Anti-MUC1-C Antibody-Conjugated Nanoparticles Potentiate the Efficacy of Fractionated Radiation Therapy.
Anti-MUC1-C Antibody-Conjugated Nanoparticles Potentiate the Efficacy of Fractionated Radiation Therapy.
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抗MUC1-C抗体偶联的纳米颗粒增强了分离放射疗法的功效。
DOI：
10.1016/j.ijrobp.2020.06.069
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发表时间：
2020-12-01
期刊：
影响因子：
--
通讯作者：
Ghoroghchian PP
中科院分区：
文献类型：
--
作者：
Detappe A;Mathieu C;Jin C;Agius MP;Diringer MC;Tran VL;Pivot X;Lux F;Tillement O;Kufe D;Ghoroghchian PP
重金属螯合剂和无机纳米粒子（NP）已被检查为潜在的放射增强剂，可提高外束放射治疗对各种癌症的疗效。不幸的是，这些药物中的大多数表现出相对较差的药代动力学特性，这限制了定位于肿瘤的注射剂量的百分比（%ID/g），并且由于快速的肿瘤清除而缩短了有效辐射增强的窗口。为了应对这些挑战，我们试图将基于钆的超小（<5 nm）纳米颗粒与针对致癌 MUC1-C 亚基的抗体结合，该亚基在许多不同的人类癌症类型的表面过度表达。抗MUC1-C抗体3D1与癌细胞表面MUC1-C的结合与其内化相关，从而与抗体相关有效负载的有效细胞内递送相关，促进其有效的肿瘤保留。因此，我们检查了全身施用抗MUC1-C抗体缀合的钆纳米粒子（抗MUC1-C/NPs）是否可以在表达MUC1-C的（H460）肺癌和（E0771）乳腺癌的细胞系异种移植模型中积累，以提高放射治疗（XRT）的疗效。发现肿瘤内积累的抗 MUC1-C/NP 的 %ID/g 与未缀合的对应物相似（分别为 6.6 ± 1.4 和 5.9 ± 1.7 %ID/g）。重要的是，抗 MUC1-C/NPs 在体内肿瘤微环境中表现出长期保留；因此，在分割治疗过程中维持了放射加强（3 × 5.2 Gy）。我们发现，与给予对照 NP 和 XRT（31.1 ± 2.4 天）或单独使用 XRT（27.3 ± 1.6 天；P < .01，对数秩）相比，通过 XRT 给予抗 MUC1-C/NP 可以显着增强肿瘤生长抑制并延长动物的总生存期（46.2 ± 3.1 天）。这些发现表明，抗 MUC1-C/NP 可用于增强放射治疗的有效性，并有可能改善临床结果。
Heavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy for various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentage of injected dose (%ID/g) that localizes to tumors and which shorten the window for effective radiation enhancement due to rapid tumor washout. To address these challenges, we sought to conjugate gadolinium-based ultrasmall (<5 nm) NPs to an antibody directed against the oncogenic MUC1-C subunit that is overexpressed on the surface of many different human cancer types. The binding of the anti-MUC1-C antibody 3D1 to MUC1-C on the surface of a cancer cell is associated with its internalization and, thereby, to effective intracellular delivery of the antibody-associated payload, promoting its effective tumor retention. As such, we examined whether systemically administered anti-MUC1-C antibody-conjugated, gadolinium-based NPs (anti-MUC1-C/NPs) could accumulate within cell-line xenograft models of MUC1-C-expressing (H460) lung and (E0771) breast cancers to improve the efficacy of radiation therapy (XRT). The %ID/g of anti-MUC1-C/NPs that accumulated within tumors was found to be similar to that of their unconjugated counterparts (6.6 ± 1.4 vs 5.9 ± 1.7 %ID/g, respectively). Importantly, the anti-MUC1-C/NPs demonstrated prolonged retention in in vivo tumor microenvironments; as a result, the radiation boost was maintained during the course of fractionated therapy (3 × 5.2 Gy). We found that by administering anti-MUC1-C/NPs with XRT, it was possible to significantly augment tumor growth inhibition and to prolong the animals’ overall survival (46.2 ± 3.1 days) compared with the administration of control NPs with XRT (31.1 ± 2.4 days) or with XRT alone (27.3 ± 1.6 days; P < .01, log-rank). These findings suggest that anti-MUC1-C/NPs could be used to enhance the effectiveness of radiation therapy and potentially to improve clinical outcomes.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
14
作者：
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Su, Ming
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4.6
作者：
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通讯作者：
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影响因子：
78.5
作者：
Kufe, Donald W.
通讯作者：
Kufe, Donald W.
影响因子：
10.8
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Kunjachan S;Detappe A;Kumar R;Ireland T;Cameron L;Biancur DE;Motto-Ros V;Sancey L;Sridhar S;Makrigiorgos GM;Berbeco RI
通讯作者：
Berbeco RI