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.

Intraperitoneal administration of cisplatin via an in situ cross-linkable hyaluronic acid-based hydrogel for peritoneal dissemination of gastric cancer.

PURPOSE: To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively. METHODS: CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer. RESULTS: The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group. CONCLUSIONS: In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.

In situ cross-linkable hydrogel of hyaluronan produced via copper-free click chemistry.

Injectable hydrogels are useful in biomedical applications. We have synthesized hyaluronic acids chemically modified with azide groups (HA-A) and cyclooctyne groups (HA-C), respectively. Aqueous HA-A and HA-C solutions were mixed using a double-barreled syringe to form a hydrogel via strain-promoted [3 + 2] cycloaddition without any catalyst at physiological conditions. The hydrogel slowly degraded in PBS over 2 weeks, which was accelerated to 9 days by hyaluronidase, while it rapidly degraded in a cell culture media with fetal bovine serum within 4 days. Both HA-A and HA-C showed good biocompatibility with fibroblast cells in vitro. They were administered using the double-barreled syringe into mice subcutaneously and intraperitoneally. Residue of the hydrogel was cleared 21 days after subcutaneous administration, while it was cleared 7 days after intraperitoneal administration. This injectable HA hydrogel is expected to be useful for tissue engineering and drug delivery systems utilizing its orthogonality.

Development of a Potassium-Ion-Responsive Star Copolymer with Controlled Aggregation/Dispersion Transition.

Stimuli-responsive star polymers are promising functional materials whose aggregation, adhesion, and interaction with cells can be altered by applying suitable stimuli. Among several stimuli assessed, the potassium ion (K+), which is known to be captured by crown ethers, is of considerable interest because of the role it plays in the body. In this study, a K+-responsive star copolymer was developed using a polyglycerol (PG) core and grafted copolymer arms consisting of a thermo-responsive poly(N-isopropylacrylamide) unit, a metal ion-recognizing benzo-18-crown-6-acrylamide unit, and a photoluminescent fluorescein O-methacrylate unit. Via optimization of grafting density and copolymerization ratio of grafted arms, along with the use of hydrophilic hyperbranched core, microsized aggregates with a diameter of 5.5 µm were successfully formed in the absence of K+ ions without inducing severe sedimentation (the lower critical solution temperature (LCST) was 35.6 °C). In the presence of K+ ions, these aggregates dispersed due to the shift in LCST (47.2 °C at 160 mM K+), which further induced the activation of fluorescence that was quenched in the aggregated state. Furthermore, macrophage targeting based on the micron-sized aggregation state and subsequent fluorescence activation of the developed star copolymers in response to an increase in intracellular K+ concentration were performed as a potential K+ probe or K+-responsive drug delivery vehicle.

Preparation of monodisperse chitosan microcapsules with hollow structures using the SPG membrane emulsification technique.

We describe herein successful preparations of monodisperse chitosan microcapsules with hollow structures using the SPG membrane emulsification technique. Two preparation procedures were examined in this study. In the first method, monodisperse calcium alginate microspheres were prepared and then coated with unmodified chitosan. Subsequently, tripolyphosphate treatment was conducted to physically cross-link chitosan and solubilize the alginate core at the same time. In the second method, photo-cross-linkable chitosan was coated onto the monodisperse calcium alginate microspheres, followed by UV irradiation to chemically cross-link the chitosan shell and tripolyphosphate treatment to solubilize the core. For both methods, it was determined that the average diameters of the chitosan microcapsules depended on those of the calcium alginate microparticles and that the microcapsules have hollow structures. In addition, the first physical cross-linking method using tripolyphosphate was found to be preferable to obtain the hollow structure, compared with the second method using chemical cross-linking by UV irradiation. This was because of the difference in the resistance to permeation of the solubilized alginate through the chitosan shell layers.

Fast Controlled Living Polymerization of Arylisocyanide Initiated by Aromatic Nucleophile Adduct of Nickel Isocyanide Complex.

The fast living polymerization of chiral arylisocyanide in the presence of the aromatic nucleophile adduct of tetra(t-butylisocyano)nickel(II) complex as an initiator gave the predominantly one-handed helical polyisocyanide with narrow polydispersity. X-ray crystal structures of initiators and MALDI-TOF MS and NMR studies of the polymer products elucidated the key role of the aromatic substituents in the initiator and monomer achieving narrow polydispersity. The aromatic groups in the initiator and monomer stabilized the electronic structure of the carbene-like ligand to suppress dissociation of the active nickel complex that leads to chain transfer and termination. The aromatic groups also controlled the reactivity of the active site for initiation and propagation.