Ultrasound mediated delivery of oxygen and LLL12 loaded stimuli responsive microdroplets for the treatment of hypoxic cancer cells.
LLL12 exhibits high specificity for inhibiting STAT3 phosphorylation and dimerization, and inducing apoptosis to constitutively activated STAT3 cancer cells without cytotoxicity to normal cells with dormant STAT3. However, clinical deployment of LLL12 in cancer treatment is hindered by its low bioavailability and hypoxia-induced resistance. To overcome these limitations, we encapsulate both oxygen and LLL12 in stimuli responsive microdroplets (SRMs) by a gas-driven coaxial flow focusing (CFF) process for ultrasound mediated treatment of hypoxic cancer cells. Our benchtop experiments demonstrate that the CFF process is able to produce SRMs with uniform size distribution, large oxygen loading capacity, high LLL12 encapsulation efficiency, well protection of bioactivity, and steadily long shelf time. The in vitro therapeutic studies in pancreatic cancer cells (PANC-1 and CAPAN-1) demonstrate the immediate release of oxygen and LLL12 in exposure to therapeutic ultrasound pulses as well as the improved anticancer effects under hypoxic conditions. The findings suggest that the proposed oxygen and LLL12 loaded SRMs provide a promising drug delivery strategy for more effective treatment of hypoxic cancer cells.
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.|Chongqing Key Laboratory of Ultrasound Molecular Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Jinshun
J
Xu
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.|School of Engineering Science, University of Science and Technology of China, Hefei, Anhui, 230026, China.
Shuai
S
Yuan
Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Jilai
J
Tian
Department of Mechanical Engineering, The Ohio State University, Columbus, OH, 43210 USA.
Kyle A
KA
Martin
Division of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210 USA.
Jinhua
J
Song
Division of Medicinal Chemistry and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210 USA.|Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Chenglong
C
Li
Chongqing Key Laboratory of Ultrasound Molecular Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Zhigang
Z
Wang
Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Jiayuh
J
Lin
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.|School of Engineering Science, University of Science and Technology of China, Hefei, Anhui, 230026, China.
Ting
T
Si
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.|School of Engineering Science, University of Science and Technology of China, Hefei, Anhui, 230026, China.
Ronald X
RX
Xu
D000880:Anthraquinones / Q000008:administration & dosage* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D065546:Drug Liberation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007700:Kinetics; D010100:Oxygen / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry; D000072258:Tumor Hypoxia / Q000187:drug effects*; D000069453:Ultrasonic Waves
D000880:Anthraquinones; D000970:Antineoplastic Agents; C549232:LLL12 compound; D013449:Sulfonamides; D010100:Oxygen