Co-delivery of 5-fluorouracil and miRNA-34a mimics by host-guest self-assembly nanocarriers for efficacious targeted therapy in colorectal cancer patient-derived tumor xenografts

Rationale: A co-delivery system that can transport chemotherapeutic drugs and nucleotide drugs to distinct targets in tumors is an attractive strategy for cancer therapy. In this study, well-defined targeted quantum dot (QD)-based multifunctional nanocarriers were developed through self-assembly driven by host-guest interactions. 5-fluorouracil (5-FU) and microRNA-34a mimics (miR-34a(m)) were co-administered to achieve synergistic effects for colorectal cancer (CRC) therapy for the first time. Furthermore, the CRC patient-derived tumor xenograft (PDX) model, which closely mimics human CRC tumor pathological properties, was used for evaluating the therapeutic effect in this research. Methods: Multiple β-cyclodextrin (CD)-attached QD nanoparticles were used as host molecules. An adamantane (ADA)-modified TCP1 peptide-targeting ligand (TCP1) was used as the guest molecule. 5-FU and miR-34a(m) were loaded into TCP1-CD-QD nanocarriers, which were used to treat CRC in vitro and in vivo. In addition, the CRC PDX model was used to evaluate the treatment efficacy of this co-delivery system. Results: 5-FU and miR-34a(m) can be efficiently encapsulated into TCP1-CD-QD nanocarriers and delivered into CRC cells, which led to the inhibition of the proliferation and migration of CRC cells in vitro and suppression of tumor growth in a CRC cell-derived tumor xenograft model. The obtained data further suggested that co-delivery of 5-FU and miR-34a(m) could achieve synergistic effects for CRC therapy. Notably, targeted therapy via the co-delivery of 5-FU and miR-34a(m) by TCP1-CD-QD nanocarriers significantly inhibited the growth of PDX tumors. Conclusions: These studies strongly indicate that such a nanocarrier-based co-delivery system is a promising combined therapeutic strategy that utilizes chemotherapeutic drugs and nucleotide drugs for enhancing colorectal cancer targeting and synergistic therapy.