Mixed Nanosized Polymeric Micelles as Promoter of Doxorubicin and miRNA‐34a Co‐Delivery Triggered by Dual Stimuli in Tumor Tissue

Dual stimuli‐sensitive mixed polymeric micelles (MM) are developed for co‐delivery of the endogenous tumor suppressor miRNA‐34a and the chemotherapeutic agent doxorubicin (Dox) into cancer cells. The novelty of the system resides in two stimuli‐sensitive prodrugs, a matrix metalloproteinase 2 (MMP2)‐sensitive Dox conjugate and a reducing agent (glutathione, GSH)‐sensitive miRNA‐34a conjugate, self‐assembled in a single particle decorated with a polyethylene glycol corona for longevity, and a cell‐penetrating peptide (TATp) for enhanced intracellular delivery. The MMP2‐sensitivity of the system results in threefold higher cytotoxicity in MMP2‐overexpressing HT1080 cells compared to low MMP2‐expressing MCF7 cells. Cellular internalization of Dox increases by more than 70% after inclusion of TATp to the formulation. MMP2‐sensitive MM also inhibits proliferation and migration of HT1080 cells. Moreover, GSH‐sensitive MM allows for an efficient downregulation of Bcl2, survivin, and notch1 (65%, 55%, and 46%, respectively) in HT1080 cells. Combination of both conjugates in dual sensitive MM reduces HT1080 cell viability to 40% and expression of Bcl2 and survivin. Finally, 50% cell death is observed in 3D models of tumor mass. The results confirm the potential of the MM to codeliver miRNA‐34a and doxorubicin triggered by dual stimuli inherent of tumor tissues.