Functionalized hydroxypropyl-β-cyclodextrin inclusion complex for combined tumor therapy through intelligent delivery of paclitaxel and polarization of M2-like tumor associated macrophages

The treatment outcomes of chemotherapy are far from satisfactory due to suboptimal cellular uptake and inadequate intracellular release of antitumor drugs. Meanwhile, M2-like tumor associated macrophages (TAMs) in the tumor microenvironment promote cancer growth and metastasis. The combined strategy of chemotherapy and reprogramming M2-like TAMs within tumor microenvironment has emerged as a novel paradigm for cancer therapy. Hence, a pH-sensitive double-targeted inclusion complex was constructed for combined cancer therapy through the controlled paclitaxel (PTX) delivery and re-education of M2-like TAMs. The inclusion complex employed arginine and biotin modified hydroxypropyl-β-cyclodextrin (Arg-CD-Bio) as the host, with benzimidazole and mannose modified hyaluronic acid (BM-HA-Man) as the pH-sensitive plug. PTX was encapsulated in the inclusion complex. In vitro experiments indicated that the Arg-CD-Bio/BM-HA-Man inclusion complex could facilitate the specific release of PTX at the tumor site. The inclusion complex could be effectively internalized by M2-like TAMs and MCF-7 cells and further reprogramme M2-like TAMs to M1-like TAMs. In vivo antitumor therapy in 4T1 tumor-bearing mice had achieved remarkable suppression efficacy. These results suggested that the PTX-loaded Arg-CD-Bio/BM-HA-Man inclusion complex was a promising platform for efficient cancer treatment.