TY - JOUR
T1 - A diaCEST MRI approach for monitoring liposomal accumulation in tumors
AU - Chan, Kannie W.Y.
AU - Yu, Tao
AU - Qiao, Yuan
AU - Liu, Qiang
AU - Yang, Ming
AU - Patel, Himatkumar
AU - Liu, Guanshu
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Bulte, Jeff W.M.
AU - Van Zijl, Peter C.M.
AU - Hanes, Justin
AU - Zhou, Shibin
AU - McMahon, Michael T.
N1 - Funding Information:
The authors sincerely thank Abraham Anonuevo for the help in preparing liposomes, Clark Zhang for helping us in cytotoxicity studies, Alan Meeker and Jessica Hicks for immunohistochemical staining, and Qingguo Xu for helpful discussions. This work was supported by The Virginia and D.K. Ludwig Fund for Cancer Research , and NIH grants R01EB015031 , R01EB015032 , U54CA151838 , R01EB012590 , and CA62924 .
PY - 2014/4/28
Y1 - 2014/4/28
N2 - Nanocarrier-based chemotherapy allows preferential delivery of therapeutics to tumors and has been found to improve the efficacy of cancer treatment. However, difficulties in tracking nanocarriers and evaluating their pharmacological fates in patients have limited judicious selection of patients to those who might most benefit from nanotherapeutics. To enable the monitoring of nanocarriers in vivo, we developed MRI-traceable diamagnetic Chemical Exchange Saturation Transfer (diaCEST) liposomes. The diaCEST liposomes were based on the clinical formulation of liposomal doxorubicin (i.e. DOXIL®) and were loaded with barbituric acid (BA), a small, organic, biocompatible diaCEST contrast agent. The optimized diaCEST liposomal formulation with a BA-to-lipid ratio of 25% exhibited 30% contrast enhancement at B1 = 4.7 μT in vitro. The contrast was stable, with ∼ 80% of the initial CEST signal sustained over 8 h in vitro. We used the diaCEST liposomes to monitor the response to tumor necrosis factor-alpha (TNF-α), an agent in clinical trials that increases vascular permeability and uptake of nanocarriers into tumors. After systemic administration of diaCEST liposomes to mice bearing CT26 tumors, we found an average diaCEST contrast at the BA frequency (5 ppm) of 0.4% at B1 = 4.7 μT while if TNF-α was co-administered the contrast increased to 1.5%. This novel approach provides a non-radioactive, non-metallic, biocompatible, semi-quantitative, and clinically translatable approach to evaluate the tumor targeting of stealth liposomes in vivo, which may enable personalized nanomedicine.
AB - Nanocarrier-based chemotherapy allows preferential delivery of therapeutics to tumors and has been found to improve the efficacy of cancer treatment. However, difficulties in tracking nanocarriers and evaluating their pharmacological fates in patients have limited judicious selection of patients to those who might most benefit from nanotherapeutics. To enable the monitoring of nanocarriers in vivo, we developed MRI-traceable diamagnetic Chemical Exchange Saturation Transfer (diaCEST) liposomes. The diaCEST liposomes were based on the clinical formulation of liposomal doxorubicin (i.e. DOXIL®) and were loaded with barbituric acid (BA), a small, organic, biocompatible diaCEST contrast agent. The optimized diaCEST liposomal formulation with a BA-to-lipid ratio of 25% exhibited 30% contrast enhancement at B1 = 4.7 μT in vitro. The contrast was stable, with ∼ 80% of the initial CEST signal sustained over 8 h in vitro. We used the diaCEST liposomes to monitor the response to tumor necrosis factor-alpha (TNF-α), an agent in clinical trials that increases vascular permeability and uptake of nanocarriers into tumors. After systemic administration of diaCEST liposomes to mice bearing CT26 tumors, we found an average diaCEST contrast at the BA frequency (5 ppm) of 0.4% at B1 = 4.7 μT while if TNF-α was co-administered the contrast increased to 1.5%. This novel approach provides a non-radioactive, non-metallic, biocompatible, semi-quantitative, and clinically translatable approach to evaluate the tumor targeting of stealth liposomes in vivo, which may enable personalized nanomedicine.
KW - Barbituric acid
KW - CEST
KW - Doxorubicin
KW - Liposomes
KW - MRI
KW - Tumor necrosis factor
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U2 - 10.1016/j.jconrel.2014.02.005
DO - 10.1016/j.jconrel.2014.02.005
M3 - Article
C2 - 24548481
AN - SCOPUS:84895550020
SN - 0168-3659
VL - 180
SP - 51
EP - 59
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -