A review of advances in the last decade on targeted cancer therapy using 177Lu: focusing on 177Lu produced by the direct neutron activation route

Abstract

Lutetium-177 [T½ = 6.76 d; E_β (max) = 0.497 MeV; maximum tissue range ~2.5 mm; 208 keV γ-ray] is one of the most important theranostic radioisotope used for the management of various oncological and non-oncological disorders. The present review chronicles the advancement in the last decade in ¹⁷⁷Lu-radiopharmacy with a focus on ¹⁷⁷Lu produced via direct ¹⁷⁶Lu (n, γ) ¹⁷⁷Lu nuclear reaction in medium flux research reactors. The specific nuances of ¹⁷⁷Lu production by various routes are described and their pros and cons are discussed. Lutetium, is the last element in the lanthanide series. Its chemistry plays a vital role in the preparation of a wide variety of radiopharmaceuticals which demonstrate appreciable in vivo stability. Traditional bifunctional chelators (BFCs) that are used for ¹⁷⁷Lu-labeling are discussed and the upcoming ones are highlighted. Research efforts that resulted in the growth of various ¹⁷⁷Lu-based radiopharmaceuticals in preclinical and clinical settings are provided. This review also summarizes the results of clinical studies with potent ¹⁷⁷Lu-based radiopharmaceuticals that have been prepared using medium specific activity ¹⁷⁷Lu produced by direct neutron activation route in research reactors. Overall, the review amply demonstrates the practicality of the medium specific activity ¹⁷⁷Lu towards formulation of various clinically useful radiopharmaceuticals, especially for the benefit of millions of cancer patients in developing countries with limited reactor facilities.

Keywords: 177Lu; DOTATATE; PSMA-617; TENIS; direct neutron activation; intrinsically radiolabeled nanoparticles; medium flux research reactors; specific activity; targeted therapy.

Figure 1

Production of ¹⁷⁷Lu in (A) cyclotron via ¹⁷⁶Yb (d, n) ¹⁷⁷Lu and ¹⁷⁶Yb (d, p) ¹⁷⁷Yb→¹⁷⁷Lu reactions and (B) nuclear reactor via ¹⁷⁶Lu (n, γ) ¹⁷⁷Lu and ¹⁷⁶Yb (n, γ) ¹⁷⁷Yb→¹⁷⁷Lu reactions.

Figure 2

Comparative evaluation of the yield of ¹⁷⁷Lu produced via direct ¹⁷⁶Lu (n, γ) ¹⁷⁷Lu and indirect ¹⁷⁶Yb (n, γ) ¹⁷⁷Yb→¹⁷⁷Lu routes when irradiated at flux of (A) 5 × 10¹³ n.cm^-2.s^-1, (B) 1.5 × 10¹⁴ n.cm^-2.s^-1, (C) 5 × 10¹⁴ n.cm^-2.s^-1 and (D) 1 × 10¹⁵ n.cm^-2.s^-1 for different irradiation times.

Figure 3

Calculated ^177mLu/¹⁷⁷Lu ratios during production of ¹⁷⁷Lu via direct ¹⁷⁶Lu (n, γ) ¹⁷⁷Lu route when irradiated at different fluxes for different irradiation times in nuclear reactor.

Figure 4

Structures of the common bifunctional chelator used for radiolabeling with ¹⁷⁷Lu.

Figure 5

Structure of AAZTA chelator.

Figure 6

Post-therapy, ⁶⁸Ga-DOTA-NOC PET scans in a 57-year-old man with pancreatic neuroendocrine tumor with extensive liver metastases. The patient was treated with four cycles of ¹⁷⁷Lu-DOTATATE and on regular follow-up showed significant decreases in both the primary tumor in the pancreas and hepatic metastases. Adapted from Ref [88].

Figure 7

Structure of PSMA-617.

Figure 8

¹⁷⁷Lu-PSMA-617 therapy in a 65-year-old man with mCRPC. (A) The baseline pre-therapy diagnostic ⁶⁸Ga-PSMA-11 PET/CT showed PSMA-avid extensive skeletal metastases, (B) Posterior whole body scintigraphy (WBS) 24 h after administration of first cycle of ¹⁷⁷Lu-PSMA-617, (C) Posterior WBS 24 h after administration of second cycle of ¹⁷⁷Lu-PSMA-617 showed remarkable reduction in uptake, (D) Posterior WBS 24 h after administration of third cycle of ¹⁷⁷Lu-PSMA-617 did not show any abnormal uptake, (E) After three cycles of therapy, the follow-up diagnostic ⁶⁸Ga-PSMA-11 PET/CT scan showed near complete metabolic response with resolution of the PSMA-avid metastases. Adapted from Ref [120].

Figure 9

Structures of (A) EDTMP, (B) DOTMP, (C) BPAMD and (D) DOTA^zol.

Figure 10

Anterior and posterior images from (A) ^99mTc-MDP WBS of a 55-year-old woman with breast cancer showing widespread skeletal metastases, (B) ¹⁷⁷Lu-DOTMP post-therapy images showing uptake pattern similar to that of ^99mTc-MDP bone scan.

Figure 11

A 55-year-old male diagnosed with prostatic adenocarcinoma was administered with ¹⁷⁷Lu-DOTA^zol. (A) Post-therapy WBS 24 h post-administration showed uptake in multiple skeletal sites, (B) Post-therapy SPECT/CT showed uptake in the pelvic bone metastases. Adapted from Ref [157].

Figure 12

A 54-year-old woman with papillary thyroid carcinoma who developed TENIS syndrome after receiving 500 GBq of ¹³¹I in cumulative doses, was administered with ¹⁷⁷Lu-DOTA-E[(cRGDfK)₂] therapy. ⁶⁸Ga-DOTA-E[(cRGDfK)₂] PET/CT was performed to evaluate disease extent and for pre-therapy assessment. (A) Pre-therapy, the maximum intensity projection (MIP) image with ⁶⁸Ga-DOTA-E[(cRGDfK)₂] PET scan, transaxial fused PET/CT images showed increased tracer uptake in the (B) thyroid remnant, (C) cervical lymph nodes (D) mediastinal lymph node, lytic skeletal lesions with soft tissue component in the sternum and left iliac bone, (E) multiple lung nodules. Post-therapy WBS in (F) anterior and (G) posterior views revealing the overall distribution of ¹⁷⁷Lu-DOTA-E[(cRGDfK)₂] and transaxial fused SPECT/CT images (H-K) showing tracer uptake at sites corresponding to ⁶⁸Ga-DOTA- E[(cRGDfK)₂] -avid lesions. (L) Post-therapy follow-up ⁶⁸Ga-DOTA- E[(cRGDfK)₂] PET/CT MIP image and transaxial fused PET/CT images showed tracer uptake in the (M) thyroid remnant with cervical lymph nodes, (N) mediastinal lymph node, lytic skeletal lesions with significant reduction in soft tissue component in the sternum, (O) left iliac bone and (P) multiple lung nodules, suggesting response to therapy. Adapted from Ref [161].

Figure 13

A 60-year-old breast cancer patient (HER2 +ve) was administered with ¹⁷⁷Lu-DOTA-trastuzumab therapy. A. WBS at day 1 and day 7 post administration of ¹⁷⁷Lu-DOTA-trastuzumab. Tracer uptake can be observed in primary breast tumor (black arrow head). The bone metastasis in the acetabulum region was visualized at day 1 and day 7 (blue arrow heads). B. SPECT/CT, CT, and SPECT images showing lymph node metastases which could not be localized on WBS (white arrow heads). Adapted from Ref [171].

Figure 14

A 56-year-old male patient with rheumatoid arthritis of wrist joint. SPECT/CT image 24 h post-administration of 222 MBq of ¹⁷⁷Lu-HA.

Figure 15

Schematic illustration of the synthesis of intrinsically radiolabeled [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite. Adapted from Ref [211].

Figure 16

Tumor regression studies with [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite. (A) Tumor growth index and (B) body weight index curves of C57BL/6 mice bearing melanoma tumor after intravenous injection of saline (control), Lu₂O₃-HSA (control), 9.25 MBq of [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite, 18.5 MBq [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite, 37 MBq [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite and 55.5 MBq [¹⁷⁷Lu]Lu₂O₃-HSA nanocomposite. Adapted from Ref [211].