Radiometallated receptor-avid peptide conjugates for specific in vivo targeting of cancer cells
Introduction
Opportunities are increasing steadily for designing effective site-directed bioconjugates that will provide for future advances in diagnosis and treatment of neoplastic diseases [28], [33], [43], [47], [97], [24]. This is primarily due to the accelerated rate at which many biomolecular vectors and their cell associated molecular targets expressed on cancer cells are being identified and characterized [77], [27], [65], [38], [40], [71]. Although significant progress has been made with radiolabeled monoclonal antibodies, and several successful clinical applications reported over the past decade [20], [73], [9], the anticipated utility of these agents has been limited for a number of reasons. For example, their tumor accumulation is frequently less than desirable and clearance of radioactivity from the blood and non-target tissues is slow [20], [9], [69], [48], [1]. Because of these and other limitations, a number of lower molecular weight site-directed biomolecules (e.g., peptides) have been suggested as more suitable vehicles to enhance specific delivery of radionuclides to target cells, in vivo [77], [38], [40], [87], [43], [47], [59].
The development of radiolabeled receptor-avid peptides for highly selective in vivo targeting of cancers expressing their cognate receptors will have a major impact and diagnosis and treatment outcomes in human patients [78], [86], [97], [29], [60], [83]. The value of radiometallated peptides is admirably exemplified by the development of 111In-DTPA-Octreotide (111In-Octreoscan®, MMI), and 99mTc-Depreotide (NeoTect®), metabolically stabilized analogues of somatostatin (SSN) which selectively localize in neoplastic cells expressing SSN receptors [7], [55], [39], [11]. Clinical studies with these agents and new 111In+3 and 90Y+3-SSN conjugates demonstrate the diagnostic and therapeutic efficacy of these SSN receptor-avid peptide-based radiopharmaceuticals [56], [71], [24], [54], [23].
A variety of other receptor systems that are uniquely or overexpressed on cancer cells have been identified and are providing unparalled opportunities to design effective site-directed radiolabeled peptides for targeting cancer cells [78], [29], [60], [50], [64]. The number of studies being conducted to develop new tracers that maximize selective uptake and residualization of the radiolabeled vectors in tumors, while optimizing their pharmacokinetic properties, has rapidly accelerated over the past decade. Investigators face major challenges when developing these types of cancer specific radiotracers. For example, any peptide conjugate that is designed to specifically target receptors on cancer cells, must be constructed in a way to produce high specific activity products where the radiometal is incorporated in a manner that enhances, or at least does not impede, binding affinity and in vivo performance [33], [27]. This review highlights design strategies being used in the development of synthetic peptide analogues that exhibit high binding affinity with three different receptors (GRP, α-MSH, and GC-C receptors) expressed on cancer cells. Results obtained with these systems exemplify the rationale and approaches that can be employed to formulate new radiometallated peptide analogues as potential diagnostic and therapeutic radiopharmaceuticals.
Section snippets
Synthetic bombesin (BBN) analogues
Since the discovery of BBN, the amphibian analogue to mammalian gastrin releasing peptide (GRP) in the early 1970’s, a wealth of information concerning GRP-receptor expression and physiological function has been elucidated. Several groups have undertaken extensive efforts to synthesize a large number of BBN peptide analogues, which function as antagonists when bound to GRP receptors [76], [21]. The goal of developing antagonists was focused on an anti-growth factor therapy approach designed to
Synthetic α-MSH peptide analogs for melanoma imaging and therapy
Malignant melanoma has become a serious public health problem due to an increase in incidence and to the difficulties in discovering and treating melanoma metastases [61]. Early melanoma tumor diagnosis and prompt surgical removal are a patient’s best hope for a cure. Metastatic malignant melanoma is resistant to current chemotherapeutic and immunotherapeutic drugs. Combinations of chemotherapeutic agents or chemo/immunotherapeutic agents offer the highest response rates. Despite recent
GC-C receptor-avid radioconjugates
Over the past decade there has been impressive progress made to characterize the guanylin/guanylate cyclase-C (GC-C) receptor located on the brush border domain of enterocytes on the intestinal mucosa [31], [85], [41], [84], [36]. GC-C receptors bind guanylin peptides (incl., human guanylin and uroguanylin) and bacteria heat-stable peptides with a high degree of specificity [31], [30], [26], [53]. This receptor was reported to be expressed on virtually all of the histologically confirmed
Conclusion
The receptor systems highlighted in this review are three representative examples of a spectrum of receptors expressed on cancer cells that hold potential for development of site-specific radiopharmaceuticals. Results from studies with the GRP, α-MSH, and GC-C receptors describe strategies that can be used to identify, design, and evaluate new radiometallated receptor-avid peptide conjugates. The radionuclides used in these studies focused primarily on the use of diagnostically useful
Acknowledgements
This work was funded by grants from the Department of Energy ER61661 to TPQ and ER60875 (WAV), National Institute of Health CA72942-03 (WAV) and a Research Project Grant #99-331-01-CDD from the American Cancer Society (TJH).
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