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177Lu-labeled Gold Nanoparticles for Radiation Therapy of Locally Advanced Breast Cancer.

机译：177Lu标记的金纳米粒子用于局部晚期乳腺癌的放射治疗。

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摘要

Locally advanced breast cancer (LABC) occurs in about 10-15% of patients diagnosed with breast cancer (BC) and 30% of these patients have triple negative breast cancer (TNBC) that are often epidermal growth factor receptor (EGFR)-positive. The goal of the proposed research was design and evaluate preclinically a novel radiation nanomedicine for LABC composed of EGFR-targeted gold nanoparticles (AuNP) by covalently conjugating panitumumab and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexing 177Lu incorporated into a metal-chelating polymer (MCP) (177 Lu-T-AuNP) which could be used as a neoadjuvant treatment to improve the outcome of patients with LABC. 177Lu-T-AuNP were efficiently internalized by EGFR-positive BC cells and were significantly more effective than 177Lu-labeled and non-targeted (NT)-AuNP for killing these cells. For radiation treatment of EGFR-positive tumours, both 177Lu-T-AuNP and 177Lu-NT-AuNP were intratumourally (i.t.) injected into athymic mice with MDA-MB-468 BC xenografts for comparison. Biodistribution studies showed that 177Lu-T-AuNPs exhibited 2-fold higher tumour retention than 177Lu-NT-AuNPs following i.t. injection at 48 h p.i. Both forms of radiolabeled AuNP were highly effective for inhibiting tumour growth without normal organ toxicity due to local tumour retention of both form of AuNP. To minimize the displacement of 177Lu-labeled MCP from AuNP, polyethylene glycol (PEG) ligands presenting a disulfide [ 177Lu-DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a lipoic acid (LA) [177Lu-DOTA-PEG-lipoic acid (LA)] or multi-LA [PEG- pGlu(177Lu-DOTA)8-LA4] for multivalent binding were synthesized and the stability of MCP-AuNP complexes determined. In vitro challenge study with thiol-containing molecules or human plasma, PEG-pGlu(DOTA)8-LA4-AuNP were most stable. In whole body elimination study, elimination of radioactivity due to displacement of 177Lu-MCP from AuNP in mice injected with 177Lu-DOTA-PEG-OPSS-AuNP was more rapid, indicating that 177Lu-DOTA-PEG-OPSS-AuNP was less stable than two other forms of 177Lu-MCP-AuNP. Since MCP presenting a terminal multi-LA group provides the greatest stability, this conjugation chemistry is the most promising for construction of 177 Lu-labeled and antibody-targeted AuNP for neoadjuvant treatment of LABC.
机译：在诊断为乳腺癌（BC）的患者中，约有10-15％会发生局部晚期乳腺癌（LABC），而这些患者中有30％的三阴性乳腺癌（TNBC）通常是表皮生长因子受体（EGFR）阳性。拟议研究的目标是通过共价结合panitumumab和1,4,7,10-四氮杂环十二烷-1,4,7,10-来设计和临床前评估LABC的新型放射纳米药物，该药物由EGFR靶向的金纳米粒子（AuNP）组成。四乙酸（DOTA）配合物177Lu掺入金属螯合聚合物（MCP）（177 Lu-T-AuNP）中，可用作新辅助治疗以改善LABC患者的预后。 177Lu-T-AuNP被EGFR阳性BC细胞有效地内在化，并且比177Lu标记和非靶向（NT）-AuNP杀死这些细胞的效率明显更高。为了对EGFR阳性肿瘤进行放射治疗，将177Lu-T-AuNP和177Lu-NT-AuNP均通过瘤内（i.t.）注射到了MDA-MB-468 BC异种移植的无胸腺小鼠中进行比较。生物分布研究表明，经i.t处理后，177Lu-T-AuNPs的肿瘤保留率比177Lu-NT-AuNPs高2倍。每天48小时注射由于两种形式的AuNP的局部肿瘤保留，两种形式的放射性标记的AuNP都非常有效地抑制肿瘤生长而没有正常器官毒性。为了最小化177Lu标记的MCP从AuNP的置换，聚乙二醇（PEG）配体呈现二硫化物[177Lu-DOTA-PEG-邻吡啶二硫化物（OPSS）]，硫辛酸（LA）[177Lu-DOTA-PEG-合成了用于多价结合的硫辛酸（LA）]或多LA [PEG-pGlu（177Lu-DOTA）8-LA4]，并确定了MCP-AuNP复合物的稳定性。用含硫醇的分子或人血浆进行的体外攻击研究中，PEG-pGlu（DOTA）8-LA4-AuNP最稳定。在全身消除研究中，在注射177Lu-DOTA-PEG-OPSS-AuNP的小鼠中，由于从AuNP置换177Lu-MCP而导致的放射性消除更快，表明177Lu-DOTA-PEG-OPSS-AuNP的稳定性较弱。其他两种形式的177Lu-MCP-AuNP。由于MCP带有一个末端多LA基团，提供了最大的稳定性，因此这种共轭化学对于构建177个Lu标记的和靶向抗体的AuNP最有希望，可用于LABC的新辅助治疗。

著录项

  • 作者

    Yook, Simmyung.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Pharmaceutical sciences.;Oncology.;Biochemistry.;Nanotechnology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 228 p.
  • 总页数 228
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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