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载药氨甲基丙烯酸酯共聚物纳米粒:从药物辅料到有效的癌症免疫治疗药物。

Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics.

机构信息

Department of Pharmaceutics, University of Bonn, Bonn, Germany.

Institute of Physiology II, Medical Faculty, University of Bonn, Bonn, Germany.

出版信息

Biomaterials. 2018 Jun;166:1-12. doi: 10.1016/j.biomaterials.2018.02.053. Epub 2018 Mar 2.

Abstract

Nanoparticles create exciting platforms for anticancer immunotherapy and vaccination, though their inherent immunomodulatory properties have remained underexploited. Ammonio methacrylate copolymers (AMC) are well-established excipients in pharmaceutical industry and components of controlled-release oral formulations. Here, we demonstrate that nanoscaling of type A and B AMC (Eudragit RL and RS) endows these inactive ingredients immunostimulatory properties exploitable for cancer therapy. The particles induce the secretion of various pro-inflammatory cytokines and chemokines from the cells of innate immunity. Though the underlying mechanisms are not fully uncovered, the current work established the partial involvement of Toll-like Receptor 4 (TLR4) and Nuclear factor κB (NF-κB). The size and charge-dependency of the particles' pro-inflammatory properties and cytokine/chemokine induction profile was also demonstrated. Within the context of cancer immunotherapy, biweekly peritumoral nanoparticle injection led to a complete regression of the syngeneic colorectal tumor, or a significant growth retardation thereof, considerably extending the survival of tumor-bearing animals. Additionally, presence of the immunological memory in treated animals was established. Given their better economical and relatively safer profile compared to well-established chemo- and immunotheraputics, and their ability to serve as carriers for drug targeting, vaccination and combination therapy, AMC nanoparticles (AMCNP) are fascinating subjects for further research in the field of cancer therapy.

摘要

纳米颗粒为癌症免疫治疗和疫苗接种创造了令人兴奋的平台,尽管它们固有的免疫调节特性尚未得到充分利用。丙烯酰胺共聚物(AMC)是制药行业中成熟的赋形剂,也是控释口服制剂的组成部分。在这里,我们证明 A 型和 B 型 AMC(Eudragit RL 和 RS)的纳米化赋予了这些非活性成分免疫刺激特性,可用于癌症治疗。这些颗粒诱导先天免疫细胞分泌各种促炎细胞因子和趋化因子。虽然潜在的机制尚未完全揭示,但目前的工作已经确定了 Toll 样受体 4(TLR4)和核因子 κB(NF-κB)的部分参与。还证明了颗粒的促炎特性和细胞因子/趋化因子诱导谱的大小和电荷依赖性。在癌症免疫治疗的背景下,每周两次在肿瘤周围注射纳米颗粒导致同源结直肠肿瘤完全消退,或显著减缓其生长,大大延长了荷瘤动物的存活时间。此外,还确定了治疗动物中存在免疫记忆。与成熟的化疗和免疫疗法相比,由于其具有更好的经济性和相对更安全的特性,以及作为药物靶向、疫苗接种和联合治疗载体的能力,AMC 纳米颗粒(AMCNP)是癌症治疗领域进一步研究的迷人课题。

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