Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents.
Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents.
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DOI：
10.1021/acs.molpharmaceut.8b00717
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发表时间：
2018-11-05
影响因子：
4.9
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Chen Y;Sun J;Huang Y;Lu B;Li S
开发一种有效的针对晚期肿瘤的免疫化疗制剂是非常必要的，也是一个巨大的挑战。我们之前已经报道了一种基于聚乙二醇NLG的免疫刺激纳米载体(PEG2k-Fmoc-NLG919)，用于联合传递IDO1抑制剂(NLG919)和化疗药物(紫杉醇，PTX)。负载PTX的纳米载体虽然增强了抗肿瘤免疫反应，但髓系抑制细胞(MDSCs)的积聚也显著增加，这可能限制了治疗的整体效果。在目前的工作中，我们开发了一种改进的双功能纳米载体(PEG5K-FMOC-NLG2)来共负载PTX和舒尼替尼(SUN，一种多靶点受体酪氨酸激酶抑制剂)，以改善癌症免疫化疗。我们发现，招募的MDSCs对PTX负载的PEG-NLG纳米载体的整体抗肿瘤活性产生了负面影响。机制研究表明，这可能归因于PTX介导的一系列趋化因子的诱导，这些趋化因子参与MDSCs的招募。我们进一步证明，这些趋化因子的诱导被SUN彻底阻断。通过PEG5k-Fmoc-NLG9192纳米载体共传递PTX和SUN可进一步提高治疗效果，并伴随MDSCs的减少。
It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for codelivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX). Although antitumor immune responses were enhanced with PTX-loaded nanocarrier, the accumulation of myeloid-derived suppressor cells (MDSCs) was also significantly increased, which may limit the overall efficacy of therapy. In the present work, we developed an improved dual-functional nanocarrier (PEG5k-Fmoc-NLG2) to co-load PTX and sunitinib (SUN, a multi-target receptor tyrosine kinase inhibitor) for improved cancer immunochemotherapy. We found that the recruited MDSCs negatively impacted the overall antitumor activity of PTX-loaded PEG-NLG nanocarrier. Mechanistic study suggests that this is likely attributed to the PTX-mediated induction of a number of chemokines that are involved in the recruitment of MDSCs. We have further shown that the induction of these chemokines was drastically blocked by SUN. Codelivery of PTX and SUN via PEG5k-Fmoc-NLG9192 nanocarrier led to a further improvement in the therapeutic efficacy with a concomitant reduction in MDSCs.
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影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
5.6
作者：
Greten TF;Manns MP;Korangy F
通讯作者：
Korangy F
影响因子：
17.1
作者：
Highfill SL;Cui Y;Giles AJ;Smith JP;Zhang H;Morse E;Kaplan RN;Mackall CL
通讯作者：
Mackall CL
影响因子：
45.3
作者：
Burstein, Harold J.;Elias, Anthony D.;Miller, Kathy D.
通讯作者：
Miller, Kathy D.
影响因子：
11.2
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
通讯作者：
Munn, David H.