title: Tumortropic monocyte-mediated delivery of echogenic polymer bubbles and therapeutic vesicles for chemotherapy of tumor hypoxia.
abstract: Overcoming limitations often experienced in nanomedicine delivery toward hypoxia regions of malignant tumors remains a great challenge. In this study, a promising modality for active hypoxia drug delivery was developed by adopting tumortropic monocytes/macrophages as a cellular vehicle for co-delivery of echogenic polymer/C5F12 bubbles and doxorubicin-loaded polymer vesicles. Through the remote-controlled focused ultrasound (FUS)-triggered drug liberation, therapeutic monocytes show prominent capability of inducing apoptosis of cancer cells. The in vivo and ex vivo fluorescence imaging shows appreciable accumulation of cell-mediated therapeutics in tumor as compared to the nanoparticle counterpart residing mostly in liver. Inhibition of tumor recurrence with γ-ray pre-irradiated Tramp-C1-bearing mice receiving therapeutic monocytes intravenously alongside the FUS activation at tumor site was significantly observed. Immunohistochemical examination of tumor sections confirms successful cellular transport of therapeutic payloads to hypoxic regions and pronounced cytotoxic action against hypoxic cells. Following the intravenous administration, the cellular-mediated therapeutics can penetrate easily to a depth beyond 150 μm from the nearest blood vessels within pre-irradiated tumor while nanoparticles are severely limited to a depth of ca 10-15 μm. This work demonstrates the great promise of cellular delivery to carry therapeutic payloads for improving chemotherapy in hypoxia by combining external trigger for drug release.
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Wen-Chia
authors: WC
authors: Huang
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Wen-Hsuan
authors: WH
authors: Chiang
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Ya-Hui
authors: YH
authors: Cheng
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Wan-Chi
authors: WC
authors: Lin
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Ching-Fang
authors: CF
authors: Yu
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Chia-Yi
authors: CY
authors: Yen
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Chih-Kuang
authors: CK
authors: Yeh
authors: Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei 106, Taiwan.
authors: Chorng-Shyan
authors: CS
authors: Chern
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: cschiang@mx.nthu.edu.tw.
authors: Chi-Shiun
authors: CS
authors: Chiang
authors: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: hscchiu@mx.nthu.edu.tw.
authors: Hsin-Cheng
authors: HC
authors: Chiu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers
keywords: Cell-mediated drug delivery; Co-delivery; Tumor hypoxia; Tumortropic monocytes/macrophages