正电子发射断层扫描/计算机断层扫描（PET/CT）和放射免疫治疗NRG小鼠头颈癌患者来源的异种移植物治疗[64Cu]Cu-DOTA-Panitumumab F(ab')2和[177Lu]Lu-DOTA-Panitumumab F(ab')2。

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Pharmaceutics Pub Date : 2025-10-21 DOI:10.1021/acs.molpharmaceut.5c01009

Meysam Khosravifarsani, Conrad Chan, Anthony Ku, Noor Alsaden, Jalna Meens, Laurie Ailles, Scott Bratman, Raymond M Reilly

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引用次数: 0

摘要

头颈部鳞状细胞癌（HNSCC）在90%的病例中表达表皮生长因子受体（EGFR）。在这里，我们使用抗EGFR [64Cu]Cu-DOTA-panitumumab F(ab')2研究了NRG小鼠中EGFR低（#61531）、中（#73191）或高（#88955）表达的三种临床相关HNSCC患者来源的异种移植物（PDX）的PET/CT成像。我们进一步评估了β-颗粒发射[177Lu]Lu-DOTA-panitumumab F(ab')2对这些PDX放射免疫治疗（RIT）的有效性。在注射[64Cu]Cu-DOTA-panitumumab F（ab’）2后24 h （p.i.）通过PET/CT观察所有PDX。此外，在PDX #88955小鼠中，在[177Lu]Lu-DOTA-panitumumab F(ab')2的3至12 d p.i.时，用PET成像腋窝淋巴结转移，用SPECT/CT成像肺转移。[64Cu]Cu-DOTA-panitumumab F（ab’）2在24 h p.i.时的肿瘤摄取与EGFR表达直接相关（PDX #61531， #73191和#88955分别为6.7±3.5%,13.5±2.5%和16.7±1.0% ID/g）。健康NRG小鼠静脉注射5.0 MBq （50 μg）的[177Lu]Lu-DOTA-panitumumab F（ab’）2无血液学、肝脏或肾脏毒性或体重下降。RIT添加4.0-5.0 MBq (50 μg) [177Lu]Lu-DOTA-panitumumab F（ab’）2后，与0.9% NaCl相比，PDX #61531、#73191和#88955小鼠的肿瘤生长速率分别降低了2倍、9倍和3.2倍（P = 0.014, P < 0.001, P = 0.004）。用未标记的DOTA-panitumumab F(ab')2治疗小鼠没有降低PDX#61531的肿瘤生长速度（P = 0.457），但适度降低PDX# 73191的肿瘤生长速度1.3倍（P = 0.024）和PDX# 88955的肿瘤生长速度1.4倍（P = 0.027）。RIT是egfr特异性的，与抗her2无关[177Lu] lu - dota -曲妥珠单抗F(ab')2与0.9% NaCl相比对PDX #73191无效（P = 0.282）。RIT使用[177Lu]Lu-DOTA-panitumumab F（ab’）2治疗中度EGFR表达的PDX #73191的有效性是高EGFR表达的PDX #88955的3倍。这可能是由于PDX #73191的人乳头瘤病毒（HPV）阳性，因为HPV阳性的HNSCC对外部放射束治疗更敏感。我们得出结论，[64Cu]Cu-DOTA-panitumumab F（ab’）2和[177Lu]Lu-DOTA-panitumumab F（ab’）2是一种很有希望用于HNSCC PET/CT成像和RIT的治疗组合。

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Positron Emission Tomography/Computed Tomography (PET/CT) and Radioimmunotherapy of Head and Neck Cancer Patient Derived Xenografts in NRG Mice with Theranostic [⁶⁴Cu]Cu-DOTA-Panitumumab F(ab')₂ and [¹⁷⁷Lu]Lu-DOTA-Panitumumab F(ab')₂.

Head and neck squamous cell carcinoma (HNSCC) expresses epidermal growth factor receptors (EGFR) in 90% of cases. Here we studied PET/CT imaging of three clinically relevant HNSCC patient derived xenografts (PDX) with low (#61531), moderate (#73191) or high (#88955) EGFR expression in NRG mice using anti-EGFR [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂. We further assessed the effectiveness of β-particle-emitting [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ for radioimmunotherapy (RIT) of these PDX. All PDX were visualized by PET/CT at 24 h postinjection (p.i.) of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂. In addition, in mice with PDX #88955, an axillary lymph node metastasis was imaged by PET and lung metastases were imaged by SPECT/CT at 3 to 12 d p.i. of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂. Tumor uptake of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ at 24 h p.i. was directly correlated with EGFR expression (6.7 ± 3.5%, 13.5 ± 2.5% and 16.7 ± 1.0% ID/g for PDX #61531, #73191 and #88955, respectively). Intravenous administration of 5.0 MBq (50 μg) of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ to healthy NRG mice caused no hematologic, liver or kidney toxicity or decrease in body weight. RIT with 4.0-5.0 MBq (50 μg) of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ decreased the tumor growth rate vs 0.9% NaCl by 2, 9 and 3.2-fold, respectively in mice with PDX #61531, #73191 and #88955 (P = 0.014, P < 0.001, P = 0.004). Treatment of mice with unlabeled DOTA-panitumumab F(ab')₂ did not decrease the tumor growth rate of PDX#61531 (P = 0.457) but modestly decreased the tumor growth rate of PDX #73191 by 1.3-fold (P = 0.024) and PDX #88955 by 1.4-fold (P = 0.027). RIT was EGFR-specific as irrelevant anti-HER2 [¹⁷⁷Lu]Lu-DOTA-trastuzumab F(ab')₂ was not effective for treatment of PDX #73191 vs 0.9% NaCl (P = 0.282). RIT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ was 3-fold more effective for treating moderately EGFR-expressing PDX #73191 than PDX #88955 with high EGFR expression. This may be explained by the human papilloma virus (HPV) positivity of PDX #73191 since HPV-positive HNSCC is more responsive to external radiation beam treatment. We conclude that [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ and [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ are a promising theranostic pair for PET/CT imaging and RIT of HNSCC.

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.