Triggered Enzymatic Biodegradable Drug Delivery Systems Based on Supramolecular Micelles

摘要

A novel supramolecular stimuli-sensitive biodegradable system was exploited and applied for stimuli-responsible release of doxorubicin (DOX). In this study, poly-rotaxane micelles were synthesized by partially threading a-cyclodextrin (a-CD) on the side chain of 8-arm polyethylene glycol (PEG), and blocking the end of the polymer with both biodegradable and non-biodegradable linkage. The resulted polyrotaxane (PR) could form micelle structure in water with a hydrophobic crystalline CD core and a hydrophilic PEG shell, which has been characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and critical micellization concentration (CMC). Furthermore, the micelles with enzymatic biodegradable end groups, though sufficiently stable in water, were prone to fast degradation in the presence of papain, due to the reductive cleavage of the enzymatic biodegradable end groups. The nano-sized particles showed great potential to be used as carrier for the release of DOX with high drug loading efficiency (78%) and sustained in vitro release for more than 2 months. Interestingly, biodegradable polyrotaxane micelles exhibited a triggered faster in vitro release under a reductive environment, suggesting their stimuli-responsible properties. In a further development of intracellular study, the micelles significantly enhanced the cellular uptake of DOX and its cytotoxicity against cancer cells. Remarkably, the polyrotaxane micelles accomplished much faster internalization, rapid release of DOX inside cells and higher anticancer efficacy as compared to the free DOX control. As a continuation of current study, these polyrotaxane micelles highlight a great potential in sustained and efficient intracellular drug delivery.