TY - JOUR
T1 - Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles
AU - Ho, Yi Ju
AU - Wang, Tzu Chia
AU - Fan, Ching Hsiang
AU - Yeh, Chih Kuang
N1 - Funding Information:
The authors gratefully acknowledge the support of the Ministry of Science and Technology, Taiwan under grant nos. MOST 106-2627-M-007-007, 106-2221-E-007-008, and 106-2218-E-007-022-MY3, the National Tsing Hua University (Hsinchu, Taiwan) under grant no. 106N522CE1, and Chang Gung Memorial Hospital (Linkou, Taiwan) under grant no. CIRPD2E0051.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/30
Y1 - 2018/5/30
N2 - Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and drug penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and drug penetration within tumors and thereby improve the efficacy of combination therapies.
AB - Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and drug penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and drug penetration within tumors and thereby improve the efficacy of combination therapies.
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U2 - 10.1021/acsami.8b05508
DO - 10.1021/acsami.8b05508
M3 - Article
C2 - 29727168
AN - SCOPUS:85046685043
SN - 1944-8244
VL - 10
SP - 17784
EP - 17791
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 21
ER -