A ‘tandem’ nanomedicine approach against osteoclastogenesis. Polysulfide micelles synergically scavenge ROS and release rapamycin

We show the first example of a synergic approach of oxidant (ROS) scavenging carrier and ROS-responsive drug release in the context of a potential therapy against osteoporosis, aiming to inhibit the differentiation of inflammatory cells into osteoclasts. In our ‘tandem’ approach, a branched amphiphilic, PEGylated polysulfide (PPSES-PEG) was preferred over a linear analogue, because of improved homogeneity in the aggregates (spherical micelles vs. mixture of worm-like and spherical), increased stability and higher drug loading (up to ~22%wt. of anti-osteoclastic rapamycin). These effects are ascribed to the branching inhibiting crystallization in the polysulfide blocks. The ROS-scavenging micelles alone were already able to reduce osteoclastogenesis in a RAW 264.7 model, but the ‘drug’ combination (the polymer itself + rapamycin released only under oxidation) completely abrogated the process. An important take-home message is that the synergic performance depended very strongly on the oxidant:oxidizable gr...