α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies-Part 2

Abstract

The use of radioactive sources to deliver cytotoxic ionizing radiation to disease sites dates back to the early 20th century, with the discovery of radium and its physiologic effects. α-emitters are of particular interest in the field of clinical oncology for radiotherapy applications. The first part of this review explored the basic radiochemistry, high cell-killing potency, and availability of α-emitting radionuclides, together with hurdles such as radiolabeling methods and daughter redistribution. The second part of this review will give an overview of the most promising and current uses of α-emitters in preclinical and clinical studies.

Keywords: clinical trials; radiochemistry; radiotherapy; α-emitters.

FIGURE 1.

Preclinical study design. TAT = targeted α-therapy; MTD = maximum tolerated dose.

FIGURE 2.

Preclinical studies, potency, imaging, and pitfalls of α-therapy. (A) Bioluminescence imaging of ²¹¹At-B10-1F5 (anti-CD20) radioimmunotherapy in Granta-519^Luc cell line, a minimal residual disease model of lymphoma. Animals were treated on day 6 with 278 kBq or 555 kBq and received 1 × 10⁷ bone marrow cells intravenously from syngeneic donors 2 d after treatment. (Reprinted with permission of (3).) (B) Biodistribution of ²¹³Bi-DOTA-biotin after pretargeting radioimmunotherapy with 1F5(single-chain variable-region)4-streptavidin (anti-CD20) and CC49(single-chain variable-region)4-streptavidin (negative control). (Reprinted with permission of (7).) (C) Transient lymphocyte decrease after CD70-targeted ²²⁷Th-conjugate therapy indicative of myelosuppression (15). (D) Cerenkov imaging 24 h after injection of ²²⁵Ac-DOTA-c(RGDyK) in U87MG tumor–bearing mice. Top images show efficient tumor accumulation; bottom images show reduced tumor uptake on blockage and demonstrate specificity of radiotherapy for α_vβ₃ integrin (17).

FIGURE 3.

Preclinical α- vs. β-studies. (A) Kaplan–Meier survival curves of neu-N transgenic mice treated with 14.8 kBq of ²²⁵Ac-7.16.4, 4.4 MBq of ²¹³Bi-7.16.4, and 4.4 MBq of ⁹⁰Y-7.16.4, 3 d after intravenous injection of 1 × 10⁵ NT2.5 cells. (Reprinted with permission of (19).) (B, top) Photographs of kidneys from neu-N mouse surviving 1 y after treatment with 14.8 kBq (400 nCi) of ²⁵⁵Ac-7.16.4 compared with healthy neu-N mouse. (B, bottom) Hematoxylin and eosin staining of kidneys from neu-N mice surviving 1 y after treatment with 14.8 kBq (left) and 7.4 + 7.4 kBq (right) of ²²⁵Ac-7.16.4. Arrows indicate collapse of cortical tissue due to loss of tubular epithelium in kidney cortex. (Reprinted with permission of (19).) (C) Quantification of γ-H2AX–positive cells after immunofluorescent staining of DNA double-strand breaks in AR42J tumors after treatment with 47 kBq of ²²⁵Ac-DOTATOC, 30 MBq of ¹⁷⁷Lu-DOTATOC, 1 μg of DOTATOC (unlabeled), or phosphate-buffered saline (20). (D) Tumors showing growth delay after treatment with equitoxic doses of ²²⁵Ac-DOTATOC (44 kBq) and ¹⁷⁷Lu-DOTATOC (34 MBq) (20).

FIGURE 4.

Clinical application of α-radiotherapy. (A, left) ⁶⁸Ga-DOTATOC PET maximum-intensity projection of neuroendocrine tumor patient showing extensive tumor burden in liver and disseminated bone marrow metastases. (A, right) Significant reduction of liver metastases after administration of 10.5 GBq of ²¹³Bi-DOTATOC into common hepatic artery (27). (B) Kaplan–Meier estimates of overall survival of patients with symptomatic CRPC after treatment with ²²³Ra-dichloride as compared with placebo group. (Reprinted with permission of (31).) (C) Evolution of ⁶⁸Ga-PSMA-11 PET/CT scans of patient with metastatic CRPC showing extended peritoneal carcinomatosis and liver metastases. After 2 cycles of ¹⁷⁷Lu-PSMA-617, patient showed disease progression and was offered ²²⁵Ac-PSMA-617. After 3 cycles, PET/CT indicated complete response and PSA level dropped to immeasurable levels (2). CI = confidence interval.