DOTA Conjugate with an Albumin-Binding Entity Enables the First Folic Acid–Targeted ¹⁷⁷Lu-Radionuclide Tumor Therapy in Mice

Abstract

The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folatebased radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA-folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios. Methods: The folate conjugate cm09 was radiolabeled with 177 LuCl 3 , and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein-binding properties of 177 Lu-cm09. In vivo, 177 Lu-cm09 was tested in KB tumor-bearing mice using SPECT/CT. The therapeutic anticancer effect of 177 Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n 5 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls. Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of 177 Lu-cm09 to serum proteins (;91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of 177 Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 % ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (;70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 · 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls. Conclusion: The modification of a folate radioconjugate with an albuminbinding entity resulted in a significant increase of the tumor-tokidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid-targeted radionuclide therapy in mice.

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

“…In this respect, a novel DOTA-folate conjugate (cm10) was used. In vitro 47 Sc-cm10 showed results comparable to the previously investigated 177 Lu-cm09 (14). In vivo, 47 Sc-cm10 was assessed in biodistribution studies over 7 d using KB tumor-bearing mice.…”

“…The DOTA-folate conjugate (cm10) used in this study is composed of the same functionalities as was the case for the previously evaluated folate conjugate cm09 (14). Folic acid binds selectively to the folate receptor (FR), which is expressed on a variety of tumor types, including cancer of the ovaries and of the lungs (15,16).…”

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

“…The radiosynthesis of 177 Lu-EC0800 and the evaluation of its stability were carried out as previously reported (Supplementary Methods; ref. 30). It was shown that 177 Lu-EC0800 was stable (>95%) over at least 24 hours in PBS and human blood plasma.…”

Chelating agents for radiolanthanides: Applications to imaging and therapy

“…13) structure with subtle variations in the nature of the peripheral groups to modulate solubility and lipophilicity. The 140 Nd complex of TPP has also been reported, 101 possesses high lipophilicity, and apparently showed good radiochemical purity after two days incubation in human serum. The lipophilic character of the complex led to biodistribution in mice into major organs such as liver, lungs and spleen, but also showed significant accumulation in tumours.…”

“…The long physical halflife of 155 Tb was found to be a good match to the long biological half-lives of the complexes. The corresponding 177 Lu-DOTA-chCE7 139 and 177 Lu-DOTA-cm09 140 species are also known, the latter being the first folic acid targeted radiolanthanide. Bifunctional NETA (Fig.…”