Abstract
Abstract Tumor-homing bone marrow-derived monocytes were utilized as a cell-based vehicle to deliver chlorin e6 (Ce6)/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded oxygen microbubbles to the hypoxia regions of malignant tumors for improving therapeutic efficacy of the combined hyperthermia and photodynamic therapy (PDT). The polymeric membranes of the oxygen microbubbles were mainly composed of poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)) and able to efficiently carry Ce6 species and SPIONs. In the absence of pertinent external triggers the SPION/Ce6-loaded oxygen bubbles after being internalized by monocytes are found rather benign to the host, thereby allowing to retain high cell viability and migration ability with the treatment under simulated tumor microenvironments. While being co-incubated with TRAMP-C1 cells (murine prostate cancer cells) and then exposed to both high frequency magnetic field (HFMF) and NIR illumination (660 nm), the payload-containing monocytes displayed prominent performance to inhibit tumor cell proliferation. Notably, compared to only slight deposition of both free Ce6 and cargo-loaded oxygen bubbles in the tumor region of TRAMP-C1 tumor-bearing mice after i.v. injection, the tumor accumulation of SPION/Ce6-encapsulated oxygen bubbles transported via monocytes was significantly enhanced. The tumor growth of TRAMP-C1 tumor-bearing mice intravenously injected with payload-containing monocytes and then subjected to both HFMF and NIR illumination treatment was greatly inhibited. In addition, the histological examinations of tumor sections confirmed the successful cellular transport of Ce6 molecules to the tumor hypoxic regions and the pronounced in vivo cytotoxicity elicited by the NIR-triggered generation of reactive oxygen species. This work demonstrates that the cellular delivery system using tumor-tropic monocytes to carry functionalized oxygen bubbles have great potential to enhance the antitumor efficacy, particularly in hypoxia regions, by combining the hyperthermia and PDT treatment.