Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist
文献类型：期刊论文
| 作者 | Verschuere, Hanne2,4,5; Kasmi, Sabah3,4; Nuhn, Lutz6; D'Almeida, Senan Mickael7; Zhu, Qiwen8,9; Zhong, Zifu3,4; Adjemian, Sandy2,4,5; Louage, Benoit3,4; De Vrieze, Jana3,4; Yu, Haijun8,9
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| 刊名 | RSC ADVANCES
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| 出版日期 | 2025-04-09 |
| 卷号 | 15期号:15页码:11662-11674 |
| DOI | 10.1039/d5ra00163c |
| 英文摘要 | The efficacy of conventional chemotherapy does not only rely on the cytotoxic action of the drug compound itself. Indeed, proper drug-induced immunogenic cell death (ICD) can stimulate immunosurveillance and mount a systemic anti-tumor response. We aimed to further amplify the therapeutic activity of oxaliplatin (OxPt) chemotherapy-induced ICD by combining this with an imidazoquinoline (IMDQ) TLR7/8 agonist. We hypothesized that innate immune activation by TLR7/8 activation primes the immune system against tumor neoantigens, thereby mounting tumor-specific T cell responses that contribute to killing primary tumor cells and distal metastases. To this end, we initially synthesized a covalent conjugate of OxPt, an imidazoquinoline TLR7/8 agonist (i.e., IMDQ), and an alkyl lipid. We hypothesized that such a lipidated conjugate would, upon intratumoral injection, increase the residence time in the tumor and reduce systemic dissemination and, hence, off-target toxicity. Whereas combination therapy with OxPt and IMDQ in native form improved, relative to single treatment, the anti-tumor efficacy against the primary treated tumor and a secondary distal tumor, this was not the case for OxPt-IMDQ-lipid conjugate therapy. We then altered the molecular design of the combination therapy and synthesized amphiphilic OxPt and IMDQ conjugates, comprising a cholesteryl motif and a hydrophilic poly(ethylene glycol) (PEG) chain. Intratumoral combination therapy with OxPt-PEG-cholesteryl and IMDQ-PEG-cholesteryl reduced, compared to native drug compounds, systemic innate inflammatory responses, and more efficiently eradicated primary and distal tumors. Furthermore, we found that combination therapy with OxPt-PEG-cholesteryl and IMDQ-PEG-cholesteryl induced antigen-specific anti-tumor responses and high infiltration levels of CD8+ T cells into the tumor. |
| WOS关键词 | CANCER ; DEATH ; NANOPARTICLES ; DELIVERY ; AGENTS |
| 资助项目 | Fonds Wetenschappelijk Onderzoek[3G033120] ; Fonds Wetenschappelijk Onderzoek[3G0A9322] ; Fund for Scientific Research (FWO) research projects[EOS 30826052] ; Fund for Scientific Research (FWO) research projects[3G0I5722] ; EOS research consortium[01M00709] ; EOS research consortium[01IB3920] ; UGent Special Research Fund Methusalem[365A08921] ; Foundation against Cancer ; VIB ; FWO |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001465907900001 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317413]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | De Geest, Bruno G.; Vandenabeele, Peter |
| 作者单位 | 1.Univ Ghent, Methusalem Program, Ghent, Belgium 2.VIB Ctr Inflammat Res, Cell Death & Inflammat Unit, Ghent, Belgium 3.Univ Ghent, Dept Pharmaceut, Ghent, Belgium 4.Univ Ghent, Canc Res Inst Ghent CRIG, Ghent, Belgium 5.Univ Ghent, Dept Biomed Mol Biol DBMB, Ghent, Belgium 6.Julius Maximilians Univ Wurzburg, Dept Chem & Pharm, Wurzburg, Germany 7.Ecole Polytech Fed Lausanne EPFL, CyTOF Flow Cytometry Core Facil, Lausanne, Switzerland 8.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 9.Chinese Acad Sci, Ctr Pharmaceut, Shanghai Instituteof Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Verschuere, Hanne,Kasmi, Sabah,Nuhn, Lutz,et al. Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist[J]. RSC ADVANCES,2025,15(15):11662-11674. |
| APA | Verschuere, Hanne.,Kasmi, Sabah.,Nuhn, Lutz.,D'Almeida, Senan Mickael.,Zhu, Qiwen.,...&Vandenabeele, Peter.(2025).Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist.RSC ADVANCES,15(15),11662-11674. |
| MLA | Verschuere, Hanne,et al."Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist".RSC ADVANCES 15.15(2025):11662-11674. |
入库方式： OAI收割
来源：上海药物研究所
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