Long-Term Retarded Release for the Proteasome Inhibitor Bortezomib through Temperature-Sensitive Dendritic Glycopolymers as Drug Delivery System from Calcium Phosphate Bone Cement.

For the local treatment of bone defects, highly adaptable macromolecular architectures are still required as drug delivery system (DDS) in solid bone substitute materials. Novel DDS fabricated by host-guest interactions between ß-cyclodextrin-modified dendritic glycopolymers and adamantane-modified temperature-sensitive polymers for the proteasome inhibitor bortezomib (BZM) is presented. These DDS induce a short- and long-term (up to two weeks) retarded release of BZM from calcium phosphate bone cement (CPC) in comparison to a burst release of the drug alone. Different release parameters of BZM/DDS/CPC are evaluated in phosphate buffer at 37 °C to further improve the long-term retarded release of BZM. This is achieved by increasing the amount of drug (50-100 µg) and/or DDS (100-400 µg) versus CPC (1 g), by adapting the complexes better to the porous bone cement environment, and by applying molar ratios of excess BZM toward DDS with 1:10, 1:25, and 1:100. The temperature-sensitive polymer shells of BZM/DDS complexes in CPC, which allow drug loading at room temperature but are collapsed at body temperature, support the retarding long-term release of BZM from DDS/CPC. Thus, the concept of temperature-sensitive DDS for BZM/DDS complexes in CPC works and matches key points for a local therapy of osteolytic bone lesions.

Immunomodulatory Effects of Dendritic Poly(ethyleneimine) Glycoarchitectures on Human Multiple Myeloma Cell Lines, Mesenchymal Stromal Cells, and in Vitro Differentiated Macrophages for an Ideal Drug Delivery System in the Local Treatment of Multiple Myeloma.

The use of a drug delivery system (DDS) represents a novel therapeutic approach in the treatment of multiple myeloma in bone lesion. We show the immunomodulatory effects of anionic and cationic dendritic poly(ethyleneimine) glycoarchitectures (PEI-DGAs) on human myeloma cell lines and cells in their microenvironment, in vitro differentiated macrophages, and mesenchymal stromal cells (MSCs). PEI-DGAs do not influence the secretion of IL-6, which is a major growth and survival factor in multiple myeloma. Cationic PEI-DGAs in turn have cytostatic properties on multiple myeloma cell lines. Anionic PEI-DGAs induce the secretion of proinflammatory cytokines IL-1ß, TNFα, and IL-6 in macrophages and MSCs, whereas cationic PEI-DGAs do not. Macrophages and MSCs show remarkably high cell viability in the presence of high concentration of PEI-DGAs. RNA sequencing of MSCs exposed to cationic PEI-DGAs supports the hypothesis that smaller cationic PEI-DGAs are less toxic and could improve osteogenic differentiation in an ideal DDS.