Polysaccharide-based emulsion gels for the prevention of postoperative adhesions and as a drug delivery system using 5-fluorouracil.

Postoperative tissue adhesion is a well-recognized and common complication. Despite ongoing developments in anti-adhesion agents, complete prevention remains a challenge in clinical practice. Colorectal cancer necessitates both adhesion prevention and postoperative chemotherapy. Accordingly, drug-loading into an anti-adhesion agent could be employed as a treatment strategy to maximize the drug effects through local application and minimize side effects. Herein, we introduce an anti-adhesion agent that functions as a drug delivery system by loading drugs within an emulsion that forms a gel matrix in the presence of polysaccharides, xanthan gum, and pectin. Based on the rheological analysis, the xanthan gum-containing emulsion gel formed a gel matrix with suitable strength and mucosal adhesiveness. In vitro dissolution tests demonstrated sustained drug release over 12 h, while in vivo pharmacokinetic studies revealed a significant increase in the Tmax (up to 4.03 times) and area under the curve (up to 2.62 times). However, most of the drug was released within one day, distributing systemically and raising toxicity concerns, thus limiting its efficacy as a controlled drug delivery system. According to in vivo anti-adhesion efficacy evaluations, the xanthan gum/pectin emulsion gels, particularly F2 and F3, exhibited remarkable anti-adhesion capacity (P < 0.01). The emulsion gel formulation exhibited no cytotoxicity against fibroblasts or epithelial cell lines. Thus, the xanthan gum/pectin emulsion gel exhibits excellent anti-adhesion properties and could be developed as a drug delivery system.

Design of smart chemotherapy of doxorubicin hydrochloride using nanostructured lipid carriers and solid lipid nanoparticles for improved anticancer efficacy.

Doxorubicin hydrochloride (DOX) is an anticancer agent used in cancer chemotherapy. The purpose of this study was to design nanostructured lipid carriers (NLCs) of DOX as smart chemotherapy to improve its photostability and anticancer efficacy. The characteristics of DOX and DOX-loaded NLCs were investigated using UV-Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, particle size, and zeta potential study. The cytotoxicity of DOX was evaluated against three cancer cell lines (HeLa, A549, and CT-26). The particle size and zeta potential were in the range 58.45-94.08 nm and -5.80 mV - -18.27 mV, respectively. The chemical interactions, particularly hydrogen bonding and van der Waals forces, between DOX and the main components of NLCs was confirmed by FTIR. NLCs showed the sustained release profile of DOX. The photostability results revealed that the NLC system improved the photostability of DOX. Cytotoxicity results using the three cell lines showed that all formulations improved the anticancer efficacy of free DOX, and the efficacy was dependent on cell type and particle size. These results suggest that DOX-loaded NLCs are promising chemotherapeutic agents for cancer treatment.

Deep-Learning Algorithm and Concomitant Biomarker Identification for NSCLC Prediction Using Multi-Omics Data Integration.

Early diagnosis of lung cancer to increase the survival rate, which is currently at a low range of mid-30%, remains a critical need. Despite this, multi-omics data have rarely been applied to non-small-cell lung cancer (NSCLC) diagnosis. We developed a multi-omics data-affinitive artificial intelligence algorithm based on the graph convolutional network that integrates mRNA expression, DNA methylation, and DNA sequencing data. This NSCLC prediction model achieved a 93.7% macro F1-score, indicating that values for false positives and negatives were substantially low, which is desirable for accurate classification. Gene ontology enrichment and pathway analysis of features revealed that two major subtypes of NSCLC, lung adenocarcinoma and lung squamous cell carcinoma, have both specific and common GO biological processes. Numerous biomarkers (i.e., microRNA, long non-coding RNA, differentially methylated regions) were newly identified, whereas some biomarkers were consistent with previous findings in NSCLC (e.g., SPRR1B). Thus, using multi-omics data integration, we developed a promising cancer prediction algorithm.

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo.

BACKGROUND: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) involves mixing oxaliplatin with 5% dextrose solution (5DW) to prevent the structural degradation of oxaliplatin in chloride-containing fluids. This study evaluated oxaliplatin degradation in carrier fluids containing different chloride ion concentrations to determine a carrier fluid that is optimal for use in oxaliplatin-based HIPEC. METHODS: Five types of carrier fluids (normal saline, half saline, 5DW, Dianeal PD-2 peritoneal dialysis solution, and non-chloride Dianeal solution) were compared. An in vitro study was performed that monitored an oxaliplatin concentration of 1 ml (2 mg/ml) oxaliplatin mixed in 24 ml of each carrier fluid during 3 days to evaluate the rate of oxaliplatin degradation in each carrier fluid. An in vivo study, which subjected Sprague-Dawley rats to HIPEC for 60 min, also was performed. The efficacy of each carrier fluid for preserving oxaliplatin was evaluated using area under the curve (AUC) ratios between peritoneal fluid and plasma. RESULTS: The degradation rate of oxaliplatin in non-chloride fluids was significantly lower than in chloride-containing fluids. However, the rate was less than 10 to 15% at 30 min. The in vivo study indicated that oxaliplatin concentrations in peritoneal fluids did not differ significantly, whereas those in plasma did differ. The AUC ratios of both normal saline and Dianeal were higher than those of 5DW and non-Cl- Dianeal solutions. CONCLUSIONS: Chloride-containing fluids, such as normal saline or Dianeal, which display high absorption rates of oxaliplatin and acceptable degradation rates, may be more beneficial for use in oxaliplatin-based HIPEC than 5DW.

A novel thermosensitive poloxamer-hyaluronic acid- kappa-carrageenan-based hydrogel anti-adhesive agent loaded with 5-fluorouracil: A preclinical study in Sprague-Dawley rats.

Although the first-choice treatment for colorectal cancer is cytoreductive surgery combined with chemotherapy, post-surgical peritoneal adhesion and extant malignancy can cause fatal complications. Studies examining hydrogel-based postoperative anti-adhesion treatments are still limited. In this study, several formulations of 5-fluorouracil (5-FU) loaded into hyaluronic acid (HA) and kappa-carrageenan (kCGN)-poloxamer 407 (P407)-based cross-linked hydrogels were prepared and evaluated in vitro and in vivo for their efficacy in preventing adhesion. These hydrogels met a set of desired specifications such as thermosensitive behavior, strong elasticity at body temperature (tan δ < 1.0 at 37 °C), and ability to encapsulate hydrophilic drug and deliver it in a sustained released manner. Our secondary purpose is to provide in situ 5-FU for additional local antitumor effect when the anti-adhesion agent is spread over the tumor site. Over 60% of the total loaded drug was released within 4 h, and about 80% of 5-FU was released after three days. Both the Higuchi and Korsmeyer-Peppas models showed that the mechanism of sustained drug release involved diffusion. The constructed hydrogels were evaluated for in vivo intra-abdominal anti-adhesion barrier efficiency; the HA/kCGN 1%/3% w/v hydrogel formulation showed the best anti-adhesion effect in this preclinical study using Sprague-Dawley rat models.

Gelatin Coating for the Improvement of Stability and Cell Uptake of Hydrophobic Drug-Containing Liposomes.

PURPOSE: Most therapeutic agents have limitations owing to low selectivity and poor solubility, resulting in post-treatment side effects. Therefore, there is a need to improve solubility and develop new formulations to deliver therapeutic agents specifically to the target site. Gelatin is a natural protein that is composed of several amino acids. Previous studies revealed that gelatin contains arginyl-glycyl-aspartic acid (RGD) sequences that become ligands for the integrin receptors expressed on cancer cells. Thus, in this study, we aimed to increase the efficiency of drug delivery into cancer cells by coating drug-encapsulating liposomes with gelatin (gelatin-coated liposomes, GCLs). METHODS: Liposomes were coated with gelatin using electrostatic interaction and covalent bonding. GCLs were compared with PEGylated liposomes in terms of their size, zeta potential, encapsulation efficiency, stability, dissolution profile, and cell uptake. Results: Small-sized and physically stable GCLs were prepared, and they showed high drug-encapsulation efficiency. An in vitro dissolution study showed sustained release depending on the degree of gelatin coating. Cell uptake studies showed that GCLs were superior to PEGylated liposomes in terms of cancer cell-targeting ability. CONCLUSIONS: GCLs can be a novel and promising carrier system for targeted anticancer agent delivery. GCLs, which exhibited various characteristics depending on the coating degree, could be utilized in various ways in future studies.

The Health-Promoting Properties and Clinical Applications of Rice Bran Arabinoxylan Modified with Shiitake Mushroom Enzyme-A Narrative Review.

Rice bran arabinoxylan compound (RBAC) is derived from defatted rice bran hydrolyzed with Lentinus edodes mycelial enzyme. It has been marketed as a functional food and a nutraceutical with health-promoting properties. Some research has demonstrated this rice bran derivative to be a potent immunomodulator, which also possesses anti-inflammatory, antioxidant, and anti-angiogenic properties. To date, research on RBAC has predominantly focused on its immunomodulatory action and application as a complementary therapy for cancer. Nonetheless, the clinical applications of RBAC can extend beyond cancer therapy. This article is a narrative review of the research on the potential benefits of RBAC for cancer and other health conditions based on the available literature. RBAC research has shown it to be useful as a complementary treatment for cancer and human immunodeficiency virus infection. It can positively modulate serum glucose, lipid and protein metabolism in diabetic patients. Additionally, RBAC has been shown to ameliorate irritable bowel syndrome and protect against liver injury caused by hepatitis or nonalcoholic fatty liver disease. It can potentially ease symptoms in chronic fatigue syndrome and prevent the common cold. RBAC is safe to consume and has no known side effects at the typical dosage of 2-3 g/day. Nevertheless, further research in both basic studies and human clinical trials are required to investigate the clinical applications, mechanisms, and effects of RBAC.

Alu cell-free DNA concentration, Alu index, and LINE-1 hypomethylation as a cancer predictor.

INTRODUCTION: The liquid biopsy approach, a less-invasive diagnostic tool, enables the detection of disease-specific genetic and epigenetic aberrations. Approximately 66-69% of the human genome may be composed of transposable repetitive elements, including Alu and LINE-1. This study aimed to investigate whether Alu-derived cell-free DNA (cfDNA) concentrations, Alu index, and LINE-1 methylation could be used to distinguish patients with cancers from healthy individuals. METHODS: Two sets of primers, shorter and longer Alu fragments, were used to amplify Alu elements, followed by the quantitation of Alu DNA concentration and its integrity index. LINE-1 methylation status was then analyzed with quantitative PCR using methylation- and unmethylation-specific TaqMan probes. RESULTS: Both Alu index and LINE-1 methylation level were significantly different in comparison between patients with lung or breast cancer and the healthy controls. The area under the ROC curve of the Alu index and LINE-1 hypomethylation was 0.742 and 0.848 for lung cancer, respectively, and 0.724 and 0.890 for breast cancer, respectively. However, Alu longer fragment DNA concentration was significantly correlated with Alu index in comparison to LINE-1 hypomethylation. Regression analysis suggested that the LINE-1 methylation level, rather than the Alu index, was a good discriminator for lung and breast cancers. CONCLUSIONS: This study investigated the genome-wide Alu index and LINE-1 methylation status; their associations with cancers suggested that these combinatory panels could be implemented as a triage test to discriminate cancer patients from healthy individuals.

Preparation and Evaluation of Intraperitoneal Long-Acting Oxaliplatin-Loaded Multi-Vesicular Liposomal Depot for Colorectal Cancer Treatment.

Colorectal cancer with peritoneal metastasis has a poor prognosis because of inadequate responses to systemic chemotherapy. Cytoreductive surgery followed by intraperitoneal (IP) chemotherapy using oxaliplatin has attracted attention; however, the short half-life of oxaliplatin and its rapid clearance from the peritoneal cavity limit its clinical application. Here, a multivesicular liposomal (MVL) depot of oxaliplatin was prepared for IP administration, with an expected prolonged effect. After optimization, a combination of phospholipids, cholesterol, and triolein was used based on its ability to produce MVL depots of monomodal size distribution (1-20 µm; span 1.99) with high entrapment efficiency (EE) (92.16% ± 2.17%). An initial burst release followed by a long lag phase of drug release was observed for the MVL depots system in vitro. An in vivo pharmacokinetic study mimicking the early postoperative IP chemotherapy regimen in rats showed significantly improved bioavailability, and the mean residence time of oxaliplatin after IP administration revealed that slow and continuous erosion of the MVL particles yielded a sustained drug release. Thus, oxaliplatin-loaded MVL depots presented in this study have potential for use in the treatment of colorectal cancer.

Effects of fermented rice bran on DEN-induced oxidative stress in mice: GSTP1, LINE-1 methylation, and telomere length ratio.

N-diethylnitrosamine (DEN), a well-known carcinogen, not only induces excessive reactive oxygen species but also suppresses DNA methylation. This study investigated the effect of fermented rice bran (FRB) treatment on DEN-induced oxidative stress through DNA methylation and telomere length analysis. To evaluate the potential protective role of FRB in oxidative stress, two different doses of FRB, DEN, and their combination were administered to mice that were preadapted or not to FRB. Glutathione-S-transferase P1 (GSTP1) methylation levels significantly decreased at 2 and 24 hr after FRB and DEN co-administration in mice with and without pre-adaptation. Moreover, GSTP1 mRNA was upregulated under DEN-induced oxidative stress. Furthermore, changes in long interspersed nuclear element-1 methylation were observed from the viewpoint of genomic instability. In addition, FRB preadapted mice displayed a lower telomere length ratio than the non-adapted mice, suggesting that FRB adaptation offers advantages over the non-adapted conditions in terms of inflammation suppression. PRACTICAL APPLICATIONS: DEN induces excessive ROS, which is associated with oxidative stress on DNA and other cellular components, resulting in inflammation. This study shows that FRB may alleviate DEN-triggered oxidative stress, based on changes in GSTP1, LINE-1 methylation, and telomere length ratios, thereby, revealing the potential of dietary intervention during inflammation. Furthermore, this study furthers the current understanding of DNA methylation mechanisms underlying the antioxidant and anti-inflammatory effects of functional food components. These results indicate that dietary inclusion of FRB may help decrease oxidative DNA damage and its associated inflammation at early stages of a disease.

Fresh Saengshik Showed a Positive Effect on Mitigating Dextran Sulfate Sodium-Induced Experimental Colitis in Mice.

This study was to compare the anticolitis activity of fresh Saengshik (FSS) with heated Saengshik (HSS) with dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Both FSS- and HSS-fed colitis mice exhibited the effects of the increase in the body weight, the alleviation in the colon shortening, and the reduction of the ratio of colon weight to length. However, FSS-fed colitis mice showed a much more significant decrease in DSS-induced tissue damage by mucosal edema and crypt deficiency than did HSS-fed ones. Besides, FSS contributed to decreasing the serum levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and inhibiting the colonic mRNA expressions of these cytokines in colitis tissue of the mice. FSS also resulted in the lower colonic mRNA expression level of inflammation-related inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colitis mice than did HSS. Overall results confirmed Saengshik, especially FSS, inhibits more effectively against DSS-induced inflammation reaction in colitis mice than HSS.

A Mixed Micellar Formulation for the Transdermal Delivery of an Indirubin Analog.

Indirubin is an active component of Dang Gui Long Hui Wan, which has been used in traditional Chinese medicine to treat inflammatory diseases as well as for the prevention and treatment of human cancer, such as chronic myeloid leukemia. The therapeutic effects of indirubin analogs have been underestimated due to its poor water solubility and low bioavailability. To improve the solubility and bioavailability of indirubin analogs, we prepared a mixed micellar formulation with Kolliphor® EL and Tween 80 as surfactants, and PEG 400 as a co-surfactant, followed by complexation with (2-hydroxyproply)-ß-cyclodextrin at appropriate ratios. Overall, improving the solubility and skin penetration of indirubin analogs can increase clinical efficacy and provide maximum flux through the skin.

Pharmacokinetic Profile and Anti-Adhesive Effect of Oxaliplatin-PLGA Microparticle-Loaded Hydrogels in Rats for Colorectal Cancer Treatment.

Colorectal cancer (CRC) is one of the most malignant and fatal cancers worldwide. Although cytoreductive surgery combined with chemotherapy is considered a promising therapy, peritoneal adhesion causes further complications after surgery. In this study, oxaliplatin-loaded Poly-(d,l-lactide-co-glycolide) (PLGA) microparticles were prepared using a double emulsion method and loaded into hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based cross-linked (HC) hydrogels. From characterization and evaluation study PLGA microparticles showed smaller particle size with higher entrapment efficiency, approximately 1100.4 ± 257.7 nm and 77.9 ± 2.8%, respectively. In addition, microparticle-loaded hydrogels showed more sustained drug release compared to the unloaded microparticles. Moreover, in an in vivo pharmacokinetic study after intraperitoneal administration in rats, a significant improvement in the bioavailability and the mean residence time of the microparticle-loaded hydrogels was observed. In HC21 hydrogels, AUC0-48h, Cmax, and Tmax were 16012.12 ± 188.75 ng·h/mL, 528.75 ± 144.50 ng/mL, and 1.5 h, respectively. Furthermore, experimental observation revealed that the hydrogel samples effectively protected injured tissues from peritoneal adhesion. Therefore, the results of the current pharmacokinetic study together with our previous report of the in vivo anti-adhesion efficacy of HC hydrogels demonstrated that the PLGA microparticle-loaded hydrogels offer novel therapeutic strategy for CRC treatment.

The Delivery Strategy of Paclitaxel Nanostructured Lipid Carrier Coated with Platelet Membrane.

Strategies for the development of anticancer drug delivery systems have undergone a dramatic transformation in the last few decades. Lipid-based drug delivery systems, such as a nanostructured lipid carrier (NLC), are one of the systems emerging to improve the outcomes of tumor treatments. However, NLC can act as an intruder and cause an immune response. To overcome this limitation, biomimicry technology was introduced to decorate the surface of the nanoparticles with various cell membrane proteins. Here, we designed paclitaxel (PT)-loaded nanostructured lipid carrier (PT-NLC) with platelet (PLT) membrane protein because PLT is involved with angiogenesis and interaction of circulating tumor cells. After PLT was isolated from blood using the gravity-gradient method and it was used for coating PT-NLC. Spherical PT-NLC and platelet membrane coated PT-NLC (P-PT-NLC) were successfully fabricated with high encapsulation efficiency (EE) (99.98%) and small particle size (less than 200 nm). The successful coating of PT-NLC with a PLT membrane was confirmed by the identification of CD41 based on transmission electron microscopy (TEM), western blot assay and enzyme-linked immunosorbent assay (ELISA) data. Moreover, the stronger affinity of P-PT-NLC than that of PT-NLC toward tumor cells was observed. In vitro cell study, the PLT coated nanoparticles successfully displayed the anti-tumor effect to SK-OV-3 cells. In summary, the biomimicry carrier system P-PT-NLC has an affinity and targeting ability for tumor cells.

Oxaliplatin-loaded chemically cross-linked hydrogels for prevention of postoperative abdominal adhesion and colorectal cancer therapy.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among both men and women worldwide. New therapeutic strategies involving cytoreductive surgery and intra-peritoneal chemotherapy could lead to a definitive cure in some cases. However, postoperative intra-abdominal adhesion can cause further complications. In this study, hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based novel cross-linked hydrogels (HC hydrogels) were synthesized and fully characterized. We demonstrated that varied compositions of HA and CMCNa altered the microstructure, rheology, and degradation behavior of hydrogels. Pre-constructed hydrogels were further loaded with oxaliplatin to prevent intra-abdominal adhesion following chemotherapy. Sustained release of oxaliplatin was observed from hydrogels compared that from solutions, which release drugs through diffusion, following the Higuchi and Korsmeyer-Peppas models. Moreover, low adhesion scores in an in vivo SD rat model demonstrated inhibition of intra-peritoneal adhesion in response to HC hydrogels. Therefore, HC hydrogels offer a novel formulation strategy for providing an intra-abdominal anti-adhesion barrier after cytoreductive surgery and intra-peritoneal chemotherapy for CRC treatment.

Pharmacologic Properties of the Carrier Solutions for Hyperthermic Intraperitoneal Chemotherapy: Comparative Analyses Between Water and Lipid Carrier Solutions in the Rat Model.

BACKGROUND: Carrier solutions play an important role in the distribution, plasma absorption, chemical stability, and solubility of anticancer agents during hyperthermic intraperitoneal chemotherapy (HIPEC). In the current study, lipophilic properties of carrier solutions were evaluated to determine whether they improved anticancer drug absorption rates using mitomycin-C (MMC) or oxaliplatin HIPEC as compared to hydrophilic carrier solutions. METHODS: Sprague-Dawley rats were divided into two groups: MMC and oxaliplatin treatment groups. Each group was then further subdivided by carrier solution: Dianeal® PD-2 peritoneal dialysis solution, 5% dextrose solution and 20% lipid solution (Lipision®). HIPEC was performed over 60 min at 41-42 °C using the anticancer drugs MMC (35 mg/m2) or oxaliplatin (460 mg/m2). The plasma area under the curve (AUC; AUCplasma), peritoneal AUC (AUCperitoneum), and peritoneal/plasma AUC ratios were compared among HIPEC carrier solutions. RESULTS: Plasma drug concentrations were significantly different among carrier solutions, varying by time. In contrast, peritoneal drug concentrations did not change with carrier solution. In the MMC group, the peritoneal/plasma AUC ratio of a lipid solution was three times higher than Dianeal® (p < 0.001). In the oxaliplatin group, the peritoneal/plasma AUC ratio was significantly different between carrier solutions (p = 0.046). Although the oxaliplatin AUCperitoneum did not vary (p = 0.941), the AUCplasma of a lipid solution was lower than that of 5% dextrose solution (p = 0.039). CONCLUSIONS: The lipid carrier solution increases the peritoneal/plasma AUC ratio and decreases plasma absorption rates. However, further study is required before clinical uses, considering its pharmacologic properties and possible risks after HIPEC.

Surface modification of paclitaxel-loaded liposomes using d-α-tocopheryl polyethylene glycol 1000 succinate: Enhanced cellular uptake and cytotoxicity in multidrug resistant breast cancer cells.

Liposomes can achieve a controlled release and an improved bioavailability of water- insoluble drug with minimized side effects. Paclitaxel is an efficient anticancer drug for the treatment of various cancers. However, paclitaxel has a solubility of 0.5 mg/L in water and a low bioavailability of 6.5%. Moreover, paclitaxel is a substrate for p-glycoprotein, which shows a decreased accumulation of drug within the cancer cell expressed by a p-glycoprotein. Therefore, the purpose of this study is to prepare a paclitaxel-loaded liposome and evaluate the effect of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an inhibitor of p-glycoprotein on the paclitaxel-loaded liposome. The paclitaxel-loaded liposome and TPGS coated paclitaxel-loaded liposome had spherical vesicles, with mean particle size 184.9 ±â€¯18.45 nm with PDI 0.324 ±â€¯0.018 and 282.6 ±â€¯20.41 nm with PDI 0.269 ±â€¯0.013, respectively. Paclitaxel-loaded liposome and TPGS coated paclitaxel-loaded liposome showed a controlled and sustained release of PTX over 72 h. The cellular uptake of paclitaxel from TPGS coated paclitaxel-loaded liposome was a 3.56-fold increase for 2 h and 5.75-fold increase for 4 h compared to that from paclitaxel-loaded liposome in MCF-7/ADR cells, resulting in improved cytotoxicity against MCF-7/ADR cells. Western blot assay revealed the P-gp inhibitory effect of TPGS-coated PTX-liposome. In conclusion, TPGS coated liposome with a sustained releasing capability and the inhibitory effect of p-glycoprotein may be a promising carrier for future applications in cancer therapy.

Cyclosporine Amicellar delivery system for dry eyes.

BACKGROUND: The objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy. MATERIALS AND METHODS: CsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining. RESULTS: MS-CsA had a smaller particle size (average diameter 14-18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups (P<0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells. CONCLUSION: The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.