TY - JOUR
T1 - Development of a Liposomal Formulation of Acetyltanshinone IIA for Breast Cancer Therapy
AU - Wang, Qi
AU - Luo, Man
AU - Wei, Na
AU - Chang, Alex
AU - Luo, Kathy Qian
N1 - Funding Information:
This study was supported by grants awarded to K.Q.L. from the Johns Hopkins Singapore Research Fund, the Start-Up Fund from the Faculty of Health Sciences, and the Start-Up Research Grant (no. SRG2016-00068-FHS) from the University of Macau. We would like to thank Prof. Sierin Lim for her kind help in managing the JHS Research Fund.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/9/3
Y1 - 2019/9/3
N2 - Acetyltanshinone IIA (ATA), synthesized in our group exhibiting good anti-breast cancer effects, is expected to replace the commonly used anti-ER+ breast cancer (breast cancer cells overexpressing the estrogen receptor) drug tamoxifen. To promote the clinical progress of ATA, polyethylene glycol (PEG)-modified liposomes were used to encapsulate ATA along with improving its bioavailability and in vivo anticancer efficiency. The resulting liposomal ATA exhibited a spherical shape with an average size of 188.5 nm. In vitro evaluations showed that liposomal ATA retained the anti-breast cancer efficacy of ATA while exerting much less cytotoxicity toward noncancerous cells. Significantly, pharmacokinetics analysis showed that the AUC0-24h of liposomal ATA was 59 times higher than that of free ATA, demonstrating increased bioavailability of ATA. Preclinical experiments demonstrated that liposomal ATA reduced the growth of ER-positive human breast tumor xenografts by 73% in nude mice, and the liposomal ATA exhibited a much lower level of toxicity than that of free ATA with respect to zebrafish larval mortality, body formation, and heart function during development. Moreover, 7-day and 21-day tissue toxicity levels were determined in mice by intravenous administration of a maximum dosage of liposomal ATA (120 mg/kg). The results showed no obvious tissue damage in major organs, including the heart, liver, spleen, kidney, and brain. In summary, we have developed a clinical formulation of liposomal ATA with the high bioavailability and potent efficacy for the treatment of ER-positive breast cancer.
AB - Acetyltanshinone IIA (ATA), synthesized in our group exhibiting good anti-breast cancer effects, is expected to replace the commonly used anti-ER+ breast cancer (breast cancer cells overexpressing the estrogen receptor) drug tamoxifen. To promote the clinical progress of ATA, polyethylene glycol (PEG)-modified liposomes were used to encapsulate ATA along with improving its bioavailability and in vivo anticancer efficiency. The resulting liposomal ATA exhibited a spherical shape with an average size of 188.5 nm. In vitro evaluations showed that liposomal ATA retained the anti-breast cancer efficacy of ATA while exerting much less cytotoxicity toward noncancerous cells. Significantly, pharmacokinetics analysis showed that the AUC0-24h of liposomal ATA was 59 times higher than that of free ATA, demonstrating increased bioavailability of ATA. Preclinical experiments demonstrated that liposomal ATA reduced the growth of ER-positive human breast tumor xenografts by 73% in nude mice, and the liposomal ATA exhibited a much lower level of toxicity than that of free ATA with respect to zebrafish larval mortality, body formation, and heart function during development. Moreover, 7-day and 21-day tissue toxicity levels were determined in mice by intravenous administration of a maximum dosage of liposomal ATA (120 mg/kg). The results showed no obvious tissue damage in major organs, including the heart, liver, spleen, kidney, and brain. In summary, we have developed a clinical formulation of liposomal ATA with the high bioavailability and potent efficacy for the treatment of ER-positive breast cancer.
KW - acetyltanshinone IIA (ATA)
KW - anti-breast cancer drugs
KW - bioavailability
KW - mPEG-liposomes
KW - pharmacokinetics
KW - toxicity study
UR - http://www.scopus.com/inward/record.url?scp=85070946494&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070946494&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.9b00493
DO - 10.1021/acs.molpharmaceut.9b00493
M3 - Article
C2 - 31389706
AN - SCOPUS:85070946494
SN - 1543-8384
VL - 16
SP - 3873
EP - 3886
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 9
ER -