Targeted Alpha Therapy of Glioma Using ²¹¹At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins

Abstract

Targeted radionuclide therapy based on α-emitters plays an increasingly important role in cancer treatment. In this study, we proposed to apply a heterodimeric peptide (iRGD-C6-lys-C6-DA7R) targeting both VEGFR and integrins as a new vector for 211At radiolabeling to obtain high-performance radiopharmaceuticals with potential in targeted alpha therapy (TAT). An astatinated peptide, iRGD-C6-lys­(211At-ATE)-C6-DA7R, was prepared with a radiochemical yield of ∼45% and high radiochemical purity of >95% via an electrophilic radioastatodestannylation reaction. iRGD-C6-lys­(211At-ATE)-C6-DA7R showed good stability in vitro and high binding ability to U87MG (glioma) cells. Systematic in vitro antitumor investigations involving cytotoxicity, apoptosis, distribution of the cell cycle, and reactive oxygen species (ROS) clearly demonstrated that 211At-labeled heterodimeric peptides could significantly inhibit cell viability, induce cell apoptosis, arrest the cell cycle in G2/M phase, and increase intracellular ROS levels in a dose-dependent manner. Biodistribution revealed that iRGD-C6-lys­(211At-ATE)-C6-DA7R had rapid tumor accumulation and fast normal tissue/organ clearance, which was mainly excreted through the kidneys. Moreover, in vivo therapeutic evaluation indicated that iRGD-C6-lys­(211At-ATE)-C6-DA7R was able to obviously inhibit tumor growth and prolong the survival of mice bearing glioma xenografts without notable toxicity to normal organs. All these results suggest that TAT mediated by iRGD-C6-lys­(211At-ATE)-C6-DA7R can provide an effective and promising strategy for the treatment of glioma and some other tumors.

Targeted Alpha Therapy for Glioblastoma: Review on In Vitro, In Vivo and Clinical Trials

“… − Combination therapy: At-211-MM4 plus anti-PD-1 (PARP inhibitor) had longest progression free of 65 days and best tumour response (p<0.05) compared to either alone. Ma 2022 [ 42 ] At-211-FAPI-04/ Cell viability: At-211-FAPI-04: 61.9 % at 12 kBq; 42.1 % at 92 kBq At-211: 84.2 % at 12 kBq; 56.5 % at 92 kBq Cell cycle arrest: Treated cells (23 kBq/ml) in G2/M and G0/G1 phase was 62.7% and 21.9% and pre-treatment was 15.7% and 69.9% Clonogenic assay: Relative survival 28.1, 8.1 and 1.97 % for 4.6, 9.2 and 18.5 kBq Target 24.9%; non-target 6.87%; At-211 alone <1% − Liu 2022 [ 43 ] iRGD-C6-lys(211At-ATE)-C6-DA7R Cell viability (at 75 kBq/ml): Reduced to 47.5 % and 62% with labelled- At-211 and At-211 Cell cycle arrest: Treated cells in G2/M and G0/G1 phase were 62.1% and 32.2% and untreated cells were 11.9 % and 68.7% Target 32%; At-211 alone ~1% − Nishri 2022 [ 52 ] Am-241/ U87MG Viability assay: Combined TMZ + alpha particles nearly doubled the cytotoxicity relative to each treatment alone. − RBE 10 = 1.5 Survival fraction decreased by 40-50% with TMZ GB glioblastoma, TMZ temozolomide, EBRT External Beam Radiation Therapy, %ID/g percent of the injected dose per gram, EMRT engineered modular recombinant transporters, IC50 half maximal inhibitory concentration, DSB double strand break, γH2A.X phosphorylated that forms when DSB appear, Ki67 proliferation marker, RBE 10 values calculated at 10 % survival, REB α initial slope of the survival curve (α test radiation/ α reference radiation), RBE Relative Biological Effectiveness, RBE 3GyE Survival level after 3 Gy, BCH 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, LAT1-IN-1 an inhibitor of system L amino acid transporter, PADPR poly-ADP-ribosylation (plays a role in detecting and repairing DNA damage in cells), WAF1 gene that is localised to chromosome 6p21.2, and its sequence, structure, and activation by p53 (a lower fold induction of WAF1 indicates that the cells are more sensitive to that particular type of irradiation) …”

Effective Treatment of SSTR2-Positive Small Cell Lung Cancer Using 211At-Containing Targeted α-Particle Therapy Agent Which Promotes Endogenous Antitumor Immune Response

“…Astatine-211 was produced via the 209 Bi (α, 2n) 211 At nuclear reaction by irradiating an internal bismuth target with α-particles accelerated to 28 MeV using a CS-30 cyclotron at Sichuan University. , The single separation yield of 211 At was 550–740 MBq, and the radioactivity was detected by dose calibrator (CRC-15R, American. Inc.).…”

Carrier systems of radiopharmaceuticals and the application in cancer therapy

“…Additionally, radiolabeled heterodimeric peptides have shown extremely favorable results in preclinical studies for gliomas. For example, in 2022, Liu et al used radiolabeled heterodimeric peptides iRGD-C6-lys( 211 At-ATE)-C6- D A7R targeting both integrins and VEGF receptor for glioma therapy [ 81 ], which significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice. Furthermore, radiolabeled bicyclic peptides hold tremendous promise in cancer therapy, and are currently under development.…”

“…Radiolabeled peptide is a relatively new and very specific radiopharmaceutical group. There is a growing interest in the development of stable and well-defined novel peptide carrier systems, such as heterodimers and cyclic peptides, which bring hope for new radiolabeled peptides in cancer therapy [ 23 , 81 ]. However, the available evidence in this regard is limited and further research is needed to fully evaluate its potential.…”