Blackwell Publishing Journal Backfiles 1879-2005
Melanoma tumour targeting was investigated with radiolabelled α-MSH peptides and with α-MSH derivatives attached to large carriers such as liposomes. The main focus of this paper will be current targeting concepts of melanoma (α-melanoma tumour diagnosis and internal radiotherapy) using α-MSH peptides for specific delivery of diagnostic and therapeutic radiometals. Several new α-MSH analogues (MSH1-n) were synthesized in our laboratory and conjugated to 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA), a universal metal chelator. The resulting DOTA-MSH1-n derivatives were found to retain good binding capacity to the melanoma cell MC1 receptor (MC1R) in the low nanomolar range. In vivo tissue distribution of 5 µCi [111In]-labelled DOTA-MSH in female B6D2F1 mice with intracutaneous B16F1 melanoma tumours and with micrometastases in the lung and liver demonstrated that the radioligands accumulated specifically in the tumour tissue, reaching a maximum, for example with DOTA-MSH4, of 9.43 ± 1.06% I.D./g 4-h postinjection. Co-injection of an excess of α-MSH (50 µg) blocked the MC1Rs and hence reduced the 4-h tumour uptake by an average of 90%, which indicates that radioligand uptake by the melanoma tumours was a receptor-mediated process. Blood clearance was very rapid and 4 h after injection, the blood-associated radioactivity was as little as 0.03 ± 0.00% I.D./g. This was associated with a fast elimination of the radioactivity from all MC1R-negative tissues, except the kidneys which serve as main excretory organ. The ratios of radioactivity in melanoma tissue to that in non-target tissues 4 h after injection were all above 10 and often greater than 100, except for the kidneys. The identification of radiopeptide structures yielding reduced retention of radioactivity by the kidneys but nevertheless excellent tumour uptake is currently the main goal of our studies. The specificity of targeting melanoma metastases using radiolabelled MSH peptides was further analyzed by positron-emission tomography (PET) as well as with autoradiography of tumour tissue sections with surrounding healthy tissue after in vivo injection of the radiopeptides into tumour-bearing animals: the radioactivity was concentrated exclusively in and localized uniformly throughout the tumour tissue. Non-radioactive approaches to MC1R-mediated melanoma targeting include cytotoxic MSH–peptides, MSH–carrier conjugates and MSH–liposome constructs. A brief summary of the current state of the different approaches including their advantages and disadvantages will be presented.
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