Improved Tumor Rediotherapy by MORF Pretargeting

通过 MORF 预靶向改进肿瘤放射治疗

基本信息

批准号：
7258505
负责人：
DONALD J HNATOWICH
金额：
$ 24.08万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7258505
关键词：
90Y Acids Acute Adenine Affinity Agreement Americas Amides Amines Anhydrides Animal Rights Animals Anti-CEA Antibody Antibodies Area Area Under Curve Attention Avidin Base Sequence Behavior Beta Particle Binding Binding Sites Biodistribution Biological Assay Biotin Bispecific Antibodies Bladder Blood Blood Circulation Boston Buffers CC49 antibody Cancer Patient Carbodiimides Caring Cell surface Cells Characteristics Charge Chelating Agents Chemical Structure Cities Clinical Collimator Complement Complementary DNA Condition Contralateral Control Animal Control Groups Controlled Study Count Coupling Cultured Cells Cytosine DNA Daily Data Data Set Dendrimers Deposition Detection Development Development, Other Dextrans Diagnosis Diagnostic Diffusion Dimensions Discipline of Nuclear Medicine Dissociation Dorsal Dose Drug Kinetics Electrons Equilibrium Exhibits Exposure to Fluorescence Fluorescence Resonance Energy Transfer Frequencies Funding Furuncles Future Gamma Cameras Goals Growth Half-Life Hand Harvest Health Sciences Heart Heating High Pressure Liquid Chromatography Hour Human Image Immunoglobulin G Implant In Situ In Vitro Incubated Individual Infection Inflammation Injection of therapeutic agent Institution Investigation Ion-Exchange Chromatography Procedure Ions Iowa Kidney Kidney Neoplasms Knowledge Label Laboratories Left Length Lesion Literature Liver Liver neoplasms Lucite Lung Lysine Mass Spectrum Analysis Measurement Measures Melanocytic nevus Metabolism Methods Metric Microspheres Modality Modeling Mole the mammal Molecular Molecular Target Molecular Weight Monoclonal Antibody CC49 Mus Muscle N,N-diisopropylethylamine Nature Neoplasm Antibodies Normal Horse Serum Normal tissue morphology Nude Mice Numbers Oklahoma Optics Organ Organ Size Paper Patients Penetration Pentetic Acid Peptide Nucleic Acids Phase Phosphate Buffer Photons Pliability Polyethylene Glycols Polylysine Polymers Polystyrenes Positioning Attribute Preparation Principal Investigator Printing Procedures Process Property Protein Binding Publications Purines Purpose Pyrimidine Pyrimidines Pyrrolidinones Radiation Radiation therapy Radio Radioactivity Radioimmunoconjugate Radioisotopes Radiolabeled Radiopharmaceuticals Rate Reagent Recombinant DNA Relative (related person)Reporting Research Research Design Research Personnel Rest Ribosomal DNA Right-On Risk Rotation S-acetylmercaptoacetyltriglycine N-hydroxysuccinimide Saline Salivary Scheme Series Serum Side Signal Transduction Simulate Site Skin Societies Solubility Solutions Source Spleen Standards of Weights and Measures Stomach Streptavidin Structure Students Surface Surface Plasmon Resonance System Tartrates Technetium Tc 99m Mertiatide Temperature Testing Text Therapeutic Therapeutic Effect Thick Thigh structure Thinking Thymine Thyroid Gland Time Tissues Tracer Transient Global Amnesia Tumor Antibodies Tumor Tissue Tumor Weights Uncertainty United States National Institutes of Health Universities Urine Variant Vertebral column Water Weight Width absorption acetone hydrazone antibody conjugate antibody engineering aqueous base bone cancer diagnosis carboxylate chemical synthesis concept cost day density design dextran disuccinimidyl glutarate disuccinimidyl suberate dosage experience falls fluorescence imaging fluorophore immunoreactivity improved in vivo inhibitor/antagonist interest maleic acid malignant breast neoplasm man microautoradiography molecular modeling mouse model multidisciplinary neoplastic cell novel strategies optical imaging perrhenate phosphodiester phosphorothioate posters pre-clinical prevent programs purine radiotracer residence sensor simulation size success tartrate tool trend tumor tumor growth uptake vinyl ether whole body imaging

项目摘要

DESCRIPTION (provided by applicant): Pretargeting of tumor is becoming a mature, reasonably well understood and successful imaging modality. The advantage of pretargeting is usually not in higher absolute tumor accumulation but in higher tumor/normal tissue ratios achieved rapidly. This laboratory is exploring several novel approaches to pretargeting, each having in common the use of oligomers in place of either streptavidin/biotin or bispecific antibodies. In the course of investigating oligomers for "conventional" pretargeting, it became apparent that these interesting molecules have many useful properties for this application. In addition to conventional pretargeting, these studies have led to the development of three new subfields of investigation that we call "amplification pretargeting", "affinity enhancement pretargeting with oligomers" and, most recently, "optical pretargeting". Because of the novelty of using oligomers in radiopharmaceutical design, and in particular MORFs for pretargeting applications, we were required to develop methods of labeling MORFs with 99mTc and 188Re, develop new methods of conjugating antibodies and polymers with MORFs, develop methods of synthesizing bivalent MORFs with different spacings and, most recently, explore cellular accumulations of fluorophore conjugated MORFs. In addition, it was necessary to calibrate our tumor mouse model to better understand its properties with respect to pretargeting so that tumor and normal tissue accumulations could be accurately predicted with changes in variables. These and other developments have been successfully accomplished as documented in our publications in print, in press, submitted and in preparation. We intend to continue these investigations of MORF pretargeting by emphasizing our conventional preclinical pretargeting radiotherapy studies with 188Re-MORFs into (with supplemental funding) tracer studies in patients; 2) improving upon pretargeting by continuing our MORF amplification and MORF affinity enhancement pretargeting of tumors. We will also continue our MORF pretargeting studies with optical detection. Our multidisciplinary UMMS team consisting of chemists, radiation physicists and a molecular biologist has experience in each phase of this investigation. The proposed studies will now build upon our past results to achieve our goal of greatly improving upon conventional molecular targeting of tumor for improved cancer diagnosis and, especially, radiotherapy.

描述（由申请人提供）：肿瘤的预定性正在成为一种成熟，合理的理解和成功的成像方式。预先定位的优势通常不是在较高的绝对肿瘤积累中，而是在较高的肿瘤/正常组织比率中迅速达到。该实验室正在探索几种有限的新方法，每种方法都具有代替链霉亲和生物素或双特异性抗体的寡聚物使用。在调查“常规”有限态度的低聚物的过程中，很明显，这些有趣的分子在此应用中具有许多有用的特性。除了常规的预测外，这些研究还导致了三个新的调查子领域的发展，我们称之为“放大预先目标”，“与低聚物的亲和力增强”，以及最近的“光学预测”。由于在放射性药物设计中使用寡聚的新颖性，尤其是用于预步骤应用的MORF，我们被要求开发使用99mtc和188RE标记MORF的方法，开发了与MORF共同结合抗体和聚合物的新方法，与MORF相结合，开发了与不同的隔离型培养的方法，这些方法与不同的隔离式相结合，并培养了不同的型号，这些方法与不同的隔离式相结合，并探索了不同的方法，并且大多数均与大多数群体相结合，并且大多数人都可以融合抗体和聚合物。共轭摩尔夫。此外，有必要校准我们的肿瘤小鼠模型，以更好地了解其在预先目标方面的特性，以便可以随着变量的变化来准确预测肿瘤和正常组织的积累。这些发展和其他发展已成功完成，正如我们的印刷品，印刷，提交和准备中所记录的那样。我们打算通过强调我们的常规临床前预性放射疗法研究，以188re-Morfs对患者的示踪剂研究（具有补充资金的）示踪剂研究，以继续对MORF有限的研究； 2）通过继续我们的MORF扩增和MORF亲和力增强肿瘤的预测，改善了进步。我们还将通过光学检测继续我们的MORF预步骤研究。我们的多学科UMMS团队由化学家，辐射物理学家和分子生物学家组成，在此研究的每个阶段都有经验。拟议的研究现在将基于我们过去的结果，以实现我们的目标，即在肿瘤的常规分子靶向方面大大改善癌症诊断，尤其是放疗。