Self-Assembled Nanogels of Cholesterol-Bearing Hydroxypropyl Cellulose: A Thermoresponsive Building Block for Nanogel Tectonic Materials.

Hydroxypropyl cellulose (HPC) is a fascinating polysaccharide to use in developing a nanogel to be a thermoresponsive building unit for nanogel tectonic materials. Cholesterol-bearing HPC (Ch-HPC) self-assembled to form nanogels through hydrophobic interactions of the cholesteryl groups in water. Ch-HPC nanogels had a lower critical solution temperature in line with that of native HPC. The particle size of Ch-HPC nanogels was reversibly controlled by the temperature and salting-out effect. The thermoresponsive property was also observed in Ch-HPC nanogel-cross-linked macrogels. These results suggest that a Ch-HPC nanogel is an attractive building block for thermoresponsive nanogel tectonic materials.

Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies.

Synthesis and function of amphiphilic glucan dendrimers as nanocarriers for protein delivery.

We report the combined enzymatic synthesis of five glucan dendrimers with control of molecular weight and particle size. Amphiphilic properties were introduced through dodecyl group substitution. A Tokyo-green fluorescence assay showed that amphiphilic glucan dendrimers were able to successfully deliver active ß-galactosidase to cells.

Self-assembled nanogel of cholesterol-bearing xyloglucan as a drug delivery nanocarrier.

Xyloglucan (XG) is a multibranched polysaccharide consisting of a main chain ß-1,4-glucan with xylose and galactose side chains. In this study, cholesterol-bearing XG (CHXG) was synthesized by the reaction of XG with cholesteryl N-(6-isocyanatohexyl) carbamate. The CHXG molecules self-assembled in water to form nanogels consisting of about 100 molecules of XG, and were characterized using light scattering and transmission electron microscopy. The number of cholesteryl groups per physical cross-linking site was estimated using a fluorescence quenching method. The resulting CHXG nanogels could be complexed with molecules of low molecular weight, such as iodine and paclitaxel, making the nanogels useful as drug carriers. The CHXG nanogels could also be specifically internalized by hepatocytes via the galactose receptors on their cell surface. CHXG self-assembled nanogels may be suitable as novel drug nanocarriers with galactose-specific targetability.

Nanoscopic Structural Investigation of Physically Cross-Linked Nanogels Formed from Self-Associating Polymers.

The detailed structure of a nanogel formed by self-association of cholesterol-bearing pullulans (CHPs) was determined by contrast variation small-angle neutron scattering. The decomposition of scattering intensities into partial scattering functions of each CHP nanogel component, i.e., pullulan, cholesterol, and the cross-term between the pullulan and the cholesterol, allows us to investigate the internal structure of the nanogel. The effective spherical radius of the skeleton formed by pullulan chains was found to be 8.1 ± 0.3 nm. In the CHP nanogel, there are about 19 cross-linking points where a cross-linking point is formed by aggregation of trimer cholesterol molecules, and the spatially inhomogeneous distribution of the cross-linking points in the nanogel can be represented by the mass fractal dimension of 2.6. The average radius of gyration of the partial chains can also be determined to be 1.7 ± 0.1 nm by analyzing the extracted cross-correlation between the cross-linker and the tethered polymer chain quantitatively, and the size agrees with the value assuming random distribution of the cross-linkers on the chains. As the result, the complex structure of the nanogels is coherently revealed at the nanoscopic level.