@article{01JW9395HBPYAW5VWP0P5SCMGH,
  abstract     = {{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.}},
  author       = {{Verschuere, Hanne and Kasmi, Sabah and Nuhn, Lutz and D'Almeida, Sènan Mickaël and Zhu, Qiwen and Zhong, Zifu and Adjemian Catani, Sandy and Louage, Benoit and De Vrieze, Jana and Yu, Haijun and De Geest, Bruno and Vandenabeele, Peter}},
  issn         = {{2046-2069}},
  journal      = {{RSC ADVANCES}},
  keywords     = {{CANCER,DEATH,NANOPARTICLES,DELIVERY,AGENTS}},
  language     = {{eng}},
  number       = {{15}},
  pages        = {{11662--11674}},
  title        = {{Enhancing anti-tumor immunity through intratumoral combination therapy with amphiphilic conjugates of oxaliplatin and imidazoquinoline TLR7/8 agonist}},
  url          = {{http://doi.org/10.1039/d5ra00163c}},
  volume       = {{15}},
  year         = {{2025}},
}

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