使用 HER2 靶向治疗诊断纳米颗粒对异质性卵巢癌进行靶向药物输送和图像引导治疗。,Theranostics

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使用 HER2 靶向治疗诊断纳米颗粒对异质性卵巢癌进行靶向药物输送和图像引导治疗。
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.29964
Minati Satpathy ₁ , Liya Wang ₂ , Rafal J Zielinski ₃ , Weiping Qian ₁ , Y Andrew Wang ₄ , Aaron M Mohs ₅ , Brad A Kairdolf ₅ , Xin Ji ₄ , Jacek Capala ₆ , Malgorzata Lipowska ₂ , Shuming Nie ₅ , Hui Mao ₂ , Lily Yang ₁

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癌症异质性和耐药性限制了癌症治疗的功效。为了解决这个问题，我们开发了一种有效治疗异质性卵巢癌的综合治疗方案。方法：两亲性聚合物包覆的磁性氧化铁纳米颗粒与近红外染料标记的 HER2 亲和体和化疗药物顺铂缀合。在具有高度异质性水平的原位人卵巢癌异种移植模型中检查了治疗诊断纳米颗粒对靶向药物输送、治疗效果、非侵入性磁共振成像 (MRI) 引导治疗以及治疗耐药性肿瘤的光学成像检测的影响。 HER2 表达。结果：我们发现，在裸鼠卵巢癌异种移植模型中，全身递送靶向HER2的磁性氧化铁纳米颗粒（携带顺铂）可显着抑制原发肿瘤以及腹膜和肺转移瘤的生长。通过 MRI 可以检测到治疗诊断纳米粒子向 HER2 表达水平不同的个体肿瘤以及对治疗的不同反应的差异性递送。我们进一步发现，与原发性肿瘤相比，转移性肿瘤具有更强的治疗反应，这可能是由于转移性肿瘤细胞中 HER2 表达水平较高且增殖细胞数量较多。氧化铁纳米颗粒在肿瘤组织中相对较长的保留时间使得可以通过肿瘤组织的体内分子成像和组织学分析来探究纳米颗粒药物递送与耐药残留肿瘤的存在之间的关系。治疗后，大多数剩余肿瘤都是小的原发性肿瘤，HER2 表达水平较低，纳米颗粒药物积累也较低，从而解释了它们缺乏治疗反应。然而，一些残留肿瘤具有表达 HER2 的肿瘤细胞和可检测到的纳米颗粒药物输送，但未能做出反应，这表明存在其他内在耐药机制。然而，纳米颗粒保留在小的残留肿瘤中，产生了可通过光谱成像检测的光学信号。结论：腹膜转移瘤无法通过减瘤手术彻底切除以及化疗耐药是卵巢癌治疗的主要临床挑战。这种靶向癌症疗法有可能开发出有效治疗转移性卵巢癌的方法。

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Targeted Drug Delivery and Image-Guided Therapy of Heterogeneous Ovarian Cancer Using HER2-Targeted Theranostic Nanoparticles.

Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

更新日期：2019-01-01

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