An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivatives
An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate-specific membrane antigen small molecule derivatives
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DOI：
10.1002/cmmi.106
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发表时间：
2006-09-01
影响因子：
--
通讯作者：
Frangioni, John V.
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文献类型：
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作者：
Humblet, Valerie;Misra, Preeti;Frangioni, John V.
疾病靶向药物的生产需要将靶向分子与造影剂或治疗剂共价偶联，然后将产品纯化至均匀性。典型的靶向分子，如小分子和多肽，通常具有高电荷质量比和/或疏水性。造影剂和治疗剂本身也是多种多样的，包括用于MRI的镧系螯合剂，用于SPECT的Tc-99m螯合剂，用于放射治疗的Y-90螯合剂，用于PET的F-18衍生物，以及用于近红外荧光光学成像的七甲基吲哚菁。我们已经建立了一个通用的高效液相色谱/质谱平台，能够净化几乎任何形式的任何靶向药物。分析子系统由单个双头泵组成，该泵将流动相引导到用于纯化放射性制剂的热池或用于纯化非放射性制剂的ES-TOF MS。非放射性试剂在纯化过程中也可通过ELSD、吸光度和荧光进行监测。制备子系统由色谱柱和程序组成，允许从分析系统快速标度。为了证明该平台的实用性，我们描述了针对前列腺特异性膜抗原（PSMA）的五种小分子衍生物的制备：用于MRI的钆衍生物，用于SPECT的铟、铼和锝衍生物，以及用于放疗的钇衍生物。这五种化合物都是由一个高度阴离子靶向配体衍生而来的，该配体经过工程设计，具有单一的亲核试剂，用于n -羟基琥珀酰亚胺缀合。我们还描述了优化的柱/流动相组合和质谱设置为每一类药剂，并讨论了纯化极端电荷和/或疏水性分子的策略。综上所述，我们的研究应该加快疾病靶向、多模式诊断和治疗药物的开发。版权所有(C) 2006 John Wiley & Sons, Ltd。
The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, Tc-99m chelates for SPECT, Y-90 chelates for radiotherapy, F-18 derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N-hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents. Copyright (C) 2006 John Wiley & Sons, Ltd.