High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles.,ACS Central Science

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High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles.
ACS Central Science ( IF 12.7 ) Pub Date : 2018-12-26 , DOI: 10.1021/acscentsci.8b00746
Kin Man Au _{1,

1,

2} , Rod Balhorn ₃ , Monique C Balhorn ₃ , Steven I Park _{2,

4} , Andrew Z Wang _{1,

1,

2}

Affiliation

Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors.

中文翻译：

通过选择性高亲和力配体抗体模拟功能化阿霉素封装纳米颗粒进行高性能同步化学免疫放射疗法治疗血液癌症。

非霍奇金淋巴瘤是最常见的癌症类型之一。复发性和难治性疾病仍然很常见，并且仍然是重大挑战，因为大多数患者最终死于该疾病。在此，我们报告了一种可转化的同步化学免疫放疗（CIRT）策略，该策略利用完全合成的抗体模拟选择性高亲和力配体（SHAL）功能化的阿霉素封装纳米颗粒（Dox NP）来治疗人类白细胞抗原-D相关的(HLA-DR) 抗原过度表达的肿瘤。我们证明，我们定制的抗体模拟功能化纳米颗粒选择性地结合不同的 HLA-DR 过表达的人淋巴瘤细胞，交联细胞表面 HLA-DR，并触发纳米颗粒的内化。除了 Dox 的直接细胞毒性作用外，内化的 NP 随后释放封装的 Dox 并上调存活细胞的 HLA-DR 表达，这进一步增强了免疫原性细胞死亡 (ICD)。释放的 Dox 不仅促进 ICD，还通过诱导细胞周期停滞和阻止 DNA 损伤的修复，使癌细胞对辐射敏感。体内生物分布和毒性研究证实，靶向纳米粒子增强了肿瘤的摄取并降低了 Dox 的全身毒性。我们使用淋巴瘤异种移植肿瘤模型进行的全面的体内抗癌功效研究表明，模拟抗体的功能性纳米粒子可有效抑制肿瘤生长并使癌细胞对同时进行的 CIRT 治疗敏感，而不会产生明显的副作用。通过适当的治疗方案，SHAL功能化的Dox NPs将放射治疗的细胞杀伤效率提高了100%以上，并根除了80%以上的淋巴瘤肿瘤。

更新日期：2018-12-26

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