments, wherein the method is a method of modulating the C of the active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer. max of the active pharmaceutical ingredient.

[0402] 82. A method according to any one of the foregoing embodiments, wherein the method is a method of modulating the T of the active pharmaceutical ingredient as compared to administering the active pharmaceutical ingredient in the absence of the polymer. max of the active pharmaceutical ingredient.

[0403] 83. A method according to any one of embodiments 81 - 82, wherein the modulation is an increase.

[0404] 84. A method according to any one of embodiments 81 - 82, wherein the modulation is a decrease.

[0405] 85. A method according to any one of the foregoing embodiments, wherein the method does not affect drug metabolism.

[0406] 86. A method according to any one of the foregoing embodiments, wherein the active pharmaceutical ingredient is an antiparasitic drug.

[0407] 87. A method according to any one of the foregoing embodiments, wherein the active pharmaceutical ingredient is an anthelmintic drug.

[0408] 88. A method according to any one of the foregoing embodiments, wherein the active pharmaceutical ingredient is praziquantel.

[0409] 89. A method according to any one of the foregoing embodiments, wherein the method is a method of treating schistosomiasis in the subject.

[0410] 90. A method according to any one of the foregoing embodiments, wherein the composition further comprises a radioprotectant.

[0411] 91. The method according to any one of the foregoing embodiments, wherein the method is for targeting the small intestine.

[0412] 92. The method according to any one of the foregoing embodiments, wherein the method is a method of reducing small intestine uptake.

[0413] 93. The method according to any one of the foregoing embodiments, wherein the method is a method of reducing the uptake of one or more nutrients and active pharmaceutical ingredients by the small intestine.

[0414] 94. The method according to any one of the foregoing embodiments, wherein the method is a method of increasing the residence time in the small intestine.

[0415] 95. The method according to any one of the foregoing embodiments, wherein the method is a method of increasing the residence time of one or more nutrients and / or active pharmaceutical ingredients in the small intestine.

[0416] 96. The method according to any one of the foregoing embodiments, wherein the method keeps the intestinal lumen dilated.

[0417] 97. The method according to any one of the foregoing embodiments, wherein the method is a method of treating or preventing intestinal adhesions in the subject.

[0418] 98. The method according to any one of the foregoing embodiments, wherein the method is a method of treating or preventing intestinal obstruction in the subject.

[0419] 99. The method according to any one of the foregoing embodiments, wherein the method is a method of treating small intestine bleeding in the subject.

[0420] 100. The method according to any one of the foregoing embodiments, wherein the polymer regulates absorption in the small intestine.

[0421] 101. The method according to any one of the foregoing embodiments, wherein the polymer regulates digestion in the small intestine.

[0422] 102. The method according to any one of the foregoing embodiments, wherein the polymer regulates the absorption of one or more nutrients or active pharmaceutical ingredients or combinations thereof in the small intestine.

[0423] 103. The method according to any one of the foregoing embodiments, wherein the polymer substantially impedes the absorption of one or more nutrients or active pharmaceutical ingredients or combinations thereof into the epithelium on which the polymer is formed.

[0424] 104. A method according to any one of the foregoing embodiments, wherein the polymer substantially impedes the absorption of one or more nutrients, active pharmaceutical ingredients, or combinations thereof into the bloodstream of the subject.

[0425] 105. A method according to any one of the foregoing embodiments, wherein the method is a method of immobilizing an enzyme in the subject.

[0426] 106. A method according to any one of the foregoing embodiments, wherein the method is a method of delivering an active pharmaceutical ingredient to the subject.

[0427] 107. A method according to any one of the foregoing embodiments, wherein the method is a method of supplementing digestion in a subject.

[0428] 108. A method according to any one of the foregoing embodiments, wherein the polymer is non-toxic.

[0429] 109. A method according to any one of the foregoing embodiments, wherein the polymer is stable to physical and chemical forces.

[0430] 110. A method according to any one of the foregoing embodiments, wherein the polymer is stable to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, and saline.

[0431] 111. A method according to any one of the foregoing embodiments, wherein the polymer decomposes less than about 10% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline.

[0432] 112. The method according to embodiment 109, wherein the physical force is selected from one or more of peristalsis and segmentation.

[0433] 113. A composition comprising dopamine, an oxygen source, and optionally a buffer.

[0434] 114. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.001 to about 1000 mg / mL of dopamine, from about 0.01 to about 100 mM of the oxygen source, and optionally a buffer.

[0435] 115. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.001 to about 1000 mg / mL of dopamine.

[0436] 116. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.001 to about 500 mg / mL of dopamine.

[0437] 117. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.01 to about 100 mg / mL of dopamine.

[0438] 118. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 1 to about 20 mg / mL of dopamine.

[0439] 119. A composition according to any one of the foregoing embodiments, wherein the composition comprises about 10 mg / mL of dopamine.

[0440] 120. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.01 to about 100 mM of the oxygen source.

[0441] 121. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 0.1 to about 50 mM of the oxygen source.

[0442] 122. A composition according to any one of the foregoing embodiments, wherein the composition comprises from about 1 to about 30 mM of the oxygen source.

[0443] 123. A composition according to any one of the foregoing embodiments, wherein the composition comprises about 20 mM of the oxygen source.

[0444] 124. A composition according to any one of the foregoing embodiments, wherein the composition comprises an oxygen source at a concentration compatible with uptake by the subject.

[0445] 125. A composition according to any one of the foregoing embodiments, wherein the composition has a pH of from about 7 to about 9.

[0446] 126. A composition according to any one of the foregoing embodiments, wherein the composition comprises about 10 mg / mL of dopamine, about 20 mM of hydrogen peroxide or urea hydrogen peroxide, and optionally a buffer.

[0447] 127. A composition according to any one of the foregoing embodiments, wherein the buffer comprises phosphate, acetate, citrate, N-[tris(hydroxymethyl)methyl]glycine), (tris(hydroxymethyl)aminomethane), or (2-(bis(2-hydroxyethyl)amino)acetic acid).

[0448] 128. A composition according to any one of the foregoing embodiments, wherein the buffer comprises tris(hydroxymethyl)aminomethane.

[0449] 129. The composition according to any one of the foregoing embodiments, wherein the composition further comprises a digestive enzyme, a nutrient blocker, a nutritional preparation, a radiation protectant, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

[0450] 130. The composition according to any one of the foregoing embodiments, wherein the composition is in a liquid or solid dosage form.

[0451] 131. The composition according to any one of the foregoing embodiments, wherein the composition is in the form of a solution, a gel, a tablet, or a capsule.

[0452] 132. A method of treating a disease or disorder, comprising administering to a subject in need thereof an effective amount of the composition according to any one of the foregoing embodiments.

[0453] 133. A method of preventing a disease or disorder, comprising administering to a subject in need thereof an effective amount of the composition according to any one of the foregoing embodiments.

[0454] 134. The method according to any one of the foregoing embodiments, wherein the disease or disorder is a metabolic disorder, a systemic disease, a digestive disorder, an infectious disease, cancer, bleeding, ulcer, intestinal obstruction, mesenteric ischemia, obesity, a mental disorder, Alzheimer's disease, or transplant rejection.

[0455] 135. The method according to any one of the foregoing embodiments, wherein the metabolic disorder is hyperinsulinemia.

[0456] 136. The method according to any one of the foregoing embodiments, wherein the digestive disease is Crohn's disease, ulcerative colitis, malabsorption, inflammatory bowel disease, irritable bowel syndrome, lactose intolerance, or celiac disease.

[0457] 137. The method according to any one of the foregoing embodiments, wherein the systemic disease is mastocytosis, chronic fatigue syndrome, systemic vasculitis, sarcoidosis, hypothyroidism, diabetes, fibromyalgia, adrenal insufficiency, celiac disease, ulcerative colitis, Crohn's disease, hypertension, metabolic syndrome, AIDS, Graves' disease, systemic lupus erythematosus, arthritis, atherosclerosis, sickle cell disease, myasthenia gravis, systemic sclerosis, an inflammatory disease, an autoimmune disease, or sinusitis.

[0458] 138. The method according to any one of the foregoing embodiments, wherein the disease is obesity, hyperinsulinemia, or diabetes.

[0459] 139. The method according to any one of the foregoing embodiments, wherein the disease is an infectious disease.

[0460] 140. A method according to any one of the foregoing embodiments, wherein the disease is a bacterial, viral, fungal, or parasitic infection.

[0461] 141. A method according to any one of the foregoing embodiments, wherein the disease is a parasitic disease.

[0462] 142. A method according to any one of the foregoing embodiments, wherein the disease is giardiasis, ascariasis, or tapeworm infection.

[0463] 143. A method according to any one of the foregoing embodiments, wherein the disease is schistosomiasis.

[0464] 144. A method according to any one of the foregoing embodiments, wherein the disease is lactose intolerance.

[0465] 145. A method according to any one of the foregoing embodiments, wherein the disease is intestinal obstruction.

[0466] 146. Use of a composition for forming a polymer in vivo, which comprises administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject in vivo and the catalyst causes in situ polymerization of the monomer, and wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

[0467] 147. Use of an effective amount of a composition according to any one of the foregoing embodiments for treating a disease or disorder in a subject in need thereof.

[0468] 148. Use of an effective amount of a composition according to any one of the foregoing embodiments for preventing a disease or disorder in a subject in need thereof.

[0469] 149. A kit comprising:

[0470] a composition according to any one of the foregoing embodiments, and

[0471] instructions for administering to a subject a composition according to any one of the foregoing embodiments.

[0472] 150. A kit according to any one of the foregoing embodiments, wherein the composition comprises:

[0473] dopamine;

[0474] hydrogen peroxide or urea hydrogen peroxide;

[0475] a buffer; and

[0476] Optionally, an enzyme, a nutrient blocker, a nutritional preparation, a radiation protector, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

[0477] 151. The kit according to any one of the foregoing embodiments, wherein the buffer is tris(hydroxymethyl)aminomethane.

[0478] 152. The kit according to any one of the foregoing embodiments, wherein the composition is in the form of a capsule.

[0479] 153. The kit according to any one of the foregoing embodiments, wherein the kit further comprises an endoscope, an arthroscope, a cystoscope, a colposcope, a colonoscope, a bronchoscope, a ureteroscope, an anoscope, an esophagoscope, a gastroscope, a laparoscope, a laryngoscope, a neuroendoscope, a proctoscope, a sigmoidoscope, or a thoracoscope.

[0480] 154. A method, a composition, or a kit, wherein the composition is administered via an endoscope, an arthroscope, a cystoscope, a colposcope, a colonoscope, a bronchoscope, a ureteroscope, an anoscope, an esophagoscope, a gastroscope, a laparoscope, a laryngoscope, a neuroendoscope, a proctoscope, a sigmoidoscope, or a thoracoscope.

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Claims

1. A method for in situ forming a polymer in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source contact an endogenous catalyst in the subject and the catalyst polymerizes the monomer, wherein the monomer is dopamine or a salt thereof, the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase.

2. The method according to any one of the preceding claims, wherein the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

3. The method according to any one of the preceding claims, wherein the endogenous catalyst is catalase.

4. The method according to any one of the preceding claims, wherein the catalase is bacterial catalase.

5. The method according to any one of the preceding claims, wherein the endogenous catalyst is located in the gastrointestinal (GI) tract of the subject.

6. The method according to any one of the preceding claims, wherein the endogenous catalyst is located in the upper GI tract of the subject.

7. The method according to any one of the preceding claims, wherein the endogenous catalyst is located in the stomach of the subject.

8. The method according to any one of the preceding claims, wherein the composition further comprises an enzyme, a nutrient blocker, a nutritional preparation, a radiation protectant, an active pharmaceutical ingredient, a diagnostic agent, or a combination thereof.

9. The method according to any one of the preceding claims, wherein the composition is administered orally.

10. The method according to any one of the preceding claims, wherein at least one of the monomer and the oxygen source is stable in the stomach of the subject.

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