Role of Nanotechnology in Biological Therapies

Ocampo‐García, Blanca; Lara, Liliana Aranda; Ferro‐Flores, Guillermina; Morales-Ávila, Enrique; Isaac‐Olivé, Keila

doi:10.1002/9781119558026.ch5

Cited by 1 publication

(1 citation statement)

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“…In this context, previous research on the development of imaging radioligands targeting proteins of the tumor microenvironment, such as nanobodies against proteins of the extracellular matrix [4], radioligands to target the chemokine receptor-4 (CXCR-4) [5][6][7], fibroblast activation protein (FAP) radioinhibitors [8][9][10][11][12], and radiotracers directed to integrins and the prostate-specific membrane antigen (PSMA) expressed in the tumor neovasculature [13][14][15][16][17][18][19], among others, have proven to be helpful in detecting spatial and temporal changes in the tumor microenvironment phenotype of different cancer entities, which have been essential in defining the treatment of patients according to the expression or suppression of proteins involved in the disease. In particular, the immunotherapeutic pathway has been exploited with various agents, such as monoclonal antibodies, radioimmunoconjugates, and nano-immune systems [20,21].…”

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confidence: 99%

Synthesis and Evaluation of 177Lu-DOTA-PD-L1-i and 225Ac-HEHA-PD-L1-i as Potential Radiopharmaceuticals for Tumor Microenvironment-Targeted Radiotherapy

Luna-Gutiérrez

Cruz-Nova

Jiménez-Mancilla

et al. 2023

IJMS

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Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.

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