Prospects in folate receptor-targeted radionuclide therapy

Abstract

Targeted radionuclide therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed toward a specific tumor-associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR) has been identified as a target associated with a variety of frequent tumor types (e.g., ovarian, lung, brain, renal, and colorectal cancer). In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (K D < 10(-9) M) the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed. This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the clinic.

Keywords: cancer; folate receptor; folic acid; radionuclide therapy.

Figure 1

Folic acid and antifolates. Chemical structures of (A) folic acid and the antifolates (B) methotrexate, (C) raltitrexed (Tomudex™ ), and (D) pemetrexed (Alimta™ ).

Figure 2

Effects of antifolates on the tumor-to-kidney ratios of radiofolates. Tumor-to-kidney ratios obtained at 1 and 4 h after injection of ^99mTc(CO)₃-folate alone (green) or in combination with pre-injected methotrexate (blue), raltitrexed (red), or pemetrexed (yellow).

Figure 3

Effect of pemetrexed on the tissue distribution of radiofolates. Injection scheme (left) and whole-body SPECT/CT images of KB tumor-bearing mice 24 h after injection of ¹⁷⁷Lu-EC0800 (right). (A) Injection of only ¹⁷⁷Lu-EC0800 (20 MBq) and corresponding SPECT/CT image. (B) Injection of ¹⁷⁷Lu-EC0800 (20 MBq, Figure 4A) and PMX (0.4 mg) and corresponding SPECT/CT images. Tumors and kidneys are indicated with white and yellow arrows.

Figure 4

DOTA-folate conjugates. Chemical structures of (A) EC0800 (56, 64) and (B) cm09 (64).

Figure 5

Comparison of the tissue distribution of ¹⁷⁷Lu-EC0800 and ¹⁷⁷Lu-cm09. Biodistribution data 4 and 24 h after injection of ¹⁷⁷Lu-EC0800 and ¹⁷⁷Lu-cm09 in athymic nude mice, bearing KB tumor xenografts.

Figure 6

Graphs of tumor growth and survival. Preclinical study with athymic nude mice bearing KB tumor xenografts. (A) Relative tumor size and (B) survival rate of mice of group A (control), group B (2 × 0.8 mg pemetrexed), group C (20 MBq ¹⁷⁷Lu-EC0800 and 0.4 mg pemetrexed), and group D (20 MBq ¹⁷⁷Lu-EC0800 and 2 × 0.8 mg pemetrexed).

Figure 7

Design and results of the therapy study. (A) Application protocol and (B) average relative tumor size for mice of groups A–E. This research was originally published in Ref. (64). ©by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figure 8

Graphsof tumor growth from each individual mouse. (A) Relative tumor size of mice of the α-radionuclide therapy study (a1–a3: control mice; b1–b3: mice treated with ¹⁴⁹Tb-cm09). (B) Relative tumor size of mice of the β⁻- radionuclide therapy study (c1–c5: control mice; d1–d5: ¹⁶¹Tb-cm09 treated mice). This research was originally published in Ref. (82). ©by the Society of Nuclear Medicine and Molecular Imaging, Inc.