Enhanced MRI‐Guided Gadolinium (III) Neutron Capture Therapy by Polymeric Nanocarriers Promoting Tumor Accumulation and Intracellular Delivery
Enhanced MRI‐Guided Gadolinium (III) Neutron Capture Therapy by Polymeric Nanocarriers Promoting Tumor Accumulation and Intracellular Delivery
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DOI：
10.1002/cnma.201900730
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发表时间：
2020-02
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通讯作者：
Changyuan Qin;X. Hou;Thahomina Khan;Nobuhiro Nitta;M. Yanagawa;Y. Sakurai;Minoru Suzuki;S. Masunaga;Hiroki Tanaka;Y. Sakurai;Hiroyuki Takahashi;I. Aoki;H. Yanagie;H. Cabral
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作者：
Changyuan Qin;X. Hou;Thahomina Khan;Nobuhiro Nitta;M. Yanagawa;Y. Sakurai;Minoru Suzuki;S. Masunaga;Hiroki Tanaka;Y. Sakurai;Hiroyuki Takahashi;I. Aoki;H. Yanagie;H. Cabral
Gd(III)(Gd(III))络合物是开发核磁共振引导的中子俘获疗法(NCT)的有前途的化合物。然而，尽管它们作为MRI造影剂(CA)取得了成功，但目前的Gd(III)络合物并不能在肿瘤中表现出适当的蓄积来进行有效的NCT。为了克服这一局限性，我们开发了一系列生物相容的Gd(III)-螯合物聚合物纳米载体，即 ，即Gd-DOTA，作为非CT试剂，具有高的磁共振敏感性和肿瘤转移性。这些聚合物以聚天冬氨酸(P(Asp))为基础，并用不同相对分子质量(MW)的聚乙二醇链(PEG)进行修饰，以控制稳定性和药动学。与临床使用的Gd(III)CaS相比，Gd-DOTA共轭聚合物的T1弛豫度提高了2倍。在体内，聚乙二醇化聚合物促进了肿瘤组织中的蓄积，增强了肿瘤的MRI对比度。经中子照射后，纳米载体有效地抑制了肿瘤的生长，尤其是聚乙二醇链较短的聚乙二醇-P(Asp-Gd-DOTA)，促进了较高的细胞内转运，支持了其作为NCT制剂的潜力。
Gadolinium(III) (Gd(III)) chelates are promising compounds for developing MRI‐guided neutron capture therapies (NCT). However, despite their success as MRI contrast agents (CAs), current Gd(III) chelates do not present appropriate accumulation in tumors for effective NCT. To overcome this limitation, we developed a series of biocompatible polymeric nanocarriers conjugating Gd(III)‐chelates, i. e. Gd‐DOTA, as NCT agents with high MRI sensitivity and tumor delivery. These polymers were based on poly(aspartic acid) (P(Asp)) and were modified with poly(ethylene glycol) (PEG) chains having different molecular weight (Mw) for controlling stability and pharmacokinetics. The T1relaxivity of the Gd‐DOTA conjugated polymers increased 2‐fold compared to that of clinically used Gd(III) CAs. In vivo, the PEG‐modified polymers promoted the accumulation in tumor tissues, enhancing the MRI contrast of tumors. After neutron irradiation, the nanocarriers effectively suppressed the tumor growth, particularly the PEG‐P(Asp‐Gd‐DOTA) with shorter PEG chain, which promoted higher intracellular delivery, supporting their potential as NCT agents.