Importance of avidity for an endogenous drug carrier: an antibody carrier for CpG oligonucleotides.
Importance of avidity for an endogenous drug carrier: an antibody carrier for CpG oligonucleotides.
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亲和力对于内源药物载体的重要性：CpG 寡核苷酸的抗体载体。
DOI：
10.1021/mp100122k
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发表时间：
2010
影响因子：
4.9
通讯作者：
Cho,Moo
中科院分区：
文献类型：
--
作者：
Cheung,Roland;Cho,Moo
在动物模型中，使用CpG寡脱氧核苷酸（ODN）的成功的抗癌单一疗法已限于肿瘤内和肿瘤周围的施用途径。为了克服这一局限性，我们开发了一种利用内源性抗体作为载体的CpG ODN的传递系统。当将2，4-二硝基苯基（DNP）与CpG ODN的1：1缀合物施用给针对DNP预先免疫的荷瘤小鼠时，静脉内（iv）施用成功地抑制了肿瘤生长（Palma，E.;周，M。J.J. Controlled Release 2007，120，95 - 103）。在目前的研究中，我们再现了静脉注射的结果，并表明在相同的模型中，具有乱序核苷酸序列的受控ODN的DNP衍生物失败。也许更重要的是，对侧皮下（sc）给药途径也抑制肿瘤生长。然而，在单独的实验中，当抗DNP滴度水平低时，抗肿瘤作用被消除，这支持了络合中涉及的亲合力的重要性。由于滴度较低，注射剂量的很大一部分必须以未结合的形式存在，从而快速清除。本研究证明了化学交联的免疫复合物，使得CpG ODN在施用后不能在体内解离。
In animal models, successful anticancer monotherapy with CpG oligodeoxynucleotide (ODN) has been limited to the intratumoral and peritumoral routes of administration. To overcome this limitation, we developed a delivery system utilizing an endogenous antibody as a carrier for CpG ODNs. When a 1:1 conjugate of 2,4-dinitrophenyl (DNP) to a CpG ODN was administered to tumor-bearing mice that were preimmunized against DNP, intravenous (iv) administration successfully inhibited tumor growth (Palma, E.; Cho, M. J.J. Controlled Release2007,120, 95−103). In the present studies, we reproduced the iv results and showed that a DNP derivative of a controlled ODN with scrambled nucleotide sequence failed in the same model. Perhaps more significantly, contralateral subcutaneous (sc) routes of administration also suppressed tumor growth. However, in a separate experiment, when the anti-DNP titer level was low, the antitumor effect was abolished, supporting the importance of the avidity involved in the complexation. With the low titer, a significant fraction of injected dose must have existed as unbound that is subject to rapid clearance. The present study justifies chemically cross-linked immune complexes such that the CpG ODN cannot dissociate in the body after administration.