Hetero-bivalent agents targeting FAP and PSMA

Boinapally, Srikanth; Lisok, Alla; Lofland, Gabriela; Minn, Il; Yu, Yanying; Jiang, Zirui; Shin, Min Jay; Merino, Vanessa F.; Zheng, Lei; Brayton, Cory; Pomper, Martin G.; Banerjee, Sangeeta Ray

doi:10.1007/s00259-022-05933-3

Cited by 21 publications

(27 citation statements)

References 63 publications

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Section: Discussionmentioning

confidence: 99%

“…To date there have been only two reports on the development of PSMA/FAP bispecific tracers for imaging ( Figure 1 ) [ 32 , 33 ]. Both reports used the NOTA chelator for radioisotope complexation: one for 64 Cu [ 32 ] and the other for Al 18 F [ 33 ]. To the best of our knowledge, there has been no report on the development of 68 Ga-labeled PSMA/FAP bispecific tracers despite the growing popularity and increased accessibility of clinical 68 Ga generators.…”

Section: Discussionmentioning

confidence: 99%

“…Here, our goal is to develop PSMA/FAP bispecific radioligands with comparable or even higher tumor uptake compared to the PSMA- and FAP-targeting monospecific tracers. Previously, Boinapally et al [ 32 ] reported two 64 Cu-labelled PSMA/FAP bispecific tracers, [ 64 Cu]Cu-FP-L1 and [ 64 Cu]Cu-FP-L2 ( Figure 1 A), which showed high and specific uptake in both FAP- and PSMA-expressing tumor models. However, no head-to-head comparison of their bispecific tracers with the FAP- or PSMA-targeting monospecific tracer was reported.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Verena¹,

Zhang²,

Kuo³

et al. 2023

Molecules

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Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif. IC50(PSMA) and IC50(FAP) values of Ga-complexed bispecific ligands, Ga-AV01017, Ga-AV01030, and Ga-AV01038 were 25.2–71.6 and 1.25–2.74 nM, respectively. The uptake values in PSMA-expressing LNCaP tumor xenografts were 4.38 ± 0.55, 5.17 ± 0.51, and 4.25 ± 0.86 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were lower than the monospecific PSMA-targeting tracer [68Ga]Ga-HTK03041 (23.1 ± 6.11 %ID/g). The uptake values in FAP-expressing HEK293T:hFAP tumor xenografts were 2.99 ± 0.37, 3.69 ± 0.81, 3.64 ± 0.83 %ID/g for [68Ga]Ga-AV01017, [68Ga]Ga-AV01030, and [68Ga]Ga-AV01038, respectively, which were also lower than the monospecific FAP-targeting tracer, [68Ga]Ga-FAPI-04 (12.5 ± 2.00 %ID/g). We observed that the bispecific tracers had prolonged blood retention, in which tracers with a longer linker tend to have a higher blood uptake and lower tumor uptake. Further investigations are needed to optimize the linker selection to generate promising bispecific PSMA/FAP-targeting tracers for prostate cancer imaging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Verena¹,

Zhang²,

Kuo³

et al. 2023

Molecules

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“…Since others have attempted dual-targeting of PSMA and other cell surface proteins, most notably GRPR, we selected FAP and PSMA as our targets for the development of a dual-targeting agent. Recently, the feasibility of this strategy was confirmed by Boinapally et al 18 and Hu et al 19 via 64 Cu/ 18 F radiolabeling of the attached FAP-and PSMAbinding pharmacophores and by evaluating the biological performance of the dual-targeted tracer. In this study, we evaluated the radiation dosimetry, biodistribution, and primary imaging efficacy of a novel dual-targeted tracer, [ 68 Ga]Ga-FAPI-PSMA.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein, and its expression in PCa cells is 100−1000 times higher than that in normal prostate tissue, rendering it an excellent target for specific imaging and targeted therapy of PCa. 6 In recent years, with the advent of PSMA PET/CT, 68 Ga-/ 177 Lu-/ 18 F-radiolabeled PSMA small molecule inhibitors 7−9 with high specificity and affinity for PSMA binding have shown promising results in clinical trials for specific PCa imaging and radioligand therapy. However, the complexity of the tumor microenvironment and local biofactors tend to produce tumors with high heterogeneity, that is, positive tumors may contain negative tissue regions 10 and PSMA-targeted tracers are typically limited to their sensitivity for small nodes.…”

Section: ■ Introductionmentioning

confidence: 99%

Preclinical Evaluation of a Fibroblast Activation Protein and a Prostate-Specific Membrane Antigen Dual-Targeted Probe for Noninvasive Prostate Cancer Imaging

Wang

Liu

et al. 2023

Mol. Pharmaceutics

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Prostate-specific membrane antigen (PSMA) is a prostate cancer target that plays a crucial role in prostate cancer diagnosis and therapy. Herein, a novel dual-targeted imaging probe, [68Ga]Ga-FAPI-PSMA, was prepared by radiolabeling conjugated DOTA-FAPI-PSMA with the short half-life radionuclide gallium-68 (68Ga), which is dedicated to prostate cancer diagnostic imaging. In vitro, [68Ga]Ga-FAPI-PSMA had higher affinity for the PSMA and FAP high-expressing cell lines 22Rv1 and U87 MG with IC50 values of 4.73 and 2.10 nM, respectively, than in the corresponding negative expression cell lines PC3 and A549, and significant differences in cell uptake were also observed. In vivo, [68Ga]Ga-FAPI-PSMA was rapidly cleared from the body, and the estimated radiation dose was relatively low compared with several other FAPI probes. In 22Rv1 and U87 MG tumor xenografts, [68Ga]Ga-FAPI-PSMA rapidly accumulated in tumors after administration, and the best images can be obtained at 1 h postinjection. In conclusion, the dual-targeted probe [68Ga]Ga-FAPI-PSMA was successfully prepared for in vivo prostate cancer PET/CT imaging.

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Prostate‐Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer

Meher,

Ashley,

Bobba

et al. 2024

Adv Healthcare Materials

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Background: The uptake of large (>10 nm) non‐targeted nanocarriers by bulk tumors is thought to be dominated by passive extravasation through porous tumor vessels and limited lymphatic drainage, the enhanced permeability and retention (EPR) effect. Prior studies demonstrated radiolabeled tumor‐targeted and non‐targeted 4‐arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging. By adding small molecule ligands targeting prostate‐specific membrane antigen (PSMA) to the StarPEG polymer, marked increase in tumor uptake, penetration and retention in the tumor core was observed. These prior studies support the application of imaging surrogates for the evaluation of targeted delivery of chemotherapeutic nanomedicines and the potential for therapy using analogous β‐emitting radiopharmaceuticals.Methods: To evaluate the delivery and therapeutic efficacy of PSMA‐targeted StarPEG nanocarriers, StarPEG nanodrugs with or without three copies of PSMA‐targeting, ACUPA, ligands were designed and synthesized. One copy of the radiometal chelator, DOTA, was conjugated to each nanocarrier for labelling with b‐emitting 177Lu, providing non‐targeted [177Lu]PEG‐(DOTA)1 and PSMA targeting [177Lu]PEG‐(DOTA)1(ACUPA)3, for SPECT imaging and therapy. The radiolabeled nanodrugs were evaluated in vitro and in vivo using PSMA+ PC3‐Pip and/or PSMA‐ PC3‐Flu cell lines, subcutaneous xenografts and disseminated metastatic models.Results: The nanocarriers PEG‐(DOTA)1 and PEG‐(DOTA)1(ACUPA)3 were efficiently radiolabeled with 177Lu with molar activities of 10.8‐15.8 MBq/nmol. Along with excellent in vitro PSMA binding affinity (kD = 51.7 nM in PC3‐Pip cells), the targeted nanocarrier [177Lu]PEG‐(DOTA)1(ACUPA)3 demonstrated excellent in vivo single‐photon emission computed tomography (SPECT) imaging contrast with 21.3% ID/g uptake in PC3‐Pip tumors at 192 h post injection. Single doses of 18.5 MBq [177Lu]PEG‐(DOTA)1(ACUPA)3 showed complete resolution of the PC3‐Pip xenografts, without any regrowth up to 138 days.Conclusions and Future Directions: The StarPEG nanocarriers demonstrated high PSMA‐targeted delivery of the therapeutic isotope 177Lu with excellent imaging contrast. The targeted nanocarrier eliminated subcutaneous and metastatic PC3‐Pip tumors. Overall, these preclinical results demonstrated high treatment efficacy of the PSMA‐targeted nanocarrier [177Lu]PEG‐(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation.This article is protected by copyright. All rights reserved

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Hetero-bivalent agents targeting FAP and PSMA

Cited by 21 publications

References 63 publications

Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Synthesis and Preclinical Evaluation of Three Novel 68Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging

Preclinical Evaluation of a Fibroblast Activation Protein and a Prostate-Specific Membrane Antigen Dual-Targeted Probe for Noninvasive Prostate Cancer Imaging

Prostate‐Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer

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