Thermoresponsive Catechol Based-Polyelectrolyte Complex Coatings for Controlled Release of Bortezomib

Abstract

To overcome the high relapse rate of multiple myeloma (MM), a drug delivery coating for functionalization of bone substitution materials (BSM) is reported based on adhesive, catechol-containing and stimuli-responsive polyelectrolyte complexes (PECs). This system is designed to deliver the MM drug bortezomib (BZM) directly to the anatomical site of action. To establish a gradual BZM release, the naturally occurring caffeic acid (CA) is coupled oxidatively to form poly(caffeic acid) (PCA), which is used as a polyanion for complexation. The catechol functionalities within the PCA are particularly suitable to form esters with the boronic acid group of the BZM, which are then cleaved in the body fluid to administer the drug. To achieve a more thorough control of the release, the thermoresponsive poly(N-isoproplyacrylamide-co-dimethylaminoethylmethacrylate) (P(NIPAM-co-DMAEMA)) was used as a polycation. Using turbidity measurements, it was proven that the lower critical solution temperature (LCST) character of this polymer was transferred to the PECs. Further special temperature dependent attenuated total reflection infrared spectroscopy (ATR-FTIR) showed that coatings formed by PEC immobilization exhibit a similar thermoresponsive performance. By loading the coatings with BZM and studying the release in a model system, via UV/Vis it was observed, that both aims, the retardation and the stimuli control of the release, were achieved.

Cytotoxic constituents and a new hydroxycinnamic acid derivative from Leontodon saxatilis (Asteraceae, Cichorieae)

“…Compounds 8, 10, and 12, instead, showed moderate effects at higher concentrations and weak effects at 25 mM. On the contrary, apigenin (14) and luteolin (15) exhibited strong effects on NCI and OPM-2 cells at concentrations of 50 and 100 mM and were still moderately active at 25 mM. Moreover, both compounds showed moderate effects on U266 cells over the whole concentration range.…”

“…The same accounts for cichoric acid (13), which showed higher effects against all three myeloma cell lines than against healthy PBMC and HS5 cells. The most cytotoxic substances in this screen were apigenin (14) and luteolin (15). All tested cells displayed enhanced apoptosis with a clear preference of cell death in blood-borne cells.…”

“…All 13 isolated compounds and the 2 commercially obtained avonoids apigenin (14) and luteolin (15) were tested for their effect on NCI-H929, U266, and OPM-2 myeloma cell lines ( Fig. 5).…”

“…The group of investigated avonoids allows the most detailed discussion of their structure-activity relationship. Not only because of the two different avonoid scaffolds apigenin (14) and luteolin (15), but because of the different sugar moieties and their positions in the molecule. When looking at the results obtained for luteolin 7-O-b-D-rutinoside (7) it is evident that a disaccharidic moiety results in a complete loss of activity compared to the aglycone luteolin (15) or its monoglycosidic derivatives (10)(11)(12).…”

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

“…Similar to the first investigation, the authors found an initial burst release of adsorbed bortezomib followed by a gradual elution over 2 days. With a thermal stimulus of 42 • C, bortezomib release was accelerated due to conformational changes of the thermo-responsive coating [229]. Regarding thermally triggered drug release for bone regeneration, in vivo investigations are still lacking.…”