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Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α_vβ₃-Targeted Radionuclide Therapy.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD₂) has excellent targeting specificity for a variety of integrin α_vβ₃/α_vβ₅-positive tumors and has been labeled with the therapeutic radionuclide [¹⁷⁷Lu]LuCl₃ for targeted radiotherapy of tumors. However, the rapid clearance of [¹⁷⁷Lu]Lu-DOTA-3PRGD₂ (¹⁷⁷Lu-3PRGD₂) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD₂ with albumin-binding palmitic acid (Palm-3PRGD₂) and then radiolabeled Palm-3PRGD₂ with ¹⁷⁷Lu. [¹⁷⁷Lu]Lu-DOTA-Palm-3PRGD₂ (¹⁷⁷Lu-Palm-3PRGD₂) retained a specific binding affinity for integrin α_vβ₃/α_vβ₅, with an IC₅₀ value of 5.13 ± 1.16 nM. Compared with ¹⁷⁷Lu-3PRGD₂, the ¹⁷⁷Lu-Palm-3PRGD₂ circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, ¹⁷⁷Lu-Palm-3PRGD₂ shows great potential for clinical application.

SUBMITTER: Yang G

PROVIDER: S-EPMC9321335 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Palmitic Acid-Conjugated Radiopharmaceutical for Integrin αvβ3-Targeted Radionuclide Therapy.

Yang Guangjie G Gao Hannan H Luo Chuangwei C Zhao Xiaoyu X Luo Qi Q Shi Jiyun J Wang Fan F

Pharmaceutics 20220623 7

Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD2) has excellent targeting specificity for a variety of integrin αvβ3/αvβ5-positive tumors and has been labeled with the therapeutic radionuclide [177Lu]LuCl3 for targeted radiotherapy of tumors. However, the rapid clearance of [177Lu]Lu-DOTA-3PRG ...[more]

PMID: 35890224

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Project description:BackgroundThe motif RXDLXXL-based nanoprobes allow specific imaging of integrin αvβ6, a protein overexpressed during tumorigenesis and tumor progression of various tumors. We applied a novel RXDLXXL-coupled cyclic arginine-glycine-aspartate (RGD) nonapeptide conjugated with ultrasmall superparamagnetic iron oxide nanoparticles (referred to as cFK-9-USPIO) for the application of integrin αvβ6-targeted magnetic resonance (MR) molecular imaging for breast cancer.MethodsA novel MR-targeted nanoprobe, cFK-9-USPIO, was synthesized by conjugating integrin αvβ6-targeted peptide cFK-9 to N-amino (-NH2)-modified USPIO nanoparticles via a dehydration esterification reaction. Integrin αvβ6-positive mouse breast cancer (4 T1) and integrin αvβ6 negative human embryonic kidney 293 (HEK293) cell lines were incubated with cFK-9-AbFlour 647 (blocking group) or cFK-9-USPIO (experimental group), and subsequently imaged using laser scanning confocal microscopy (LSCM) and 3.0 Tesla magnetic resonance imaging (MRI) system. The affinity of cFK-9 targeting αvβ6 was analyzed by calculating the mean fluorescent intensity in cells, and the nanoparticle targeting effect was measured by the reduction of T2 values in an in vitro MRI. The in vivo MRI capability of cFK-9-USPIO was investigated in 4 T1 xenograft mouse models. Binding of the targeted nanoparticles to αvβ6-positive 4 T1 tumors was determined by ex vivo histopathology.ResultsIn vitro laser scanning confocal microscopy (LSCM) imaging showed that the difference in fluorescence intensity between the targeting and blocking groups of 4 T1 cells was significantly greater than that in HEK293 cells (P < 0.05). The in vitro MRI demonstrated a more remarkable T2 reduction in 4 T1 cells than in HEK293 cells (P < 0.001). The in vivo MRI of 4 T1 xenograft tumor-bearing nude mice showed significant T2 reduction in tumors compared to controls. Prussian blue staining further confirmed that αvβ6 integrin-targeted nanoparticles were specifically accumulated in 4 T1 tumors and notably fewer nanoparticles were detected in 4 T1 tumors of mice injected with control USPIO and HEK293 tumors of mice administered cFK-9-USPIO.ConclusionsIntegrin αvβ6-targeted nanoparticles have great potential for use in the detection of αvβ6-overexpressed breast cancer with MR molecular imaging.

Dataset Information

Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α_vβ₃-Targeted Radionuclide Therapy.

Publications

Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy.

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