This work was supported by grants from the National Research Foundation of Korea, funded by the government of the Republic of Korea, (Grant nos. 2012M2B2B1055245 and 2012M2A2A6011335) and by the RI-Biomics Center of Korea Atomic Energy Research Institute.

注意：放射性ヨウ素の酸化形態は非常に揮発性であり、十分なリードシールドとリードバイアルで処理する必要があります。すべての放射化学的手順は風通し木炭濾過フード内で行われるべきであり、実験手順は、放射能検出装置によって監視される必要があります。 125 I標識アジドの合成のための化学物質と逆相カートリッジの調製<ol><li> 溶液中の試薬の調製 <ol><li> 150μlの無水エタノール中アジド前駆体（2）（ 図1）1mgを溶解させます。 注：アジド前駆体の詳細な合成手順は、（2）前報22で報告されました。 </li><li> 1×リン酸緩衝生理食塩水（pHは= 7.4）20μlに1mgのクロラミンTを溶解させます。 </li><li> 20μlのH 2 Oで2 mgのメタ重亜硫酸ナトリウムを溶解させます</li></ol></li><li> Preparaカートリッジの化<ol><li> 10ミリリットルのH 2 O、続いて10ミリリットル無水エタノールでTC18カートリッジを洗います空気とカートリッジのマトリックスを乾燥させないでください。 </li></ol></li></ol> 125 I標識アジド補欠分子族の2放射合成<ol><li> 前駆体の放射性ヨウ素化反応 <ol><li> 1.5ミリリットルマイクロ遠心チューブにアジド前駆体溶液（無水エタノールを150μl中1mg）および酢酸（10μl）を追加します。 </li><li>反応混合物に0.1 MのNaOH（50μL）の[125 I]のNaI 150 MBqのを追加します。 </li><li>クロラミンT溶液（1×リン酸緩衝生理食塩水の20μlの中で1 mg）を加え、反応混合物を含むマイクロチューブを閉じます。 </li><li>放射性ヨウ素化反応が完了するまで、15分間室温で反応混合物をインキュベートします。 </li><li>反応混合物にメタ重亜硫酸ナトリウム溶液（20μlのH 2 O中の2 mg）を加えます放射性ヨウ素化反応を停止します。 </li><li>粗生成物の0.2μLを撤回した後、溶液100μl（H 2 O / CH 3 CN、1：1）を用いて希釈し、HPLC分析のために。 注：すべてのHPLC実験のために、H 2 O（A溶媒）及び溶離剤としてアセトニトリル（溶媒B）を含有する0.1％ギ酸を含む0.1％ギ酸を使用します。 </li><li>逆相分析用無線-HPLCを（逆相C18カラムを用いて希釈し、粗生成物を分析;流速：1ml /分;溶離剤勾配：0-2分20％溶媒Bのため20〜80％溶媒B 2-22分、22-23分80〜100％の溶媒B、および23から28分間、100％溶媒B;保持時間：16.4分）（ 図2）。 </li></ol></li><li> 分取HPLCで粗生成物の精製 注：このような注入器、カラム、検出器、コレクションバイアル、および流出物は収集された容器としてHPLC部品の周囲に十分な鉛遮蔽を提供します。 <ol><li>目を撤回HPLCバイアル中に反応混合物全体を電子。アセトニトリル（0.5ml）で反応管を洗浄し、同じ注射バイアルにリンスを追加します。 H 2 O（1mL）で回収した溶液を希釈します。 </li><li>取ラジオ-HPLC（逆相C18カラムを上に、粗生成物を注入し、流速：10ml /分;溶離液勾配：0-2分20％溶媒B、2-22分間の百分の20から80溶媒B、 22-23分80〜100％の溶媒B、および23から28分間、100％溶媒B）。 </li><li>ガラス試験管において125 I標識アジド（1）（これらのHPLC条件下でのt Rは 17.8から18.8分である）（ 図2）を表す放射性ピークを集めます。 </li><li>製造業者のプロトコルに従って放射能線量キャリブレータを使用して、画分の放射化学的収率を測定します。 </li><li>生成物の放射化学的純度を決定するための同一のHPLC条件を使用して分析ラジオHPLCに精製された生成物を注入します。 </li></ol></li><li> 製品の固相抽出 <ol><li> 40ミリリットルで、所望の生成物（1）を含む画分を希釈し、純粋なH 2 O </li><li>予め調整TC18カートリッジに希釈した溶液を加えます。 </li><li>追加の15ミリリットルのH 2 Oでカートリッジを洗浄</li><li>生成物を溶出（1）鉛シールドによって保護されている10-mlのガラスバイアルに2ミリリットルのアセトンでカートリッジ内に閉じ込められました。製造業者のプロトコルに従って放射能線量キャリブレータを用いて溶出し、製品の放射能を測定します。 注：ジメチルスルホキシド（DMSO）または無水エタノールは、また、カートリッジからの生成物の溶出のために使用することができます。放射能の約5〜10％、通常カートリッジに付着し、残りの放射性標識生成物が完全に有機溶媒の過剰量を用いて溶出することができません。 </li><li>窒素またはアルゴンガスの流れでアセトンを蒸発させます。 </li><li>再溶解させます次の放射性標識工程のためのDMSO（100〜200μl）を持つs​​idue。 </li></ol></li></ol> DBCO-基結合金ナノ粒子の3合成<ol><li> DBCO基含有ポリエチレングリコールと13-nmサイズの金ナノ粒子の表面修飾 <ol><li>既報24に従って、クエン酸ナトリウム安定化金ナノ粒子（3）（平均サイズ= 13 nm）を準備します。 </li><li> （10 nMの15 ml）をクエン酸で安定化した金ナノ粒子にTween 20を（1mMの1.5 ml）の水溶液を加えます。オービタルシェーカー上で20分間この溶液を振ります。 </li><li> DBCO基含有ポリエチレングリコールチオール（平均分子量= 5,000、100μM1.5 ml）の水溶液を加えます。オービタルシェーカー上で2時間のためのソリューションを振ります。 </li></ol></li><li> DBCO基変性金ナノ粒子の精製 <ol><li>精製DBCO基修飾金ナノ粒子（4）&lt;/連続的な遠心分離（11,400×gで、15分×3）によって&gt;強いです。 </li><li>上清を除去し、金ナノ粒子ペレットの再懸濁のための純水を追加します。 </li></ol></li></ol> 4.銅系クリック反応を介したDBCO基修飾金ナノ粒子の放射性標識<ol><li> 125 I標識アジドを使用して、125 I標識した金ナノ粒子の合成（1） <ol><li>遠心分離（11,400×gで、15分）を使用してDBCO基修飾金ナノ粒子の濃縮液を用意し、2μMに金ナノ粒子の濃度を調整します。 </li><li> （2μM、50μL）（4）金ナノ粒子の懸濁液にDMSO（5μL）に（1）125 I標識アジドの4.1 MBqのを追加します。 </li><li> 60分間40℃で得られた反応混合物をインキュベートします。 </li><li>粗生成物からのアリコート（0.2μl）を撤回し、シリカ共にそれを適用します薄層クロマトグラフィー（TLC）プレートated。 </li><li>移動相として酢酸エチルを使用して、TLCプレートを開発。 </li><li>製造業者のプロトコルに従って（ 図3）放射性TLCスキャナーでTLCプレートを配置し、放射性標識反応を監視するためのスキャナを実行します。 </li></ol></li><li> 粗生成物の精製 <ol><li>遠心分離（11,400×gで15分間）によって125 I標識された金ナノ粒子（4）を含む反応混合物を精製します。 </li><li>上清を除去し、金ナノ粒子ペレットの再懸濁のための純水を追加します。 </li><li>精製された生成物からのアリコート（0.2μl）を撤回し、シリカ被覆TLCプレート上にそれを適用します。 </li><li>移動相として酢酸エチルを使用して、TLCプレートを開発。 </li><li>放射性TLCスキャナーでTLCプレートを配置し、125 I標識ゴルの放射化学的収率および放射化学的純度を決定するためのスキャナを実行製造業者のプロトコルに従ってDナノ粒子（4）（ 図3）。 </li></ol></li></ol>

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The authors have nothing to disclose.

一般的に、精製された125 I標識アジド（1）の観察された放射化学収率は75±10％であった（n = 8）。放射性標識は、放射能の50から150 MBqので達成された、および放射化学的結果は非常に一貫しています。 [125 I] NaIを（T 1/2 = 59.4 d）の放射性ヨウ素化反応に使用した1ヶ月以上放射性崩壊を受け、1の放射化学的収率があることが観察された場...

The strain-promoted copper-free click reaction between azides and cyclooctynes has been extensively applied to the efficient bioorthogonal labeling of a wide range of biomolecules, nanomaterials, and living subjects1-7. Due to the excellent site-specificity and rapid reaction rate of this conjugation reaction, it has also been used to synthesize radiolabeled tracers. A few 18F-labeled azide or DBCO prosthetic groups have been prepared for in vitro labeling of various cancers targeting peptides and antibodies, as well as for in vivo pre-targeted imaging of tumors8-13. In addition to these examples, the same conjugation reaction was applied to the metal-radioisotope-labeling of nanomaterials for positron emission tomography (PET) imaging studies14-16.
For several decades, radioactive iodines have been used for biomedical research and clinical trials through PET imaging (124I), single-photon emission computed tomography (SPECT) imaging (123I, 125I), and thyroid cancer treatment (131I)17-21. Therefore, an efficient method for radioactive iodine labeling is fundamentally important for various investigations, including molecular imaging studies, analysis of organ distribution of biomolecules, biomarker identification, and drug development. A copper-free click reaction strategy could be used in radioactive iodine labeling. However, this application has not been investigated as extensively as 18F-labeled biomolecules22-23. Here, we will provide a step-by-step protocol for the synthesis of an 125I-labeled azide for radiolabeling of DBCO-group-derived molecules. The procedures in the present report will include radioiodination of the stannylated precursor, purification steps with HPLC, and solid phase extraction. We also demonstrate efficient radiolabeling of DBCO-group-modified 13-nm-sized gold nanoparticles using the 125I-labeled azide. The detailed protocol in this report will help synthetic chemists understand a new radiolabeling methodology for the synthesis of radiolabeled products.

<table><tbody><tr><td>Chloramine T trihydrate</td><td>Sigma</td><td>402869</td><td></td></tr><tr><td>[&lt;sup&gt;125&lt;/sup&gt;I]NaI in aq. NaOH</td><td>Perkin-Elmer</td><td>NEZ033A010MC</td><td></td></tr><tr><td>Sodium metabisulfite&amp;nbsp;</td><td>Sigma</td><td>S9000</td><td></td></tr><tr><td>Formic acid</td><td>Sigma</td><td>251364</td><td></td></tr><tr><td>Sep-Pak tC18 plus cartridge</td><td>Waters</td><td>WAT036800</td><td></td></tr><tr><td>Dimethyl sulfoxide&amp;nbsp;</td><td>Sigma</td><td>D2650</td><td></td></tr><tr><td>Acetone</td><td>Sigma</td><td>650501</td><td></td></tr><tr><td>Ethanol</td><td>Sigma</td><td>459844</td><td></td></tr><tr><td>Gold(III) chloride trihydrate</td><td>Sigma</td><td>520918</td><td></td></tr><tr><td>Tween 20&amp;nbsp;</td><td>Sigma</td><td>P1379</td><td></td></tr><tr><td>DBCO PEG SH (MW 5,000)</td><td>NANOCS</td><td>PG2-DBTH-5k</td><td></td></tr><tr><td>TLC silica gel 60 F&lt;sub&gt;254&lt;/sub&gt;</td><td>Merck</td><td></td><td></td></tr><tr><td>Analytical HPLC</td><td>Agilent</td><td>1290 Infinity</td><td>Model number</td></tr><tr><td>Preparative HPLC</td><td>Agilent</td><td>1260 Infinity</td><td>Model number</td></tr><tr><td>Analytical C18 reverse-phase column</td><td>Agilent</td><td>Zorbax Eclipse XDB-C18</td><td></td></tr><tr><td>Preparative C18 reverse-phase column</td><td>Agilent</td><td>PrepHT XDB-C18</td><td></td></tr><tr><td>Radio TLC scanner</td><td>Bioscan</td><td>AR-2000</td><td>Model number</td></tr><tr><td>Radioisotope dose calibrator</td><td>Capintec, Inc</td><td>CRC -25R dose calibrator</td><td>Model number</td></tr></tbody></table>

an optimized protocol for the efficient radiolabeling of gold nanoparticles by using a 125i-labeled azide prosthetic group

Here, we demonstrate a detailed protocol for the radiosynthesis of a 125I-labeled azide prosthetic group and its application to the efficient radiolabeling of DBCO-group-functionalized gold nanoparticles using a copper-free click reaction. Radioiodination of the stannylated precursor (2) was carried out by using [125I]NaI and chloramine T as an oxidant at room temperature for 15 min. After HPLC purification of the crude product, the purified 125I-labeled azide (1) was obtained with high radiochemical yield (75 &plusmn; 10%, n = 8) and excellent radiochemical purity (&gt;99%). For the synthesis of radiolabeled 13-nm-sized gold nanoparticles, the DBCO-functionalized gold nanoparticles (3) were prepared by using a thiolated polyethylene glycol polymer. A copper-free click reaction between 1 and 3 gave the 125I-labeled gold nanoparticles (4) with more than 95% of radiochemical yield as determined by radio-thin-layer chromatography (radio-TLC). These results clearly indicate that the present radiolabeling method using a strain-promoted copper-free click reaction will be useful for the efficient and convenient radiolabeling of DBCO-group-containing nanomaterials.

スタンニル化前駆体（2）の放射性ヨウ素化反応は、放射性標識生成物を提供するために15分間室温で[125 I] NaIを、酢酸、及びクロラミンTの150 MBqのを使用して実施した（1）。粗混合物を分取HPLC精製後、所望の生成物は、放射化学的収率の75±10％（N = 8）を得ました。分析用HPLCは、125 I標識産物の放射化学的純度は99％以上（ <st...

Watch this Scientific Journal Video about An Optimized Protocol for the Efficient Radiolabeling of Gold Nanoparticles by Using a 125I-labeled Azide Prosthetic Group at JoVE.com

An Optimized Protocol for the Efficient Radiolabeling of Gold Nanoparticles by Using a 125I-labeled Azide Prosthetic Group

125 I標識アジドの合成と銅のないクリック反応を用いて、dibenzocyclooctyne（DBCO） -基コンジュゲート、13-nmサイズの金ナノ粒子の放射性標識のための詳細な手順が記載されています。

使用した金ナノ粒子の効率的な放射性標識のために最適化されたプロトコル<sup&gt; 125</sup&gt; I標識アジド補綴グループ

Here, we demonstrate a detailed protocol for the radiosynthesis of a 125I-labeled azide prosthetic group and its application to the efficient ...

an-optimized-protocol-for-efficient-radiolabeling-gold-nanoparticles

Research

JoVE Journal

Chemistry

An Optimized Protocol for the Efficient Radiolabeling of Gold Nanoparticles by Using a 125I-labeled Azide Prosthetic Group

8.1K ビュー.  Korea Atomic Energy Research Institute.  125 I標識アジドの合成と銅のないクリック反応を用いて、dibenzocyclooctyne（DBCO） -基コンジュゲート、13-nmサイズの金ナノ粒子の放射性標識のための詳細な手順が記載されています。 

ビデオ: An Optimized Protocol for the Efficient Radiolabeling of Gold Nanoparticles by Using a 125I-labeled Azide Prosthetic Group

Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition

There are currently many chemical tools available to introduce chemical probes into proteins to study their structure and function. A useful method is protein conjugation by genetically introducing an unnatural amino acid containing a bioorthogonal functional group. This report describes a detailed protocol for site-specific antibody conjugation. The protocol includes experimental details for the genetic incorporation of an azide-containing amino acid, and the conjugation reaction by strain-promoted azide-alkyne cycloaddition (SPAAC). This strain-promoted reaction proceeds by simple mixing of the reacting molecules at physiological pH and temperature, and does not require additional reagents such as copper(I) ions and copper-chelating ligands. Therefore, this method would be useful for general protein conjugation and development of antibody drug conjugates (ADCs).

Here, we present a protocol to site-specifically introduce chemical probes into an antibody fragment by genetically incorporating an azide-containing amino acid, and subsequently coupling the azide with a chemical probe by strain-promoted azide-alkyne cycloaddition (SPAAC).

ひずみ促進アジド - アルキン環付加することにより、効率的で部位特異的抗体ラベリング

There are currently many chemical tools available to introduce chemical probes into proteins to study their structure and function. A useful method is ...

生化学

The Bioconjugation and Radiosynthesis of 89Zr-DFO-labeled Antibodies

The exceptional affinity, specificity, and selectivity of antibodies make them extraordinarily attractive vectors for tumor-targeted PET radiopharmaceuticals. Due to their multi-day biological half-life, antibodies must be labeled with positron-emitting radionuclides with relatively long physical decay half-lives. Traditionally, the positron-emitting isotopes 124I (t1/2 = 4.18 d), 86Y (t1/2 = 14.7 hr), and 64Cu (t1/2 = 12.7 hr) have been used to label antibodies for PET imaging. More recently, however, the field has witnessed a dramatic increase in the use of the positron-emitting radiometal 89Zr in antibody-based PET imaging agents. 89Zr is a nearly ideal radioisotope for PET imaging with immunoconjugates, as it possesses a physical half-life (t1/2 = 78.4 hr) that is compatible with the in vivo pharmacokinetics of antibodies and emits a relatively low energy positron that produces high resolution images. Furthermore, antibodies can be straightforwardly labeled with 89Zr using the siderophore-derived chelator desferrioxamine (DFO). In this protocol, the prostate-specific membrane antigen targeting antibody J591 will be used as a model system to illustrate (1) the bioconjugation of the bifunctional chelator DFO-isothiocyanate to an antibody, (2) the radiosynthesis and purification of a 89Zr-DFO-mAb radioimmunoconjugate, and (3) in vivo PET imaging with an 89Zr-DFO-mAb radioimmunoconjugate in a murine model of cancer.

The Bioconjugation and Radiosynthesis of 89Zr-DFO-labeled Antibodies

Due to its multi-day radioactive half-life and favorable decay properties, the positron-emitting radiometal 89Zr is extremely well-suited for use in antibody-based radiopharmaceuticals for PET imaging. In this protocol, the bioconjugation, radiosynthesis, and preclinical application of 89Zr-labeled antibodies will be described.

バイオコンジュゲーションとのアルタン<sup&gt; 89</sup&gt;のZr-DFO標識抗体

The exceptional affinity, specificity, and selectivity of antibodies make them extraordinarily attractive vectors for tumor-targeted PET ...

化学

Harnessing the Bioorthogonal Inverse Electron Demand Diels-Alder Cycloaddition for Pretargeted PET Imaging

Due to their exquisite affinity and specificity, antibodies have become extremely promising vectors for the delivery of radioisotopes to cancer cells for PET imaging. However, the necessity of labeling antibodies with radionuclides with long physical half-lives often results in high background radiation dose rates to non-target tissues. In order to circumvent this issue, we have employed a pretargeted PET imaging strategy based on the inverse electron demand Diels-Alder cycloaddition reaction. The methodology decouples the antibody from the radioactivity and thus exploits the positive characteristics of antibodies, while eschewing their pharmacokinetic drawbacks. The system is composed of four steps: (1) the injection of a mAb-trans-cyclooctene (TCO) conjugate; (2) a localization time period during which the antibody accumulates in the tumor and clears from the blood; (3) the injection of the radiolabeled tetrazine; and (4) the in vivo click ligation of the components followed by the clearance of excess radioligand. In the example presented in the work at hand, a 64Cu-NOTA-labeled tetrazine radioligand and a trans-cyclooctene-conjugated humanized antibody (huA33) were successfully used to delineate SW1222 colorectal cancer tumors with high tumor-to-background contrast. Further, the pretargeting methodology produces high quality images at only a fraction of the radiation dose to non-target tissue created by radioimmunoconjugates directly labeled with 64Cu or 89Zr. Ultimately, the modularity of this protocol is one of its greatest assets, as the trans-cyclooctene moiety can be appended to any non-internalizing antibody, and the tetrazine can be attached to a wide variety of radioisotopes.

The bioorthogonal inverse electron demand Diels-Alder cycloaddition has been harnessed to create an effective and modular pretargeted PET imaging strategy for cancer. In this protocol, the steps of this methodology are described in the context of a model system employing the colorectal cancer targeted antibody huA33 and a 64Cu-labeled radioligand.

プレターゲッティングPETイメージング用バイオ直交逆電子需要ディールスアルダー環化を活用

Due to their exquisite affinity and specificity, antibodies have become extremely promising vectors for the delivery of radioisotopes to cancer cells for ...

生物工学

Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

While radioimmunotherapy (RIT) is a promising approach for the treatment of cancer, the long pharmacokinetic half-life of radiolabeled antibodies can result in high radiation doses to healthy tissues. Perhaps not surprisingly, several different strategies have been developed to circumvent this troubling limitation. One of the most promising of these approaches is pretargeted radioimmunotherapy (PRIT). PRIT is predicated on decoupling the radionuclide from the immunoglobulin, injecting them separately, and then allowing them to combine in vivo at the target tissue. This approach harnesses the exceptional tumor-targeting properties of antibodies while skirting their pharmacokinetic drawbacks, thereby lowering radiation doses to non-target tissues and facilitating the use of radionuclides with half-lives that are considered too short for use in traditional radioimmunoconjugates. Over the last five years, our laboratory and others have developed an approach to in vivo pretargeting based on the inverse electron-demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). This strategy has been successfully applied to pretargeted positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a variety of antibody-antigen systems. In a pair of recent publications, we have demonstrated the efficacy of IEDDA-based PRIT in murine models of pancreatic ductal adenocarcinoma and colorectal carcinoma. In this protocol, we describe protocols for PRIT using a 177Lu-DOTA-labeled tetrazine radioligand ([177Lu]Lu-DOTA-PEG7-Tz) and a TCO-modified variant of the colorectal cancer targeting huA33 antibody (huA33-TCO). More specifically, we will describe the construction of huA33-TCO, the synthesis and radiolabeling of [177Lu]Lu-DOTA-PEG7-Tz, and the performance of in vivo biodistribution and longitudinal therapy studies in murine models of colorectal carcinoma.

This protocol describes the synthesis and characterization of a trans-cyclooctene (TCO)-modified antibody and a 177Lu-labeled tetrazine (Tz) radioligand for pretargeted radioimmunotherapy (PRIT). In addition, it details the use of these two constructs for in vivo biodistribution and longitudinal therapy studies in a murine model of colorectal cancer.

逆電子需要ディールス ・ アルダー反応に基づく pretargeted 放射免疫療法

While radioimmunotherapy (RIT) is a promising approach for the treatment of cancer, the long pharmacokinetic half-life of radiolabeled antibodies can ...

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized cancer therapies in recent years. However, only a fraction of patients responds to PD-1/PD-L1 inhibitors, owing to the heterogeneous expression of PD-L1 in tumor cells. This heterogeneity presents a challenge in the precise detection of tumor cells by the commonly used immunohistochemistry (IHC) approach. This situation calls for better methods to stratify patients who will benefit from immune checkpoint blockade therapy, to improve treatment efficacy. Positron emission tomography (PET) enables real-time visualization of the whole-body PD-L1 expression in a noninvasive way. Therefore, there is a need for the development of radiolabeled tracers to detect PD-L1 distribution in tumors through PET imaging.
Compared to their L-counterparts, dextrorotary (D)-peptides have properties such as proteolytic resistance and remarkably prolonged metabolic half-lives. This study designed a new method to detect PD-L1 expression based on PET imaging of 68Ga-labeled PD-L1-targeted D-peptide, a D-dodecapeptide antagonist (DPA), in tumor-bearing mice. The results showed that the [68Ga]DPA can specifically bind to PD-L1-overexpressing tumors in vivo, and showed favorable stability as well as excellent imaging ability, suggesting that [68Ga]DPA-PET is a promising approach for the assessment of PD-L1 status in tumors.

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

This study developed a noninvasive and real-time method to evaluate the distribution of programmed death-ligand 1 in the whole body, based on positron emission tomographic imaging of [68Ga] D-dodecapeptide antagonist. This technique has advantages over conventional immunohistochemistry and improves the efficiency of identifying appropriate patients who will benefit from immune checkpoint blockade therapy.

68ガリウム標識D-ペプチドPETトレーサーの開発によるプログラム死リガンド1発現イメージング

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized ...

がん研究

Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are emerging as promising therapeutics for organ regeneration and as immunotherapy for various cancers. Despite significant progress having been made in these areas, there is still more to be learned to better understand the pharmacokinetics and pharmacodynamics of the administered therapeutic cells in the living system. For noninvasive, in vivo tracking of cells with positron emission tomography (PET), a novel [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN)-mediated cell radiolabeling method has been developed utilizing 89Zr (t1/2 78.4 h). The present protocol describes a [89Zr]Zr-DBN-mediated, ready-to-use, radiolabeling synthon for direct radiolabeling of variety of cells, including mesenchymal stem cells, lineage-guided cardiopoietic stem cells, liver regenerating hepatocytes, white blood cells, melanoma cells, and dendritic cells. The developed methodology enables noninvasive PET imaging of cell trafficking for up to 7 days post-administration without affecting the nature or the function of the radiolabeled cells. Additionally, this protocol describes a stepwise method for the radiosynthesis of [89Zr]Zr-DBN, biocompatible formulation of [89Zr]Zr-DBN, preparation of cells for radiolabeling, and finally the radiolabeling of cells with [89Zr]Zr-DBN, including all the intricate details needed for the successful radiolabeling of cells.

Presented here is a protocol to radiolabel cells with a positron emission tomography (PET) radioisotope, 89Zr (t1/2 78.4 h), using a ready-to-use radiolabeling synthon, [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN). Radiolabeling cells with [89Zr]Zr-DBN allows noninvasive tracking and imaging of administered radiolabeled cells in the body with PET for up to 7 days post-administration.

細胞輸送の陽電子放出断層撮影イメージング:細胞放射性標識法

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are emerging as promising therapeutics for organ regeneration and as immunotherapy for ...

Radiosynthesis and PET/CT Imaging of 68Ga-Labelled Nanobody in Xenograft Models

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of 68Ga-Labelled Nano Molecules

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical cancer research, necessitating meticulous attention to radiotracer synthesis, quality assurance, and in vivo injection protocols. This study presents a comprehensive workflow tailored to enhance the robustness and reproducibility of small animal PET experiments. The synthesis process in the radiochemistry laboratory using 68Ga is detailed, highlighting stringent quality control and assurance protocols for each radiotracer production. Parameters such as concentration, molar activity, pH, and purity are rigorously monitored, aligning with standards applicable to human studies. This methodology introduces streamlined syringe preparation and a custom-designed 30G cannula for precise intravenous injections into mice. Monitoring of animal health during scanning, including temperature and heart rate, ensures their well-being throughout the procedure. Dosages for PET and SPECT scans are predetermined to balance data acquisition with minimizing radiation exposure to animals and researchers. Similarly, CT scans employ pre-programmed settings to limit radiation exposure, especially pertinent in long-term studies assessing treatment effects. By optimizing these steps, the workflow aims to standardize procedures, reduce variability, and enhance the quality of small animal PET/SPECT/CT imaging. This resource provides valuable insights for researchers seeking to improve the accuracy and reliability of preclinical investigations in molecular imaging, ultimately advancing the field.

This paper describes the radiosynthesis, formulation, quality control of a new radiolabeled probe (i.e., 68Ga-labeled nanobody NM-02), and its use for small animal PET/CT imaging in a xenograft model.

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical ...

Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo Cell Trafficking by PET/CT

This protocol illustrates the production of 64Cu and the chelator conjugation/radiolabeling of a monoclonal antibody (mAb) followed by murine lymphocyte cell culture and 64Cu-antibody receptor targeting of the cells. In vitro evaluation of the radiolabel and non-invasive in vivo cell tracking in an animal model of an airway delayed-type hypersensitivity reaction (DTHR) by PET/CT are described.
In detail, the conjugation of a mAb with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is shown. Following the production of radioactive 64Cu, radiolabeling of the DOTA-conjugated mAb is described. Next, the expansion of chicken ovalbumin (cOVA)-specific CD4+ interferon (IFN)-&#947;-producing T helper cells (cOVA-TH1) and the subsequent radiolabeling of the cOVA-TH1 cells are depicted. Various in vitro techniques are presented to evaluate the effects of 64Cu-radiolabeling on the cells, such as the determination of cell viability by trypan blue exclusion, the staining for apoptosis with Annexin V for flow cytometry, and the assessment of functionality by IFN-&#947; enzyme-linked immunosorbent assay (ELISA). Furthermore, the determination of the radioactive uptake into the cells and the labeling stability are described in detail. This protocol further describes how to perform cell tracking studies in an animal model for an airway DTHR and, therefore, the induction of cOVA-induced acute airway DHTR in BALB/c mice is included. Finally, a robust PET/CT workflow including image acquisition, reconstruction, and analysis is presented.
The 64Cu-antibody receptor targeting approach with subsequent receptor internalization provides high specificity and stability, reduced cellular toxicity, and low efflux rates compared to common PET-tracers for cell labeling, e.g.64Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (64Cu-PTSM). Finally, our approach enables non-invasive in vivo cell tracking by PET/CT with an optimal signal-to-background ratio for 48 h. This experimental approach can be transferred to different animal models and cell types with membrane-bound receptors that are internalized.

Murine Lymphocyte Labeling by 64Cu-Antibody Receptor Targeting for In Vivo  Cell Trafficking by PET/CT

Following the preparation of a 64Cu-modified monoclonal antibody binding to a transgenic murine T cell receptor, T cells are radiolabeled in vivo, analyzed for viability, functionality, labeling stability and apoptosis, and adoptively transferred into mice with an airway delayed-type hypersensitivity reaction for non-invasive imaging by positron emission tomography/computed tomography (PET/CT).

マウスリンパ球標識による<sup&gt; 64</sup以下のためのターゲット設定&gt;のCu-抗体の受容体<em&gt;インビボ</em&gt; PET / CTによる細胞輸送

This protocol illustrates the production of 64Cu and the chelator conjugation/radiolabeling of a monoclonal antibody (mAb) followed by murine lymphocyte ...

免疫・感染学

<meta charset="utf8"></head><body>ループ法メチル化によるCarbon-11放射性トレーサーの効率的な合成

Enhancing Efficiency and Radiolabeling Yields of Carbon-11 Radioligands for Clinical Research Using the Loop Method

A successful positron emission tomography imaging program involving carbon-11 radiotracers demands fast, efficient, and reliable synthesis methods, requiring an on-site cyclotron and radiochemistry group, as well as clinical staff trained to operate under the unique constraints of the carbon-11 radionuclide. This study examines the merits and advantages of a captive solvent &#39;loop method&#39; of radiolabeling four tracers with the carbon-11 radionuclide, producing the radioligands [11C]ER-176, [11C]MRB, [11C]mHED, and [11C]PiB.
The &#39;loop method&#39; is compared against the traditional reactor-based method of carbon-11 methylation in the course of synthesizing the same radiotracers on the identical automated platform. Further, a complete overview of the clinical research preparation of the [11C]ER-176 radiotracer is presented. As demonstrated by the production of [11C]ER-176, the captive solvent &#39;loop method&#39; of heterogeneous alkylation proved to be more efficient, with excellent radiochemical purity (99.6 &#177; 0.6%, n = 25), higher and more consistent radiochemical yield (end of synthesis (EOS) = 5.4 &#177; 2.2 GBq, n = 25) compared to the reactor method (EOS = 1.6 &#177; 0.5 GBq, n = 6), increased molar activity (loop method = 194 &#177; 66 GBq/&#181;mol, n = 25; reactor method = 132 &#177; 78 GBq/&#181;mol, n = 6), along with an average 5 min shorter reaction sequence.

<meta charset="utf8"></head><body>ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

This protocol presents a detailed procedure to prepare four carbon-11 radiotracers by way of the &#8220;loop method&#8221; [11C]methylation. We describe the procedure to synthesize [11C]ER-176, &#160;with data for three additional radiotracers: [11C]MRB, [11C]mHED, and [11C]PiB. The loop method provides an efficient synthesis with increased radiochemical yields against traditional reaction vessel [11C]methylation.

ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

A successful positron emission tomography imaging program involving carbon-11 radiotracers demands fast, efficient, and reliable synthesis methods, ...

使用した金ナノ粒子の効率的な放射性標識のために最適化されたプロトコル

要約

さらに動画を探す

この動画の章

ひずみ促進アジド - アルキン環付加することにより、効率的で部位特異的抗体ラベリング

バイオコンジュゲーションとのアルタン

プレターゲッティングPETイメージング用バイオ直交逆電子需要ディールスアルダー環化を活用

逆電子需要ディールス・アルダー反応に基づく pretargeted 放射免疫療法

68ガリウム標識D-ペプチドPETトレーサーの開発によるプログラム死リガンド1発現イメージング

細胞輸送の陽電子放出断層撮影イメージング:細胞放射性標識法

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of ⁶⁸Ga-Labelled Nano Molecules

マウスリンパ球標識による

ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

使用した金ナノ粒子の効率的な放射性標識のために最適化されたプロトコル

要約

さらに動画を探す

この動画の章

ひずみ促進アジド - アルキン環付加することにより、効率的で部位特異的抗体ラベリング

バイオコンジュゲーションとのアルタン

プレターゲッティングPETイメージング用バイオ直交逆電子需要ディールスアルダー環化を活用

逆電子需要ディールス ・ アルダー反応に基づく pretargeted 放射免疫療法

68ガリウム標識D-ペプチドPETトレーサーの開発によるプログラム死リガンド1発現イメージング

細胞輸送の陽電子放出断層撮影イメージング:細胞放射性標識法

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of 68Ga-Labelled Nano Molecules

マウスリンパ球標識による

ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

ループ法を用いた臨床研究のための炭素11放射性配位子の効率と放射性標識収率の向上

逆電子需要ディールス・アルダー反応に基づく pretargeted 放射免疫療法

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of ⁶⁸Ga-Labelled Nano Molecules