TY - JOUR
T1 - Real Time, Noninvasive Imaging and Quantitation of the Accumulation of Ligand-Targeted Drugs into Receptor-Expressing Solid Tumors
AU - Vlashi, Erina
AU - Sturgis, Jennifer E.
AU - Thomas, Mini
AU - Low, Philip S.
N1 - Publisher Copyright:
© 2009 American Chemical Society.
PY - 2021
Y1 - 2021
N2 - Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing tumors in live mice. Folate-rhodamine was selected to model receptor-targeted drugs, because (i) it has high affinity (Kd = 10-9 M) for FR-rich tumors, (ii) its uptake can be monitored in vivo by multiphoton microscopy, and (iii) five folate-targeted drugs of similar size are currently undergoing clinical trials. We demonstrate that (1) folate-rhodamine saturates tumor FR in <5 min, <30 min, and <100 min following intravenous, paraorbital, and intraperitoneal injection, respectively; (2) complete clearance of folate-rhodamine from receptor-negative tissues requires ≥50 min, and (3) a "binding site barrier"may retard, but does not prevent, penetration of the ligand-targeted drug. We conclude that low molecular weight ligand-targeted drugs have appropriate pharmacokinetic properties for tumor-selective delivery.
AB - Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing tumors in live mice. Folate-rhodamine was selected to model receptor-targeted drugs, because (i) it has high affinity (Kd = 10-9 M) for FR-rich tumors, (ii) its uptake can be monitored in vivo by multiphoton microscopy, and (iii) five folate-targeted drugs of similar size are currently undergoing clinical trials. We demonstrate that (1) folate-rhodamine saturates tumor FR in <5 min, <30 min, and <100 min following intravenous, paraorbital, and intraperitoneal injection, respectively; (2) complete clearance of folate-rhodamine from receptor-negative tissues requires ≥50 min, and (3) a "binding site barrier"may retard, but does not prevent, penetration of the ligand-targeted drug. We conclude that low molecular weight ligand-targeted drugs have appropriate pharmacokinetic properties for tumor-selective delivery.
KW - Targeted cancer therapy
KW - folic acid
KW - real time imaging
KW - tumor uptake
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U2 - 10.1155/2021/5393504
DO - 10.1155/2021/5393504
M3 - Article
AN - SCOPUS:85114105459
SN - 1687-8086
VL - 2021
JO - Advances in Civil Engineering
JF - Advances in Civil Engineering
M1 - 5393504
ER -