Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma.
Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma.
Joyal
John L
JL
Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
Barrett
John A
JA
Marquis
John C
JC
Chen
Jianqing
J
Hillier
Shawn M
SM
Maresca
Kevin P
KP
Boyd
Marie
M
Gage
Kenneth
K
Nimmagadda
Sridhar
S
Kronauge
James F
JF
Friebe
Matthias
M
Dinkelborg
Ludger
L
Stubbs
James B
JB
Stabin
Michael G
MG
Mairs
Rob
R
Pomper
Martin G
MG
Babich
John W
JW
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D015996:Survival Rate; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D007457:Iodine Radioisotopes; D008543:Melanins; C550120:N-(2-diethylaminoethyl)-4-(4-fluorobenzamido)-5-iodo-2-methoxybenzamide; D019275:Radiopharmaceuticals