The purpose of this study is to evaluate the retention in tumour and distribution behavior of [Lu-177]-Catalase after intratumoral injection,and preliminary evaluation the efficacy and safety of [Lu-177]-Catalase.

开始日期2023-07-06

申办/合作机构

北京市肿瘤防治研究所

100 项与 [Lu-177]-Catalase 相关的临床结果

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100 项与 [Lu-177]-Catalase 相关的转化医学

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100 项与 [Lu-177]-Catalase 相关的专利（医药）

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122

项与 [Lu-177]-Catalase 相关的文献（医药）

2025-02-01·European Journal of Medicinal Chemistry

Development of ibuprofen-modified fibroblast activation protein radioligands to improve cancer therapy

Article

作者: Hu, Kongzhen ; Zhou, Hui ; Liu, Yang ; Wang, Lijuan ; Zhong, Jiawei ; Peng, Simin ; Zhong, Yuhua ; Yan, Qingsong

FAP-targeting radioligands are used in cancer diagnosis and therapy, but their effectiveness is limited by poor tumor uptake and retention. This study aimed to develop new radioligands using an optimized amino acid linker and ibuprofen for better pharmacokinetics. Three novel quinoline-based FAP ligands with an ibuprofen moiety were synthesized and radiolabeled with gallium-68 and lutetium-177. The synthesized FAP ligands FAPI-Ibu1, 2, 3 showed high binding affinity for FAP, with IC₅₀ values of 1.17 ± 0.09, 0.29 ± 0.06, and 0.78 ± 0.12 nM, respectively. ¹⁷⁷Lu-labeled FAP ligands showed stability in vitro and demonstrated significant binding to human plasma proteins as well as FAP specificity. PET imaging and biodistribution studies of ⁶⁸Ga- or ¹⁷⁷Lu-labeled FAPI-Ibu1, 2, 3 revealed improved tumor accumulation and retention. Dosimetry calculation showed that [¹⁷⁷Lu]Lu-FAPI-Ibu3 delivered a 9.9-fold higher absorbed dose to tumor than [¹⁷⁷Lu]Lu-FAPI-04, but only 2.6-fold higher absorbed dose to kidneys leading to 3.8-fold improvement in the tumor-to-kidney absorbed dose ratios. In the endoradiotherapy study, 18.5 MBq of [¹⁷⁷Lu]Lu-FAPI-Ibu3 resulted in longer median survival than the equivalent dose of [¹⁷⁷Lu]Lu-FAPI-04 (22 vs 16 days). Three ibuprofen-modified FAP radioligands significantly improved tumor uptake, retention, and growth suppression compared to [¹⁷⁷Lu]Lu-FAPI-04, with [¹⁷⁷Lu]Lu-FAPI-Ibu3 emerging as the most promising candidate for further clinical translational studies.

2025-01-09·Journal of Medicinal Chemistry

Development of [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-NI-FAPI-04 Containing a Nitroimidazole Moiety as New FAPI Radiotracers with Improved Tumor Uptake and Retention

Article

作者: Wang, Guochang ; Zang, Jie ; Jin, Wenbin ; Zhu, Lin ; Luo, Yang ; Kung, Hank F.

Fibroblast activation protein (FAP), which is overexpressed in cancer-associated fibroblasts (CAFs), represents a promising target for cancer diagnosis and therapy. Hypoxia is a common feature of solid tumors. A bivalent agent, DOTA-NI-FAPI-04 (1), was developed by incorporating hypoxia-sensitive nitroimidazole (NI) into the FAP-targeting agent FAPI-04. Compound 1 exhibited a strong FAP binding affinity with an IC₅₀ of 7.44 nM. Radiolabeled [⁶⁸Ga]Ga-1 and [¹⁷⁷Lu]Lu-1 demonstrated enhanced in vitro cell uptake. In vivo positron emission tomography/computed tomography (PET/CT) imaging showed that [⁶⁸Ga]Ga-1 displayed significantly higher specific uptake and retention in U87MG tumor-bearing mice compared to [⁶⁸Ga]Ga-FAPI-04 (SUV_avg: 7.87 vs 1.99% ID/mL at 120 min). Biodistribution studies confirmed superior tumor uptake of [⁶⁸Ga]Ga-1 (48.15 vs 5.72% ID/g at 120 min). Similarly, [¹⁷⁷Lu]Lu-1 exhibited higher tumor uptake than [¹⁷⁷Lu]Lu-FAPI-04 (50.75 vs 20.48% ID/g at 120 min). These preliminary results suggest that a nitroimidazole-containing bivalent-targeting agent, [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-1, is a promising candidate for tumor theranostics.

2025-01-01·Journal of Nuclear Medicine

Localized In Vivo Prodrug Activation Using Radionuclides

Article

作者: Rodriguez, Victoria E ; Kang, Mikyung ; Jiang, Fangchao ; Weissleder, Ralph ; Khurana, Ishaan ; Schuemann, Jan ; Quintana, Jeremy M ; Bertolet, Alejandro ; Borges, Nicholas ; Banla, Leou I ; Ng, Thomas S C ; Le Fur, Mariane ; Hu, Huiyu ; Miller, Miles A ; Könik, Arda ; Caravan, Peter ; Valladolid Onecha, Victor ; Qin, Lei

Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof of principle, we tested whether this strategy of radionuclide-induced drug engagement for release (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy. Methods: We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule-destabilizing monomethyl auristatin E (MMAE) caged by a radiation-responsive phenyl azide, and we interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using the fibroblast activation protein inhibitor (FAPI) agents [^99mTc]Tc-FAPI-34 and [¹⁷⁷Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [¹⁷⁷Lu]Lu-PSMA-617, combined with caged MMAE or caged exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. Results: RAiDER efficiency varied by 70-fold across radionuclides (^99mTc > ¹¹¹In > ¹⁷⁷Lu > ⁶⁴Cu > ³²P > ⁶⁸Ga > ²²³Ra > ¹⁸F), yielding up to 320 nM prodrug activation/Gy of exposure from ^99mTc. Computational simulations implicated low-energy electron-mediated free radical formation as driving prodrug activation. Radionuclide-activated caged MMAE restored the prodrug's ability to destabilize microtubules and increased its cytotoxicity by up to 2,600-fold that of the nonactivated prodrug. Mice treated with [^99mTc]Tc-FAPI-34 and caged MMAE accumulated concentrations of activated MMAE that were up to 3,000 times greater in tumors than in other tissues. RAiDER with [^99mTc]Tc-FAPI-34 or [¹⁷⁷Lu]Lu-FAPI-04 delayed tumor growth, whereas monotherapies did not (P < 0.003). Clinically guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. Conclusion: This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and can potentially improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biologic and therapeutic responses.

100 项与 [Lu-177]-Catalase 相关的药物交易

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