Synthesis of Carboxy-Dimethylmaleic Amide Linked Polymer Conjugate Based Ultra-pH-sensitive Nanoparticles for Enhanced Antitumor Immunotherapy.
Synthesis of Carboxy-Dimethylmaleic Amide Linked Polymer Conjugate Based Ultra-pH-sensitive Nanoparticles for Enhanced Antitumor Immunotherapy.
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DOI：
10.1021/acsmacrolett.0c00755
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发表时间：
2020-11-17
影响因子：
7.015
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Lang S;Tan Z;Wu X;Huang X
细胞毒性T淋巴细胞（CTL）是抗癌免疫治疗的重要工具。为了激发强大的CTL活性，已经合成了基于甲氧基聚（乙二醇）-B-[聚（二异丙基氨基）乙基甲基丙烯酸酯]的超pH敏感纳米颗粒（NP）作为疫苗递送平台。将代表性CTL表位卵清蛋白（OVA）肽抗原通过酸响应性羧基-二甲基马来酰胺接头（CDM）共价缀合至聚合物主链，产生聚合物P-CDM-OVA。有趣的是，虽然P-CDM-OVA在pH 6.4缓冲液中缓慢释放OVA肽，但加入模拟细胞和/或体内环境中遇到的蛋白质的牛血清白蛋白（BSA）显著加速了释放过程。当基于P-CDM-OVA的超pH敏感颗粒与抗原呈递细胞一起孵育时，观察到OVA的成功细胞表面呈递。与游离肽或先前报道的封装OVA的缩醛化葡聚糖颗粒相比，这些P-CDM-OVA NP大大增强了体内CTL应答。还研究了P-CDM的佐剂缀合，并且P-CDM-OVA和P-CDM-佐剂缀合物NP的共施用进一步改善了体内CTL应答并有效地减少了小鼠中的肿瘤生长。因此，CDM连接的聚合物为抗癌免疫治疗提供了一个有前途的平台。
Cytotoxic T lymphocytes (CTLs) are an important tool for anticancer immunotherapy. To elicit powerful CTL activities, ultra-pH-sensitive nanoparticles (NPs) based on methoxy poly(ethylene glycol)-b-[poly(diisopropylamino)ethyl methacrylate] have been synthesized as a vaccine delivery platform. A representative CTL epitope, ovalbumin (OVA) peptide antigen, was covalently conjugated to the polymer backbone through an acid responsive carboxy-dimethylmaleic amide linker (CDM) resulting in polymer P-CDM-OVA. Interestingly, while the P-CDM-OVA released OVA peptide slowly in a pH 6.4 buffer, the addition of bovine serum albumin (BSA) mimicking proteins encountered in a cellular and/or in vivo environment significantly accelerated the release process. Successful cell surface presentation of OVA was observed when P-CDM-OVA based ultra-pH-sensitive particles were incubated with antigen presenting cells. These P-CDM-OVA NPs greatly enhanced CTL responses in vivo compared to the free peptide or the previously reported acetalated dextran particles encapsulating OVA. The P-CDM was also investigated for adjuvant conjugation, and the coadministration of P-CDM-OVA and the P-CDM-adjuvant conjugate NPs further improved CTL responses in vivo and effectively reduced tumor growth in mice. Thus, the CDM linked polymer presents a promising platform for anticancer immunotherapy.
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影响因子：
38.3
作者：
Luo M;Wang H;Wang Z;Cai H;Lu Z;Li Y;Du M;Huang G;Wang C;Chen X;Porembka MR;Lea J;Frankel AE;Fu YX;Chen ZJ;Gao J
通讯作者：
Gao J
影响因子：
15
作者：
Ma, Xinpeng;Wang, Yiguang;Zhao, Tian;Li, Yang;Su, Lee-Chun;Wang, Zhaohui;Huang, Gang;Sumer, Baran D.;Gao, Jinming
通讯作者：
Gao, Jinming
影响因子：
5.5
作者：
Ilyinskii, Petr O.;Roy, Christopher J.;O'Neil, Conlin P.;Browning, Erica A.;Pittet, Lynnelle A.;Altreuter, David H.;Alexis, Frank;Tonti, Elena;Shi, Jinjun;Basto, Pamela A.;Iannacone, Matteo;Radovic-Moreno, Aleksandar F.;Langer, Robert S.;Farokhzad, Omid C.;von Andrian, Ulrich H.;Johnston, Lloyd P. M.;Kishimoto, Takashi Kei
通讯作者：
Kishimoto, Takashi Kei
影响因子：
15.9
作者：
Hanson, Melissa C.;Crespo, Monica R.;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
10.8
作者：
Mohsen, Mona O.;Gomes, Ariane C.;Bachmann, Martin F.
通讯作者：
Bachmann, Martin F.