Targeted Drug Delivery and Image-Guided Therapy of Heterogeneous Ovarian Cancer Using HER2-Targeted Theranostic Nanoparticles
Targeted Drug Delivery and Image-Guided Therapy of Heterogeneous Ovarian Cancer Using HER2-Targeted Theranostic Nanoparticles
复制标题
DOI：
10.7150/thno.29964
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Yang, Lily
中科院分区：
文献类型：
--
作者：
Satpathy, Minati;Wang, Liya;Yang, Lily
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，我们已经开发了一个综合的治疗方案，有效地治疗异质性卵巢cancer.Methods：一个两亲性聚合物涂层的磁性氧化铁纳米粒子与近红外染料标记的HER 2受体和化疗药物顺铂缀合。在具有高度异质性水平的HER 2表达的原位人卵巢癌异种移植模型中检查治疗诊断纳米颗粒对靶向药物递送、治疗功效、非侵入性磁共振成像（MRI）引导治疗和治疗抗性肿瘤的光学成像检测的作用。我们发现全身性的HER 2-靶向磁性氧化铁纳米粒载顺铂显着抑制原发性肿瘤和腹膜及肺转移瘤的生长在卵巢癌裸鼠异种移植模型中。通过MRI可检测到治疗诊断纳米颗粒向具有异质性HER 2表达水平和对治疗的各种反应的个体肿瘤中的差异递送。我们进一步发现，与原发性肿瘤相比，转移性肿瘤的治疗反应更强，这可能是由于转移性肿瘤细胞中更高水平的HER 2表达和更多数量的增殖细胞。氧化铁纳米颗粒在肿瘤组织中的相对长时间保留允许通过肿瘤组织的体内分子成像和组织学分析来询问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，大多数剩余的肿瘤是小的原发性肿瘤，具有低水平的HER 2表达和纳米颗粒药物积累，从而解释了它们缺乏治疗反应。然而，少数残留肿瘤具有表达HER 2的肿瘤细胞和可检测的纳米颗粒药物递送，但未能响应，这表明了额外的内在耐药机制。纳米颗粒保留在小的残留肿瘤，然而，产生的光学信号检测光谱imaging.Conclusion：无法完全切除腹膜转移瘤的减积手术以及耐化疗是卵巢癌治疗的主要临床挑战。这种靶向癌症治疗有可能发展为转移性卵巢癌的有效治疗。
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.