Cargo-Free Nanomedicine with pH Sensitivity for Codelivery of DOX Conjugated Prodrug with SN38 to Synergistically Eradicate Breast Cancer Stem Cells

As a result of their ability to transform into bulk cancer cells and their resistance to radiotherapy and chemotherapy, cancer stem cells (CSCs) are currently considered as a major obstacle for cancer treatment. Application of multiple drugs using nanocarriers is a promising approach to simultaneously eliminate noncancer stem cells (non-CSCs) and CSCs. Herein, to employ the advantages of nanomedicine while avoiding new excipients, pH-responsive prodrug (PEG-CH=N-DOX) was employed as the surfactant to fabricate cargo-free nanomedicine for codelivery of DOX conjugated prodrug with SN38 to synergistically eradicate breast cancer stem cells (bCSCs) and non-bCSCs. Through the intermolecular interaction between DOX and SN38, PEG-CH=N-DOX and SN38 were assembled together to form a stable nanomedicine. This nanomedicine not only dramatically enhanced drug accumulation efficiency at the tumor site but also effectively eliminated bCSCs and non-bCSCs, which resulted in achieving a superior in vivo tumor inhibition activity. Additionally, the biosafety of this nanomedicine was systematically studied through immunohistochemistry, blood biochemistry assay, blood routine examination, and metabolomics. The results revealed that this nanomedicine significantly reduced the adverse effects of DOX and SN38. Therefore, this simple yet efficient nanomedicine provided a promising strategy for future clinical applications.