Preparation of Tumor-Targeting pH-Sensitive Polymeric Nanoprodrugs through the Self-Assembly of Biotinylated Polymer–Drug Conjugates Utilizing a Simple Diels–Alder Chemical Strategy

Smart polymeric nanoprodrugs (NPDs) are a kind of ideal platform for the targeted delivery of chemotherapeutic agents to inhibit tumor growth. However, it is still a challenge to prepare NPDs in a simple way with high drug loading efficiency. Herein, we utilized RAFT polymerization to prepare a biotinylated PEG-block-poly furfuryl methacrylate (Biotin-PEG5k-PFMA) copolymer from all commercially available materials. Then, for the first time, the pH-sensitive doxorubicin (DOX) prodrug of INNO-206 (Mal-DOX) in clinical trials was covalently conjugated with the PFMA segments through the simple Diels–Alder reaction. The NPDs were then rapidly prepared by directly dialyzing the reaction mixture. This process favors the highly effective preparation of NPDs because the essentially complicated purification procedures for both the prodrug and the polymer–drug conjugates in traditional methods are avoided. The resulting NPDs showed a very small size of 23 nm and acid-triggered DOX release dynamics with high drug loading and encapsulation efficiencies of 24% and 83%, respectively. The tumor-targeting NPDs entered the tumor cells through clathrin- and caveolin-mediated endocytosis and then delivered DOX into the nucleus, efficiently inhibiting the proliferation of the cancer cells; meanwhile, it inhibited the migration of tumor cells. In vivo, the NPDs could suppress the growth of cancer more efficiently than the free DOX and increase circulation time in the blood system. Furthermore, the NPDs were proven to be efficient in suppressing hepatic metastases of triple-negative cancer and reducing the harmful side effects associated with free DOX, such as cardiotoxicity and lung and kidney damage.