LAUSR

The lack of cellular and tissue specificity in conventional chemotherapies along with the generation of a complex tumor microenvironment (TME) limit the dosage of active agents that reaches tumor sites thereby resulting in ineffective responses and side effects. Therefore, the development of selective TME responsive nanomedicines is of due relevance towards successful chemotherapies, albeit challenging. In this framework, we have synthesized novel, ready-to-use ROS-responsive amphiphilic block copolymers (BCs) with two different spacer chemistry designs to connect a hydrophobic boronic ester-based ROS sensor into the polymer backbone. Hydrodynamic flow focusing nanoprecipitation microfluidics (MF) was used in the preparation of well-defined ROS-responsive PSs there were further characterized by a combo of techniques (1H NMR, DLS, SLS, TEM and cryo-TEM). The reaction with hydrogen peroxide releases an amphiphilic phenol or a hydrophilic carboxylic acid which impacts polymersome (PS) stability and cargo release. Therefore, the importance of the spacer chemistry in BCs deprotection and PSs stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration highlighting the potential of the well-defined ROS-responsive PSs as TME selective nanomedicines. The PSs could also find applications in other environments with high ROS-levels, such as, for instance, chronic inflammations, aging, diabetes, cardiovascular diseases and obesity.