Abstract
In order to promote the delivery of therapeutic agents toward the hypoxia regions of malignant tumors, an innovative cell-based cancer theranostic system was developed in this study by adopting the tumor-homing monocytes (bone marrow-derived monocytes) as a cellular vehicle for co-delivery of polymer bubbles and doxorubicin (Dox)-loaded polymeric vesicles. The lipid-containing copolymers, poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)), with the DSA contents of 15 and 25 mol% were used respectively as the major materials to fabricate the nano-scaled polymer vesicles and bubbles. Because of the dense lipid-rich membrane structure that prevents the premature drug leakage, the Dox-encapsulated polymeric vesicles after being internalized by monocytes are rather benign to the host cells, thereby allowing to retain the high cellular activity and viability at least for 24 h. Moreover, the polymer bubbles within the monocytes in the absence of focused ultrasound treatment exhibited the long-term profound ultrasound imaging contrast. Nevertheless, by the remote-controlled focused ultrasound-triggered disruption of polymer bubbles that generated inertial cavitation to further impair the Dox-loaded vesicle structure, the drug was promptly liberated. The results of the in vitro cytotoxicity showed that the payload-containing monocytes after being exposed to focused ultrasound while being coincubated with TRAMP-C1 cells (murine prostate cancer cells) displayed the outstanding ability to inhibit tumor cell proliferation. The cargo-loaded monocytes can retain well migration ability by the treatment with simulated tumor microenvironments. Distinct from the substantial accumulation of Dox-containing vesicles and polymeric bubbles in the liver of TRAMP-C1 tumor-bearing mice, the transport and residence of vesicles and bubbles within liver by using monocytes as the vehicles was appreciably reduced, while their tumor accumulation was remarkably increased. The in vivo antitumor studies revealed that the tumor growth of tumor-bearing mice with and without radiation therapy after being intravenously injected with cargo-loaded monocytes and then subjected to focused ultrasound treatment was largely inhibited. Besides, the histological examinations of tumor sections proved the successful transport of Dox by monocytes to the tumor hypoxic regions far away from the blood vessels compared to that by polymeric vesicles alone. This work demonstrates that the combination of tumor-homing monocytes with various functionalized nanoparticles shows great potential to achieve effective delivery of therapeutic payloads to tumor hypoxic regions.