Correlation of Polymer–drug Composition with Micelle Properties, Performance, and Cytotoxicity for the Oligoelectrolyte-mediated pH-triggered Release of Hydrophobic Drugs

Polymeric micelles have the potential to improve the efficacy and safety of drug delivery by improving drug solubility, enhancing bioaccumulation and reducing off-target toxicity. Despite excellent safety profiles, a major limitation with polymeric micelles is their inability to rapidly release their payload once they have reached their target, leading to the inadequate delivery of therapeutic doses. To address this limitation, we have developed a novel strategy to impart pH-responsiveness in non-responsive micelles through the co-encapsulation of oligoelectrolytes with drugs. Herein, we investigate the influence of copolymer composition and drug identity in combination with oligoelectrolyte—oligo(2-vinyl pyridine) (OVP)—loading on pH-triggered drug release from micelles and their cytotoxicity. A library of OVP-loaded micelles was prepared using conventional and well-established non-responsive block copolymers. Dynamic light scattering (DLS) was used to monitor the changes in the micelles as a function of pH. Regardless of the copolymer composition, an abrupt decrease in the hydrodynamic diameter (D_h) was observed as the pH was reduced due to OVP expulsion from the core, which was also confirmed by release studies. In general, co-encapsulation of OVP and model drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX), and 7-ethyl-10-hydroxycamptothecin (SN38)) in the micelles provided good to excellent encapsulation efficiency percentage (EE%) values. In vitro studies revealed the pH triggered release of drugs from the OVP-loaded micelles regardless of the drug identity, which increased as the OVP loading increased. This general behaviour was observed in all cases, largely independent of the copolymer composition, albeit with subtle differences in the release profile for different drugs. Compared to their blank counterparts, the drug-loaded micelles displayed a slight increase in cytotoxicity against a panel of cancer cell lines, in a dose dependent manner. However, drug- and OVP-loaded micelles displayed a significant increase in cytotoxicity (up to 8-fold increase) that was independent of the copolymer composition. These results demonstrate the versatility of the oligoelectrolyte-mediated approach to furnish non-responsive micelles with a pH-trigger that allows the rapid release of drugs, regardless of the micelle composition or the drug identity.