Recent developments in ureteral stent: Substrate material, coating polymer and technology, therapeutic function.

The ureteral stent is an effective treatment for clinical ureteral stricture following urological surgery, and the functional coating of the stent could effectively inhibit bacterial colonization and other complications. The present review provides an analysis and description of the materials used in ureteral stents and their coatings. Emphasis is placed on the technological advancements of functional coatings, taking into consideration the characteristics of these materials and the properties of their active substances. Furthermore, recent advances in enhancing the therapeutic efficacy of functional coatings are also reviewed. It is anticipated that this article will serve as a valuable reference providing insights for future research development on new drug-loaded ureteral stents.

The Cby3/ciBAR1 complex positions the annulus along the sperm flagellum during spermiogenesis.

Proper compartmentalization of the sperm flagellum is essential for fertility. The annulus is a septin-based ring that demarcates the midpiece (MP) and the principal piece (PP). It is assembled at the flagellar base, migrates caudally, and halts upon arriving at the PP. However, the mechanisms governing annulus positioning remain unknown. We report that a Chibby3 (Cby3)/Cby1-interacting BAR domain-containing 1 (ciBAR1) complex is required for this process. Ablation of either gene in mice results in male fertility defects, caused by kinked sperm flagella with the annulus mispositioned in the PP. Cby3 and ciBAR1 interact and colocalize to the annulus near the curved membrane invagination at the flagellar pocket. In the absence of Cby3, periannular membranes appear to be deformed, allowing the annulus to migrate over the fibrous sheath into the PP. Collectively, our results suggest that the Cby3/ciBAR1 complex regulates local membrane properties to position the annulus at the MP/PP junction.

Dielectric and Magnetic Composites of Fe3O4@APNs for Superior Microwave Thermal Effect.

As for the deep tissue infections of chronic osteomyelitis, antibiotics are hard to deliver into the infected bone tissue, which makes it difficult to be cured completely in clinic. Microwave has strong penetration, and the medium can produce a good bactericidal effect through the microwave thermal effect (MTE). Here, a new microwave sensitizer (Fe3O4@APNs) was prepared and evaluated. Black phosphorus nanosheets modified with phytic acid dodecasodium (APNs) were fabricated by a liquid-phase exfoliation method that exhibited good water oxygen stability. A complex with Fe3O4 compound and APNs (Fe3O4@APNs) was formed by an ultrasonic mixing process, which showed excellent MTE (quickly increased to 53.5 °C in 5 min at 2.45 GHz, 10 W/cm2) via dielectric versus magnetic loss (reflect loss value of -5.94 dB at 2.45 GHz). The Fe3O4@APNs microwave sensitizer developed in this study has an outstanding in vitro antibacterial effect and might show promise for the treatment of chronic osteomyelitis enabled by local tissue heating via the MTE.

Essential Roles of Efferent Duct Multicilia in Male Fertility.

Cilia are microtubule-based hair-like organelles on the cell surface. Cilia have been implicated in various biological processes ranging from mechanosensation to fluid movement. Ciliary dysfunction leads to a plethora of human diseases, known as ciliopathies. Although non-motile primary cilia are ubiquitous, motile multicilia are found in restricted locations of the body, such as the respiratory tract, the oviduct, the efferent duct, and the brain ventricles. Multicilia beat in a whip-like motion to generate fluid flow over the apical surface of an epithelium. The concerted ciliary motion provides the driving force critical for clearing airway mucus and debris, transporting ova from the ovary to the uterus, maintaining sperm in suspension, and circulating cerebrospinal fluid in the brain. In the male reproductive tract, multiciliated cells (MCCs) were first described in the mid-1800s, but their importance in male fertility remained elusive until recently. MCCs exist in the efferent ducts, which are small, highly convoluted tubules that connect the testis to the epididymis and play an essential role in male fertility. In this review, we will introduce multiciliogenesis, discuss mouse models of male infertility with defective multicilia, and summarize our current knowledge on the biological function of multicilia in the male reproductive tract.

Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis.

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.

CEP164 is essential for efferent duct multiciliogenesis and male fertility.

Cilia are evolutionarily conserved microtubule-based structures that perform diverse biological functions. Cilia are assembled on basal bodies and anchored to the plasma membrane via distal appendages. In the male reproductive tract, multicilia in efferent ducts (EDs) move in a whip-like motion to prevent sperm agglutination. Previously, we demonstrated that the distal appendage protein CEP164 recruits Chibby1 (Cby1) to basal bodies to facilitate basal body docking and ciliogenesis. Mice lacking CEP164 in multiciliated cells (MCCs) (FoxJ1-Cre;CEP164fl/fl) show a significant loss of multicilia in the trachea, oviduct, and ependyma. In addition, we observed male sterility; however, the precise role of CEP164 in male fertility remained unknown. Here, we report that the seminiferous tubules and rete testis of FoxJ1-Cre;CEP164fl/fl mice exhibit substantial dilation, indicative of dysfunctional multicilia in the EDs. We found that multicilia were hardly detectable in the EDs of FoxJ1-Cre;CEP164fl/fl mice although FoxJ1-positive immature cells were present. Sperm aggregation and agglutination were commonly noticeable in the lumen of the seminiferous tubules and EDs of FoxJ1-Cre;CEP164fl/fl mice. In FoxJ1-Cre;CEP164fl/fl mice, the apical localization of Cby1 and the transition zone marker NPHP1 was severely diminished, suggesting basal body docking defects. TEM analysis of EDs further confirmed basal body accumulation in the cytoplasm of MCCs. Collectively, we conclude that male infertility in FoxJ1-Cre;CEP164fl/fl mice is caused by sperm agglutination and obstruction of EDs due to loss of multicilia. Our study, therefore, unravels an essential role of the distal appendage protein CEP164 in male fertility.

Chibby is a weak regulator of ß-catenin activity in gastric epithelium.

The canonical Wnt-ß-catenin pathway is important in normal development. Mutations in ß-catenin or proteins involved with regulating its phosphorylation or localization result in its nuclear accumulation where it activates its target genes and stimulates cell proliferation. This pathway is dysregulated in many different types of cancer, including gastric cancer (GC). Chibby (Cby) is a 14-kDa protein that inhibits ß-catenin localization to the nucleus and represses ß-catenin-induced transcriptional activity. In the current study, we examined the expression and function of Cby in normal and cancerous human gastric tissue. Reverse-transcription polymerase chain reaction and immunohistochemistry revealed that Cby is expressed in human stomach and localized to glandular elements. Immunohistochemical staining intensity of Cby was decreased in GC tissue when compared with normal gastric epithelium. In AGS cells, a human gastric carcinoma cell line, Cby expression was low. Stable AGS cell transfectants overexpressing Cby were prepared. Cby overexpression did not affect proliferation rates or ß-catenin levels. However, confocal microscopy and subcellular fractionation studies revealed that Cby overexpression resulted in a small decrease in nuclear ß-catenin. Moreover, Cby overexpression caused a molecular weight shift in nuclear ß-catenin and resulted in decreased ß-catenin signaling in AGS cells as measured by the TopFlash assay. However, Cby overexpression did not affect c-Myc protein levels. To conclude, Cby expression was decreased in GC samples and Cby expression altered ß-catenin localization in cultured GC cells. However, Cby did not affect cell proliferation rates or ß-catenin-induced protein expression. Cby may be involved in the early events in the pathogenesis of GC.

Conditional knockout mice for the distal appendage protein CEP164 reveal its essential roles in airway multiciliated cell differentiation.

Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown. In this study, we have generated a novel conditional mouse model that lacks CEP164 in multiciliated tissues and the testis. These mice show a profound loss of airway, ependymal, and oviduct multicilia and develop hydrocephalus and male infertility. Using primary cultures of tracheal multiciliated cells as a model system, we found that CEP164 is critical for multiciliogenesis, at least in part, via its regulation of small vesicle recruitment, ciliary vesicle formation, and basal body docking. In addition, CEP164 is necessary for the proper recruitment of another distal appendage/transition fiber protein Chibby1 (Cby1) and its binding partners FAM92A and FAM92B to the ciliary base in multiciliated cells. In contrast to primary ciliogenesis, CEP164 is dispensable for the recruitment of intraflagellar transport (IFT) components to multicilia. Finally, we provide evidence that CEP164 differentially controls the ciliary targeting of membrane-associated proteins, including the small GTPases Rab8, Rab11, and Arl13b, in multiciliated cells. Altogether, our studies unravel unique requirements for CEP164 in primary versus multiciliogenesis and suggest that CEP164 modulates the selective transport of membrane vesicles and their cargoes into the ciliary compartment in multiciliated cells. Furthermore, our mouse model provides a useful tool to gain physiological insight into diseases associated with defective multicilia.

Chibby1 knockdown promotes mesenchymal-to-epithelial transition-like changes.

Chibby1 (Cby1) was originally isolated as a binding partner for ß-catenin, a dual function protein in cell-cell adhesion and in canonical Wnt signaling. The canonical Wnt/ß-catenin pathway is dysregulated in various diseases including cancer, most notably of the gastrointestinal origin. To investigate the role of Cby1 in colorectal tumorigenesis, we generated stable Cby1-knockdown (KD) SW480 colon cancer cells. Unexpectedly, we found that Cby1 KD induces mesenchymal-to-epithelial transition (MET)-like changes in SW480 as well as in HEK293 cells. Cby1-KD cells displayed a cuboidal epithelial morphology with tight cell-cell contacts. In Cby1-KD cells, the plasma membrane localization of E-cadherin and ß-catenin was dramatically increased with formation of cortical actin rings, while the levels of the mesenchymal marker vimentin were decreased. Consistent with these changes, in wound healing assays, Cby1-KD cells exhibited epithelial cell-like properties as they migrated collectively as epithelial sheets. Furthermore, the anchorage-independent growth of Cby1-KD cells was reduced as determined by soft agar assays. These findings suggest that chronic Cby1 KD in colon cancer cells may counteract tumor progression by promoting the MET process.

BAR Domain-Containing FAM92 Proteins Interact with Chibby1 To Facilitate Ciliogenesis.

Chibby1 (Cby1) is a small, conserved coiled-coil protein that localizes to centrioles/basal bodies and plays a crucial role in the formation and function of cilia. During early stages of ciliogenesis, Cby1 is required for the efficient recruitment of small vesicles at the distal end of centrioles to facilitate basal body docking to the plasma membrane. Here, we identified family with sequence similarity 92, member A (FAM92A) and FAM92B, which harbor predicted lipid-binding BAR domains, as novel Cby1-interacting partners using tandem affinity purification and mass spectrometry. We found that in cultured cell lines, FAM92A colocalizes with Cby1 at the centrioles/basal bodies of primary cilia, while FAM92B is undetectable. In airway multiciliated cells, both FAM92A and -92B colocalize with Cby1 at the base of cilia. Notably, the centriolar localization of FAM92A and -92B depends largely on Cby1. Knockdown of FAM92A in RPE1 cells impairs ciliogenesis. Consistent with the membrane-remodeling properties of BAR domains, FAM92A and -92B in cooperation with Cby1 induce deformed membrane-like structures containing the small GTPase Rab8 in cultured cells. Our results therefore suggest that FAM92 proteins interact with Cby1 to promote ciliogenesis via regulation of membrane-remodeling processes.

Chibby functions to preserve normal ciliary morphology through the regulation of intraflagellar transport in airway ciliated cells.

Airway cilia provide the coordinated motive force for mucociliary transport, which prevents the accumulation of mucus, debris, pollutants, and bacteria in our respiratory tracts. As airway cilia are constantly exposed to the environment and, hence, are an integral component of the pathogenesis of several congenital and chronic pulmonary disorders, it is necessary to understand the molecular mechanisms that control ciliated cell differentiation and ciliogenesis. We have previously reported that loss of the basal body protein Chibby (Cby) results in chronic upper airway infection in mice due to a significant reduction in the number of airway cilia. In the present work, we demonstrate that Cby is required for normal ciliary structure and proper distribution of proteins involved in the bidirectional intraflagellar transport (IFT) system, which consists of 2 distinct sub-complexes, IFT-A and IFT-B, and is essential for ciliary biogenesis and maintenance. In fully differentiated ciliated cells, abnormal paddle-like cilia with dilated ciliary tips are observed in Cby-/- airways and primary cultures of mouse tracheal epithelial cells (MTECs). In addition, IFT88, an IFT-B sub-complex protein, robustly accumulates within the dilated tips of both multicilia in Cby-/- MTECs and primary cilia in Cby-/- mouse embryonic fibroblasts (MEFs). Furthermore, we show that only IFT-B components, including IFT20 and IFT57, but not IFT-A and Bardet-Biedl syndrome (BBS) proteins, amass with IFT88 in these distended tips in Cby-/- ciliated cells. Taken together, our findings suggest that Cby plays a role in the proper distribution of IFT particles to preserve normal ciliary morphology in airway ciliated cells.

Chibby promotes ciliary vesicle formation and basal body docking during airway cell differentiation.

Airway multiciliated epithelial cells play crucial roles in the mucosal defense system, but their differentiation process remains poorly understood. Mice lacking the basal body component Chibby (Cby) exhibit impaired mucociliary transport caused by defective ciliogenesis, resulting in chronic airway infection. In this paper, using primary cultures of mouse tracheal epithelial cells, we show that Cby facilitates basal body docking to the apical cell membrane through proper formation of ciliary vesicles at the distal appendage during the early stages of ciliogenesis. Cby is recruited to the distal appendages of centrioles via physical interaction with the distal appendage protein CEP164. Cby then associates with the membrane trafficking machinery component Rabin8, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rab8, to promote recruitment of Rab8 and efficient assembly of ciliary vesicles. Thus, our study identifies Cby as a key regulator of ciliary vesicle formation and basal body docking during the differentiation of airway ciliated cells.

Cby1 promotes Ahi1 recruitment to a ring-shaped domain at the centriole-cilium interface and facilitates proper cilium formation and function.

Defects in centrosome and cilium function are associated with phenotypically related syndromes called ciliopathies. Cby1, the mammalian orthologue of the Drosophila Chibby protein, localizes to mature centrioles, is important for ciliogenesis in multiciliated airway epithelia in mice, and antagonizes canonical Wnt signaling via direct regulation of ß-catenin. We report that deletion of the mouse Cby1 gene results in cystic kidneys, a phenotype common to ciliopathies, and that Cby1 facilitates the formation of primary cilia and ciliary recruitment of the Joubert syndrome protein Arl13b. Localization of Cby1 to the distal end of mature centrioles depends on the centriole protein Ofd1. Superresolution microscopy using both three-dimensional SIM and STED reveals that Cby1 localizes to an ∼250-nm ring at the distal end of the mature centriole, in close proximity to Ofd1 and Ahi1, a component of the transition zone between centriole and cilium. The amount of centriole-localized Ahi1, but not Ofd1, is reduced in Cby1(-/-) cells. This suggests that Cby1 is required for efficient recruitment of Ahi1, providing a possible molecular mechanism for the ciliogenesis defect in Cby1(-/-) cells.

Effect of intravitreal injection of bevacizumab-chitosan nanoparticles on retina of diabetic rats.

AIM: To investigate the effects of intravitreal injection of bevacizumab-chitosan nanoparticles on pathological morphology of retina and the expression of vascular endothelial growth factor (VEGF) protein and VEGF mRNA in the retina of diabetic rats. METHODS: Seventy-two 3-month aged diabetic rats were randomly divided into 3 groups, each containing 24 animals and 48 eyes. Both eyes of the rats in group A were injected into the vitreous at the pars plana with 3µL of physiological saline, while in groups B and C were injected with 3µL (75µg) of bevacizumab and 3µL of bevacizumab-chitosan nanoparticles (containing 75µg of bevacizumab), respectively. Immunohistochemistry was used to assess retinal angiogenesis, real-time PCR assay was used to analyse the expression of VEGF mRNA, and light microscopy was used to evaluate the morphology of retinal capillaries. RESULTS: Real-time PCR assay revealed that the VEGF mRNA expression in the retina before injection was similar to 1 week after injection in group A (P>0.05), while the VEGF mRNA expression before injection significantly differed from those 4 and 8 weeks after injection (P<0.05). Retinal expression of VEGF protein and VEGF mRNA was inhibited 1 week and 4 weeks after injection (P<0.05) in group B, and the expression of VEGF protein and VEGF mRNA was obviously inhibited until 8 weeks after injection (P<0.05) in group C. Using multiple comparisons among group A, group B, and group C, the VEGF expression before injection was higher than at 1, 4 and 8 weeks after injection (P<0.05). The amount of VEGF expression was higher 8 weeks after injection than 1 week or 4 weeks after injection, and also higher 1 week after injection compared with 4 weeks after injection (P<0.05). No toxic effect on SD rats was observed with bevacizumab-chitosan nanoparticles injection alone. CONCLUSION: The results offer a new approach for inhibiting angiogenesis of diabetic retinopathy and indicate that the intravitreal injection of bevacizumab inhibits VEGF expression in retina, and bevacizumab-chitosan nanoparticles have a longer duration of action.

Triggering effect of N-acetylglucosamine on retarded drug release from a lectin-anchored chitosan nanoparticles-in-microparticles system.

The aim of this study was to investigate the use of N-acetylglucosamine (NAG) to accelerate drug release from a lectin-modified carrier. A wheat germ agglutinin (WGA)-anchored salmeterol xinafoate (SalX)-loaded nanoparticles-in-microparticles system (NiMS) was prepared with an ionotropic gelation technique combined with a spray drying method. The formulated microparticles were spherical, with diameters ranging mainly from 2 to 8 µm; the drug entrapment efficiency was >70% (w/w), and the loading capacity was approximately 8% (w/w). Drug release from WGA-SalX-NiMS, within the first 4h, was approximately 30% less than that from SalX-NiMS, indicating an effect of lectin-modification to retard drug release from the NiMS. Due to "sugar-lectin" interactions, drug release from WGA-SalX-NiMS was substantially increased after the addition of NAG to the release medium. However, no significant influence of NAG was observed on the drug release profile of SalX-NiMS without WGA anchorage. The characteristics of NAG-WGA interaction may provide valuable insights into the "triggering-effects" of specific sugars on drug release from lectin-anchored carriers. These results suggest that it is possible to control drug release from a lectin-anchored drug delivery system using a specific sugar, and that the designed novel WGA-SalX-NiMS may be a suitable formulation for chronotherapy of asthma.

A Wnt/beta-catenin pathway antagonist Chibby binds Cenexin at the distal end of mother centrioles and functions in primary cilia formation.

The mother centriole of the centrosome is distinguished from immature daughter centrioles by the presence of accessory structures (distal and subdistal appendages), which play an important role in the organization of the primary cilium in quiescent cells. Primary cilia serve as sensory organelles, thus have been implicated in mediating intracellular signal transduction pathways. Here we report that Chibby (Cby), a highly conserved antagonist of the Wnt/ß-catenin pathway, is a centriolar component specifically located at the distal end of the mother centriole and essential for assembly of the primary cilium. Cby appeared as a discrete dot in the middle of a ring-like structure revealed by staining with a distal appendage component of Cep164. Cby interacted with one of the appendage components, Cenexin (Cnx), which thereby abrogated the inhibitory effect of Cby on ß-catenin-mediated transcriptional activation in a dose-dependent manner. Cby and Cnx did not precisely align, as Cby was detected at a more distal position than Cnx. Cnx emerged earlier than Cby during the cell cycle and was required for recruitment of Cby to the mother centriole. However, Cby was dispensable for Cnx localization to the centriole. During massive centriogenesis in in vitro cultured mouse tracheal epithelial cells, Cby and Cnx were expressed in a similar pattern, which was coincident with the expression of Foxj1. Our results suggest that Cby plays an important role in organization of both primary and motile cilia in collaboration with Cnx.

Chibby suppresses growth of human SW480 colon adenocarcinoma cells through inhibition of ß-catenin signaling.

The canonical Wnt signaling pathway is crucial for embryonic development and adult tissue homeostasis. Activating mutations in the Wnt pathway are frequently associated with the pathogenesis of various types of cancer, particularly colon cancer. Upon Wnt stimulation, ß-catenin plays a central role as a coactivator through direct interaction with Tcf/Lef transcription factors to stimulate target gene expression. We have previously shown that the evolutionarily conserved protein Chibby (Cby) physically binds to ß-catenin to repress ß-catenin-dependent gene activation by 1) competing with Tcf/Lef factors for binding to ß-catenin and 2) facilitating nuclear export of ß-catenin via interaction with 14-3-3 proteins. In this study, we employed human colon adenocarcinoma SW480 cells with high levels of endogenous ß-catenin to address a potential tumor suppressor role of Cby. In SW480 stable cells expressing wild-type Cby (CbyWT), but not 14-3-3-binding- defective Cby mutant CbyS20A, a significant fraction of endogenous ß-catenin was detected in the cytoplasm. Consistent with this, CbyWT-expressing cells showed low levels of ß-catenin signaling activity, leading to reduced growth. Our results suggest that Cby, in collaboration with 14-3-3 proteins, can counteract oncogenic ß-catenin signaling in colon cancer cells.

[Wheat germ agglutinin anchored chitosan nanoparticles and its conjugation with N-acetylglucosamine].

This study is undertaken to modify the chitosan nanoparticles (CS-NPs) with wheat germ agglutinin (WGA), and investigate the conjugation between WGA-CS-NPs and N-acetylglucosamine (NAG). CS-NPs were prepared by ionotropic gelation process and then conjugated with WGA under the activation of glutaricdialdehyde. The mean diameter of the CS-NPs was approximately 113.5 nm and the poly-dispersity index (PDI) was 0.18. The binding yield of WGA to CS-NPs was comprised between 27.8% and 87.9% depending mostly on the addition of 0.3% (w/v) glutaraldehyde solution. A competitive inhibition experiment of WGA-CS-NPs to bovine submaxillary gland mucin (BSM) was taken to illuminate the binding activity of WGA-CS-NPs to the sugar of N-acetylglucosamine. After the addition of NAG, the binding rates between CS-NPs and BSM almost didn't change, while the binding rates between WGA-CS-NPs and BSM dropped down significantly, which confirmed the specific binding characteristics of WGA to NAG.

A novel spray-dried nanoparticles-in-microparticles system for formulating scopolamine hydrobromide into orally disintegrating tablets.

Scopolamine hydrobromide (SH)-loaded microparticles were prepared from a colloidal fluid containing ionotropic-gelated chitosan nanoparticles using a spray-drying method. The spray-dried microparticles were then formulated into orally disintegrating tablets (ODTs) using a wet granulation tablet formation process. A drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) were achieved for the microparticles, which ranged from 2 µm to 8 µm in diameter. Results of disintegration tests showed that the formulated ODTs could be completely dissolved within 45 seconds. Drug dissolution profiles suggested that SH is released more slowly from tablets made using the microencapsulation process compared with tablets containing SH that is free or in the form of nanoparticles. The time it took for 90% of the drug to be released increased significantly from 3 minutes for conventional ODTs to 90 minutes for ODTs with crosslinked microparticles. Compared with ODTs made with noncrosslinked microparticles, it was thus possible to achieve an even lower drug release rate using tablets with appropriate chitosan crosslinking. Results obtained indicate that the development of new ODTs designed with crosslinked microparticles might be a rational way to overcome the unwanted taste of conventional ODTs and the side effects related to SH's intrinsic characteristics.