Development of Perfluoro Decalin/Fluorinated Polyimide Core-Shell Microparticles via SPG Membrane Emulsification Using Methyl Perfluoropropyl Ether Cosolvent.

Red blood cell-inspired perfluorocarbon-encapsulated core-shell particles have been developed for biomedical applications. Although the use of perfluorodecalin (FDC) is expected for core-shell particles owing to its high oxygen solubility, the low solubility of FDC in any organic solvent, owing to its fluorous properties, prevents its use in core-shell particles. In this study, a new cosolvent system composed of dichloromethane (DCM) and heptafluoropropyl methyl ether (HFPME) was found to dissolve both FDC and fluorinated polyimide (FPI) based on a systematic study using a phase diagram, achieving a homogeneous disperse phase for emulsification composed of oxygen-permeable FPI and oxygen-soluble FDC. Using this novel cosolvent system and Shirasu porous glass (SPG) membrane emulsification, FDC-encapsulated FPI shell microparticles were successfully prepared for the first time. In addition to oxygenation, demonstrated using hypoxia-responsive HeLa cells, the fabricated core-shell microparticles exhibited monodispersity, excellent stability, biocompatibility, and oxygen capacity.

AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple-Negative Breast Cancer.

Breast cancer ranks first in incidence and fifth in cancer-related deaths among all types of cancer globally. Among breast cancer, triple-negative breast cancer (TNBC) has few known therapeutic targets and a poor prognosis. Therefore, new therapeutic targets and strategies against TNBC are required. We found that androgen-induced basic leucine zipper (AIbZIP), also known as cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4), which is encoded by Creb3l4, is highly upregulated in a particular subtype of TNBC, luminal androgen receptor (LAR) subtype. We analyzed the function of AIbZIP through depletion of AIbZIP by siRNA knockdown in LAR subtype TNBC cell lines, MFM223 and MDAMB453. In AIbZIP-depleted cells, the proliferation ratios of cells were greatly suppressed. Moreover, G1-S transition was inhibited in AIbZIP-depleted cells. We comprehensively analyzed the expression levels of proteins that regulate G1-S transition and found that p27 was specifically upregulated in AIbZIP-depleted cells. Furthermore, we identified that this p27 downregulation was caused by protein degradation modulated by the ubiquitin-proteasome system via F-box protein S-phase kinase-associated protein 2 (SKP2) upregulation. Our findings demonstrate that AIbZIP is a novel p27-SKP2 pathway-regulating factor and a potential molecule that contributes to LAR subtype TNBC progression. IMPLICATIONS: This research shows a new mechanism for the proliferation of LAR subtype TNBC regulated by AIbZIP, that may provide novel insight into the LAR subtype TNBC progression and the molecular mechanisms involved in cell proliferation.

Impact of cell cycle on repair of ruptured nuclear envelope and sensitivity to nuclear envelope stress in glioblastoma.

The nuclear envelope (NE) is often challenged by various stresses (known as "NE stress"), leading to its dysfunction. Accumulating evidence has proven the pathological relevance of NE stress in numerous diseases ranging from cancer to neurodegenerative diseases. Although several proteins involved in the reassembly of the NE after mitosis have been identified as the NE repair factors, the regulatory mechanisms modulating the efficiency of NE repair remain unclear. Here, we showed that response to NE stress varied among different types of cancer cell lines. U251MG derived from glioblastoma exhibited severe nuclear deformation and massive DNA damage at the deformed nuclear region upon mechanical NE stress. In contrast, another cell line derived from glioblastoma, U87MG, only presented mild nuclear deformation without DNA damage. Time-lapse imaging demonstrated that repairing of ruptured NE often failed in U251MG, but not in U87MG. These differences were unlikely to have been due to weakened NE in U251MG because the expression levels of lamin A/C, determinants of the physical property of the NE, were comparable and loss of compartmentalization across the NE was observed just after laser ablation of the NE in both cell lines. U251MG proliferated more rapidly than U87MG concomitant with reduced expression of p21, a major inhibitor of cyclin-dependent kinases, suggesting a correlation between NE stress response and cell cycle progression. Indeed, visualization of cell cycle stages using fluorescent ubiquitination-based cell cycle indicator reporters revealed greater resistance of U251MG to NE stress at G1 phase than at S and G2 phases. Furthermore, attenuation of cell cycle progression by inducing p21 in U251MG counteracted the nuclear deformation and DNA damage upon NE stress. These findings imply that dysregulation of cell cycle progression in cancer cells causes loss of the NE integrity and its consequences such as DNA damage and cell death upon mechanical NE stress.

p53-independent tumor suppression by cell-cycle arrest via CREB/ATF transcription factor OASIS.

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G2/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis-/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.

Balance of antiperitoneal adhesion, hemostasis, and operability of compressed bilayer ultrapure alginate sponges.

In surgery, both antiperitoneal adhesion barriers and hemostats with high efficiency and excellent handling are necessary. However, antiadhesion and hemostasis have been examined separately. In this study, six different ultrapure alginate bilayer sponges with thicknesses of 10, 50, 100, 200, 300, and 500 µm were fabricated via lyophilization and subsequent mechanical compression. Compression significantly enhanced mechanical strength and improved handling. Furthermore, it had a complex effect on dissolution time and contact angle. Therefore, the 100 µm compressed sponge showed the highest hemostatic activity in the liver bleeding model in mice, whereas the 200 µm sponge demonstrated the highest antiadhesion efficacy among the compressed sponges in a Pean crush hepatectomy-induced adhesion model in rats. For the first time, we systematically evaluated the effect of sponge compression on foldability, fluid absorption, mechanical strength, hemostatic effect, and antiadhesion properties. The optimum thickness of an alginate bilayer sponge by compression balances antiperitoneal adhesion and hemostasis simultaneously.

Cisplatin-Chelated Iminodiacetic Acid-Conjugated Hyaluronic Acid Nanogels for the Treatment of Malignant Pleural Mesothelioma in Mice.

Malignant pleural mesothelioma (MPM) is one of the intractable cancers that require a more effective therapeutic strategy for clinical practice. Hyaluronic acid (HA) nanogels were prepared by the chelation of cisplatin (CDDP) with different molecular weights of iminodiacetic acid-conjugated hyaluronic acid (HA-IDA). The sizes of the 100, 850, and 2000 kDa HA nanogels were 33, 43, and 44 nm, respectively. MSTO-211H, a human MPM cell line, was more effective in taking up all three HA nanogels compared to AB22, a mouse MPM cell line. In addition, the 850 kDa HA nanogel showed higher anticancer activity against AB22 and MSTO-211H than 100 and 2000 kDa HA nanogels. Furthermore, all the HA nanogels showed a milder cytotoxic effect on normal Met-5A mesothelial cells compared to that exhibited by free CDDP. Finally, the 850 kDa HA nanogel was administrated intrapleurally into both the MSTO-211H xenograft and AB22 allograft mouse models of MPM using an injectable HA-based hydrogel. HA nanogels showed a significant therapeutic effect in both the xenograft and allograft models.

Intraperitoneal Administration of a Cisplatin-Loaded Nanogel through a Hybrid System Containing an Alginic Acid-Based Nanogel and an In Situ Cross-Linkable Hydrogel for Peritoneal Dissemination of Ovarian Cancer.

Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRASG12V). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo. This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.

Implant Body Displacement into Medullary Cavity of Mandible: A Case Report.

One serious complication in implant surgery is displacement of the implant body into the surrounding tissue. This occurs only rarely in the mandible, however. This report describes a case of an implant body displacing into the medullary cavity of the mandible and discusses this in reference to the literature. The patient was a 72-year-old woman who was referred to our department at Tokyo Dental College Chiba Hospital (now Chiba Dental Center) by her regular dentist after an implant inserted in the left mandible in 2010 showed loosening in October 2016. Panoramic X-rays obtained at the initial examination revealed that 2 implants had been inserted into the left mandible, one on top of the other. Removal of both was recommended to prevent infection at the implant site and any potential effects on the alveolar nerve. In the absence of subjective symptoms other than implant loosening, however, the patient did not consent to this proposal. Therefore, only the broken abutment was removed. The patient was instructed to contact us immediately should infection or any other symptoms appear once the mucosa had healed, and the dental clinic that had referred her to us was requested to make her a set of dentures. To our knowledge, only 11 reports have been published to date describing displacement of an implant body into the mandible, and these address a total of just 20 cases. The possibility that an implant body in the mandible may become displaced must be kept in mind during treatment.

Advancement of Biomaterial-Based Postoperative Adhesion Barriers.

Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials' efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.

Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood-brain barrier opening.

The blood-brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.

The Balance between the Hemostatic Effect and Immune Response of Hyaluronan Conjugated with Different Chain Lengths of Inorganic Polyphosphate.

Inorganic polyphosphate (PolyP) is a potential hemostatic material. However, the effect of PolyP chain length on the immune response and hemostatic function remains to be established. We have developed PolyP-conjugated hyaluronans (HA-PolyPs) with three different short-chain PolyPs (n = 13, 40, and 100 phosphate units). All short-chain PolyPs showed biocompatibility in the cell viability and inflammatory cytokine secretion test in vitro and in vivo, wherein shorter PolyPs showed milder responses in some cases. We then produced HA-PolyP hydrogels (HAX-PolyPs) with three different short-chain PolyPs as hemostats. Interestingly, the in vivo biocompatibility and hemostatic activity of HAX-PolyP were not significantly affected by the length of conjugated PolyPs. HAX-PolyP with all chain lengths significantly decreased the amount of bleeding in a novel mouse liver bleeding model. These results indicated that the shortest PolyP (n = 13) induced milder acute inflammation and had an efficient hemostatic effect when conjugated to hyaluronic acid. The present study provides key insights into the design of PolyP-based biomaterials and bioconjugates, which are expected to grow in importance for various medical applications.

Pemetrexed-conjugated hyaluronan for the treatment of malignant pleural mesothelioma.

Pemetrexed (PMX) is a multi-targeted antifolate drug used for the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer. Hyaluronan (HA) in blood is well known as a disease marker of MPM. We synthesized PMX-conjugated hyaluronan (HA-ADH-PMX) for the first time to develop a novel anticancer chemotherapeutic agent. HAs with different molecular weights (76 and 130 kDa) were first derivatized with adipic dihydrazide (ADH) and then conjugated to PMX. The obtained HA-ADH-PMX retained inhibitory activity against folate metabolism enzymes; thymidylate synthase was inhibited to the same extent as native PMX, whereas the inhibition constant against dihydrofolate reductase was 3.3% for 76 kDa HA-ADH-PMX and 12% for 130 kDa HA-ADH-PMX when compared with that of native PMX. The in vitro cytotoxicity of HA-ADH-PMX from both molecular weights against MPM cell lines was lower than that of native PMX. On the other hand, intrapleural administration of 76 kDa HA-ADH-PMX resulted in a survival rate of MPM model mice comparable to that with native PMX, suggesting the potential for future MPM therapy.

Switching of Cell Proliferation/Differentiation in Thiol-Maleimide Clickable Microcapsules Triggered by in Situ Conjugation of Biomimetic Peptides.

Extracellular environments significantly affect cell proliferation, differentiation, and functions. The extracellular environment changes during many physiological and pathological processes such as embryo development, wound healing, and tumor growth. To mimic these changes, we developed novel thiol-maleimide clickable alginate microcapsules, which can introduce thiol-containing peptides by " in situ conjugation" with maleimide-modified alginate, even in serum-containing cell culture media. Additive peptides were rapidly concentrated into microcapsules by a diffusion-reaction process in the capsule. The proliferation of encapsulated fibroblasts was accelerated by in situ conjugation of CRGDS, while free RGDS showed no effect. Moreover, encapsulated preosteoblastic cells started osteogenic differentiation via in situ conjugation of BMP-2 mimetic peptides such as CDWIVA and CG-BMP-2 knuckle epitope peptide, while BMP-2 did not induce differentiation of the encapsulated cells. Especially in tissue engineering, accurate and inexpensive methods for inducing cell differentiation are required. We believe that this in situ conjugation approach employing various functional peptides will be useful in biomedical, bioindustrial, and biochemical fields in the future.

The Prevention of Hepatectomy-Induced Adhesions by Bilayer Sponge Composed of Ultrapure Alginate.

BACKGROUND: Adhesion formation is a critical issue in surgery, particularly in hepatectomy. The present study aimed to develop a bilayer adhesion barrier comprising alginate (Alg) of different molecular weight (Mw). It was expected that a slowly dissolving layer remains on the cut surface, functioning as a physical barrier, whereas a rapidly dissolving layer widely distributes in the peritoneal cavity to prevent de novo adhesions. METHODS: Bilayer Alg sponges were fabricated using low Mw Alg for the upper layer and high Mw Alg for the bottom layer. The dissolution behavior of each layer was evaluated in vitro in peritoneum-like environments. We constructed a Pean crush hepatectomy-induced adhesion model in rats. The effects of the bilayer sponge on cut surface and de novo adhesions were separately evaluated in terms of their extent and grade. RESULTS: The Alg sponge layer with low Mw dissolved faster than that with high Mw in vitro. One week after the hepatectomy, although no significant decrease in adhesion extent on the cut surface was observed in rats that received Seprafilm and Interceed, treatment with Alg bilayer sponge significantly decreased the adhesion extent to 38% of that without treatment. Moreover, a significant decrease in de novo adhesion extent was observed in the Alg bilayer sponge compared with the Interceed group. CONCLUSIONS: The Alg bilayer sponge was effective for preventing both cut surface and de novo adhesions in the rat Pean crush hepatectomy model. The simple yet functional design of the Alg bilayer sponge can facilitate its use in future clinical practice.

In Situ Fabrication of Double-Layered Hydrogels via Spray Processes to Prevent Postoperative Peritoneal Adhesion.

Postoperative peritoneal adhesions could cause pelvic pain, infertility, and bowel obstruction. In addition, adhesiolysis makes second surgery difficult. For the first time, we fabricated double-layered hydrogels in situ on the trauma surface via sequential double spray processes to prevent peritoneal adhesions. The spray conditions were optimized for spray distance and gas flow rate to create homogeneous and seamless double-layered hydrogels. The top layer was composed of alginate (Alg)-carboxymethyl cellulose (CMC) and serves as the barrier between the wounded tissue and surrounding tissues. The bottom layer was composed of Alg-gelatin (Gela) and comes in direct contact with the wounded tissue to promote wound healing. In vitro experiments showed that the Alg-Gela hydrogel layer promoted wound healing by accelerating horizontal cell migration. In addition, the Alg-CMC layer prevented the vertical penetration of fibroblast cells. The prevention efficacy of the sprayable double-layered hydrogels was evaluated using a partial hepatectomy-induced adhesion model in rats. The double-layered hydrogels decreased the adhesion grade and extent of liver cut surface, whereas the two single-layered hydrogels, Alg-CMC and Alg-Gela, did not show any adhesion prevention efficacy.

Implant-supported Prostheses in Patient with Sjögren's Syndrome: Clinical Report with 3-year Follow-up.

Sjögren's syndrome (SS), an autoimmune disorder, affects the exocrine glands, including the lacrimal and salivary glands. It is characterized by symptoms of dry eye and dry mouth. As secretion of saliva decreases, patients with SS experience rampant caries, pain in the oral mucosa, inflammation and hardening of the salivary glands, abnormal taste, dysphagia, and loss of teeth earlier than healthy individuals. A removable partial denture is often used as a prosthesis after tooth loss. Compromised salivary lubrication, however, can produce traumatic ulceration of the mucosa, making use of a removable prosthesis in SS patients painful. In such cases, a dental implant is likely to be requested as an alternative. This report describes dental implant treatment in an SS patient, a 50-year-old woman who presented with the chief complaint of masticatory dysfunction and pain due to a removable partial denture. Eight implants were placed in the maxillary and mandibular first molar tooth and second molar tooth regions. Following a 4-month non-loading period, second-stage surgery and provisional restoration with a screwretained implant temporary crown were performed. Screw-retained superstructures were fitted by means of a customized titanium abutment and zirconia crown as the final restoration. No complications, including inflammation of peri-implant soft tissue or resorption of peri-implant bone, were observed at 3 years following placement of the superstructures.

Injectable Hemostat Composed of a Polyphosphate-Conjugated Hyaluronan Hydrogel.

We have developed a new hydrogel hemostat composed of hyaluronan (HA) conjugated with inorganic polyphosphate (PolyP). A hemostatic hydrogel, HAX-PolyP, was formed rapidly by mixing aldehyde-modified HA and hydrazide-modified HA conjugated with PolyP (HA-PolyP). Although the gelation rate decreased with increasing PolyP content, the gelation time was below 5 min. In addition, the hydrogel swelling volume decreased with increasing PolyP content, but the degradation rate did not depend on PolyP content and the hydrogel underwent complete degradation through hydrolysis over 3 weeks in phosphate buffered saline. HAX-PolyP showed similar biocompatibility with the HA hydrogel without PolyP conjugation in vitro and in vivo. Intraperitoneal administration of HAX-PolyP did not induce any adhesion in the peritoneum and clot formation in the lungs. Finally, HA-PolyP accelerated the coagulation rate of human plasma ex vivo, and HAX-PolyP showed as strong a hemostatic effect as fibrin glue in a mouse liver bleeding model in vivo.

Intraperitoneal Delivery of Cisplatin via a Hyaluronan-Based Nanogel/in Situ Cross-Linkable Hydrogel Hybrid System for Peritoneal Dissemination of Gastric Cancer.

Intraperitoneal administration of chemotherapeutics is expected for the treatment of peritoneally disseminated gastric cancer because of poor migration of the drugs from the systemic circulation to the peritoneal cavity. In this study, for intraperitoneal delivery of cisplatin (CDDP), we developed a hyaluronan (HA)-based hybrid system in which CDDP-loaded HA nanogels were either physically encapsulated in or chemically conjugated to injectable HA hydrogels. Physical encapsulation enabled sustained release of HA nanogels from the HA hydrogel matrix for over a week. This was a longer release period than that of encapsulated free CDDP, which released 80% of the drug in 2 days. The longer release was attributed to delayed diffusion of HA nanogels from the hydrogel matrix network. The release profile could be tuned by modifying the chemical conjugation of HA nanogels to the HA hydrogel matrix, as well as the type of chelating ligands used to load CDDP to the nanogel. Furthermore, intraperitoneally administered hybrid had significant antitumor activity in a mouse model of peritoneally disseminated gastric cancer, especially for nodules smaller than 1.0 mm.

Prevalence and risk factors for peri-implant diseases in Japanese adult dental patients.

We investigated the prevalences and risk factors for peri-implant diseases in Japanese adult dental patients attending a follow-up visit at dental hospitals or clinics as part of their maintenance program. This cross-sectional multicenter study enrolled patients with dental implants who attended regular check-ups as part of a periodontal maintenance program during the period from October 2012 through September 2013. Patients with implants with at least 3 years of loading time were included in the study. The condition of peri-implant tissue was examined and classified into the following categories: healthy, peri-implant mucositis, and peri-implantitis. Patients were also evaluated for implant risk factors. A total of 267 patients (110 men, 157 women; mean age: 62.5 ± 10.7 years) were analyzed. The prevalence of patient-based peri-implant mucositis was 33.3% (n = 89), and the prevalence of peri-implantitis was 9.7% (n = 26). Poor oral hygiene and a history of periodontitis were strong risk factors for peri-implant disease. The present prevalences were lower than those previously reported. The quality of periodontal therapy before and after implant installation and patient compliance and motivation, as indicated by plaque control level, appear to be important in maintaining peri-implant tissue health.

Production of Cisplatin-Incorporating Hyaluronan Nanogels via Chelating Ligand-Metal Coordination.

Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand-metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or malonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand-platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.