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Doxorubicin (DOX)-loaded nanoparticles (NPs) based on interconnected hyaluronic acid-ceramide (HACE) structure were fabricated and their anti-tumor efficacy was evaluated in vitro. Interconnected HACE was synthesized by cross-linking HACE with adipic acid dihydrazide (ADH) and its synthesis was identified by (1)H NMR analysis. DOX-loaded NPs with <200nm mean diameter, negative zeta potential, and spherical shape were prepared. Interconnected HACE-based NPs increased drug-loading capacity and in vitro drug release, compared to HACE-based NPs. DOX release was dependent on the environmental pH, implying the feasibility of enhancing drug release in tumor region and endosomal compartments. Synthesized interconnected HACE did not show cytotoxic effect up to 1000μg/ml concentration in NIH3T3 and MDA-MB-231 cells. In cellular uptake studies using confocal laser scanning microscopy (CLSM) and flow cytometry in MDA-MB-231 cells, higher uptake of DOX was observed in the interconnected HACE-based NPs than HACE NPs. In vitro anti-tumor efficacy was assessed by MTS-based assay, in which cytotoxic effect of DOX-loaded interconnected HACE NPs was higher than that of DOX-loaded HACE NPs. Thus, these results suggest the feasibility of interconnected HACE-based NPs to be used for efficient tumor-targeted delivery of anticancer drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Encapsulation of nucleus pulposus (NP) cells within in situ forming hydrogels is a novel biological treatment for early stage intervertebral disc degeneration. The procedure aims to prolong the life of the degenerating discs and to regenerate damaged tissue. In this study we developed an injectable oxidized hyaluronic acid-gelatin-adipic acid dihydrazide (oxi-HAG-ADH) hydrogel. High molecular weight (1900 kDa) hyaluronic acid was crosslinked with various concentrations of gelatin to synthesize the hydrogels and their viscoelastic properties were analyzed. Interactions between the hydrogels, NP cells, and the extracellular matrix (ECM) were also evaluated, as were the effects of the hydrogels on NP cell gene expression. The hydrogels possess several clinical advantages, including sterilizability, low viscosity for injection, and ease of use. The viscoelastic properties of the hydrogels were similar to native tissue, as reflected in the complex shear modulus (∼11-14 kPa for hydrogels, 11.3 kPa for native NP). Cultured NP cells not only attached to the hydrogels but also survived, proliferated, and maintained their round morphology. Importantly, we found that hydrogels increased NP cell expression of several crucial ECM-related genes, such as COL2A1, AGN, SOX-9, and HIF-1A., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hyaluronic acid (HA) hydrogels prepared with three different crosslinking reagents were assessed by in vitro and in vivo degradation tests for various tissue engineering applications. Adipic acid dihydrazide grafted HA (HA-ADH) was synthesized and used for the preparation of methacrylated HA (HA-MA) with methacrylic anhydride and thiolated HA (HA-SH) with Traut's reagent (imminothiolane). (1)H NMR analysis showed that the degrees of HA-ADH, HA-MA, and HA-SH modification were 69, 29, and 56 mol%, respectively. HA-ADH hydrogel was prepared by the crosslinking with bis(sulfosuccinimidyl) suberate (BS(3)), HA-MA hydrogel with dithiothreitol (DTT) by Michael addition, and HA-SH hydrogel with sodium tetrathionate by disulfide bond formation. According to in vitro degradation tests, HA-SH hydrogel was degraded very fast, compared to HA-ADH and HA-MA hydrogels. HA-ADH hydrogel was degraded slightly faster than HA-MA hydrogel. Based on these results, HA-MA hydrogels and HA-SH hydrogels were implanted in the back of SD rats and their degradation was assessed according to the pre-determined time schedule. As expected from the in vitro degradation test results, HA-SH hydrogel was in vivo degraded completely only in 2 weeks, whereas HA-MA hydrogels were degraded only partially even in 29 days. The degradation rate of HA hydrogels were thought to be controlled by changing the crosslinking reagents and the functional group of HA derivatives. In addition, the state of HA hydrogel was another factor in controlling the degradation rate. Dried HA hydrogel at 37 degrees C for a day resulted in relatively slow degradation compared to the bulk HA hydrogel. There was no adverse effect during the in vivo tests.