TY - JOUR
T1 - Liposomal Texaphyrin Theranostics for Metastatic Liver Cancer
AU - Lee, Min Hee
AU - Kim, Eun Joong
AU - Lee, Hyunseung
AU - Kim, Hyun Min
AU - Chang, Min Jung
AU - Park, Sun Young
AU - Hong, Kwan Soo
AU - Kim, Jong Seung
AU - Sessler, Jonathan L.
N1 - Funding Information:
This research was supported by the Korean National Research Foundation (NRF) (2015R1C1A2A01054496, M.H.L; CRI 2009-0081566, J.S.K), the Korea Basic Science Institute (D35401, K.S.H), the R and D Convergence Program (CRC-15-02-KRIBB, K.S.H) of NST (National Research Council of Science and Technology) of the Republic of Korea, and the National Institutes of Health (CA68682, J.L.S).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/12/21
Y1 - 2016/12/21
N2 - Reported here is a new theranostic agent, 1, which consists of a Gd3+-texaphyrin core conjugated to a doxorubicin prodrug via a disulfide bond. Conjugate 1 was designed to undergo cleavage in the presence of glutathione (GSH), a species typically upregulated in cancer cells. As prepared, conjugate 1 displays no appreciable fluorescence. However, when exposed to excess GSH an increase in the fluorescence intensity at 592 nm is observed that is ascribed to release of free doxorubicin. To improve the solubility and enhance the tumor targeting of 1, it was loaded into folate-receptor-targeted liposomes to produce FL-1 (for folate liposome loaded with 1). As inferred from both fluorescence turn on studies and independent HPLC analyses, FL-1 was found to undergo selective uptake and cleavage to release free Dox in the KB and CT26 cell lines, which express folate receptors on the cell surface, relative to the HepG2 and NIH3T3 cell lines, which show low expression of those receptors. FL-1 was found to produce a greater antiproliferative effect in the case of the KB and CT26 cell lines as compared to that in the HepG2 and NIH3T3 cell lines. FL-1 was also found to provide enhanced magnetic resonance imaging in vivo under conditions of T1 contrast in the early stage of metastatic cancer progression. Finally, time-dependent tumor regrowth studies involving both subcutaneous and metastatic liver cancer mouse models revealed that FL-1 is capable of reducing the tumor burden in vivo.
AB - Reported here is a new theranostic agent, 1, which consists of a Gd3+-texaphyrin core conjugated to a doxorubicin prodrug via a disulfide bond. Conjugate 1 was designed to undergo cleavage in the presence of glutathione (GSH), a species typically upregulated in cancer cells. As prepared, conjugate 1 displays no appreciable fluorescence. However, when exposed to excess GSH an increase in the fluorescence intensity at 592 nm is observed that is ascribed to release of free doxorubicin. To improve the solubility and enhance the tumor targeting of 1, it was loaded into folate-receptor-targeted liposomes to produce FL-1 (for folate liposome loaded with 1). As inferred from both fluorescence turn on studies and independent HPLC analyses, FL-1 was found to undergo selective uptake and cleavage to release free Dox in the KB and CT26 cell lines, which express folate receptors on the cell surface, relative to the HepG2 and NIH3T3 cell lines, which show low expression of those receptors. FL-1 was found to produce a greater antiproliferative effect in the case of the KB and CT26 cell lines as compared to that in the HepG2 and NIH3T3 cell lines. FL-1 was also found to provide enhanced magnetic resonance imaging in vivo under conditions of T1 contrast in the early stage of metastatic cancer progression. Finally, time-dependent tumor regrowth studies involving both subcutaneous and metastatic liver cancer mouse models revealed that FL-1 is capable of reducing the tumor burden in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85006961493&partnerID=8YFLogxK
U2 - 10.1021/jacs.6b09713
DO - 10.1021/jacs.6b09713
M3 - Article
C2 - 27998081
AN - SCOPUS:85006961493
SN - 0002-7863
VL - 138
SP - 16380
EP - 16387
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 50
ER -