Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system.
Positron emission tomography (PET) of epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide a means for non-invasively characterizing EGFR expression and signaling activity in patients' tumors before, during, and after therapy with EGFR inhibitors. Towards this goal, our group has developed PET tracers which irreversibly bind to EGFR. However, tumor uptake is relatively low because of both the lipophilicity of such tracers (e.g. the morpholino-[124I]-IPQA [SKI 212243]), with octanol-to-water partition coefficients of up to 4, and a short dwell time in the blood and significant hepatobiliary clearance and intestinal reuptake. Liposomal nanoparticle delivery systems may favorably alter the pharmacokinetic profile and improve tumor targeting of highly lipophilic but otherwise promising cancer imaging tracers, such as the EGFR inhibitor SKI 243. SKI 243 is therefore an interesting model molecule for incorporation into lipid-based nanoparticles, as it would not only improve their solubility but also increase the circulation time, availability and, potentially, targeting of tumors. In the current study, we compared the pharmacokinetics and tumor targeting of the bare EGFR kinase-targeting radiotracer SKI 212243 (SKI 243) with that of the same tracer embedded in liposomes. SKI 243 and liposomal SKI 243 are both taken up by tumor xenografts but liposomal SKI 243 remained in the blood longer and consequently exhibited a 3- to 6-fold increase in uptake in the tumor among several other organs.
Molecular Pharmacology and Chemistry Department, Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue 10021 New York, New York, United States. penatemo@mskcc.org
Oula Penate
OP
Medina
Nagavarakishore
N
Pillarsetty
Athanasios
A
Glekas
Blesida
B
Punzalan
Valerie
V
Longo
Mithat
M
Gönen
Pat
P
Zanzonico
Peter
P
Smith-Jones
Steven M
SM
Larson
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D008081:Liposomes; D019275:Radiopharmaceuticals; D066246:ErbB Receptors