GSH-activable and cytolytic iPep-coupled immune nanoagonist for cancer synergetic therapy
Shuangshuang Ji1, Xiangxiang Xu2, Ang Li3
1Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China; Nanobiomedicine Division, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China.
Abstract:
Integrating an oncotic immunogenic cell death (ICD) inducer with TLR agonists to facilitate chemo-immunotherapy presents a promising avenue for addressing cancer treatment. While each agent shown remarkable potential in eliciting immune responses individually, the synergistic capabilities of oncotic chemotherapeutics in combination with TLR agonists remain an uncharted area of research. Herein, to prevent the occurrence of off-target systemic inflammatory side effects associated with the TLR7/8 agonist, the reactive amino group of Resiquimod (R848) was covalently linked to human serum albumin (HSA) via a glutathione (GSH)-activatable linker, thereby establishing a series of R848-HSA conjugates. Specifically, RS-HSA (with an R848: HSA ratio of 1.6:1, n/n) was assembled with an oncotic membrane-active peptide (iPep) to form iP-RS NPs, which exhibited reduced toxicity and synergistic effects in modulating the tumor immunosuppressive microenvironment, disrupting the surrounding desmoplastic stroma, and enhancing anti-tumor immunity. The iP-RS NPs demonstrated satisfactory chemo-immune effects, achieving complete tumor regression in orthotopic 4T1 breast tumor mice and subcutaneous Panc02 pancreatic tumor mice. Furthermore, iP-RS NPs achieved successful treatment in three out of five mice harboring a clinically relevant and challenging orthotopic model of fLuc-KPC pancreatic ductal adenocarcinoma (PDAC), leading to a significant prolongation of their survival. In stark contrast, the first-line treatment regimen of Gemcitabine + Nab-paclitaxel offered only a marginal survival extension of less than a week when compared to the PBS control group. Our findings underscore the promising prospects of combining oncotic therapeutics with TLR7/8 agonists, with a rational design aimed at minimizing the toxicity of the TLR agonist while achieving superior synergistic therapeutic efficacy.
Insights
This study developed novel nanoparticle conjugates combining oncotic agents with TLR7/8 agonists to enhance chemo-immunotherapy for cancer. These nanoparticles demonstrated significant tumor regression and improved survival in preclinical models, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Drug Delivery
Background:
- Chemo-immunotherapy combining oncotic agents and Toll-like receptor (TLR) agonists shows promise for cancer treatment.
- Systemic inflammatory side effects of TLR7/8 agonists limit their clinical application.
- Developing targeted delivery systems is crucial for enhancing therapeutic efficacy and reducing toxicity.
Purpose of the Study:
- To design and synthesize novel nanoparticle conjugates (iP-RS NPs) by linking Resiquimod (R848), a TLR7/8 agonist, to human serum albumin (HSA) via a glutathione-activatable linker.
- To evaluate the synergistic chemo-immune effects of iP-RS NPs in preclinical cancer models.
- To assess the potential of iP-RS NPs in overcoming tumor immunosuppression and disrupting the tumor microenvironment.
Main Methods:
- Covalent conjugation of R848 to HSA using a GSH-activatable linker to form R848-HSA conjugates.
- Assembly of R848-HSA conjugates with an oncotic membrane-active peptide (iPep) to create iP-RS NPs.
- In vivo evaluation of iP-RS NPs in orthotopic 4T1 breast tumor and subcutaneous Panc02 pancreatic tumor mouse models.
- Assessment of treatment efficacy in a challenging orthotopic fLuc-KPC pancreatic ductal adenocarcinoma (PDAC) model.
Main Results:
- iP-RS NPs exhibited reduced toxicity compared to free R848.
- The nanoparticles effectively modulated the tumor immunosuppressive microenvironment and disrupted the desmoplastic stroma.
- Complete tumor regression was achieved in 4T1 and Panc02 tumor models.
- Significant survival prolongation was observed in PDAC model mice treated with iP-RS NPs, outperforming Gemcitabine + Nab-paclitaxel.
Conclusions:
- The rationally designed iP-RS NPs demonstrate superior synergistic chemo-immune therapeutic efficacy.
- This approach effectively minimizes TLR agonist toxicity while maximizing anti-tumor immune responses.
- Combining oncotic therapeutics with TLR agonists via targeted nanoparticle delivery represents a promising strategy for advanced cancer treatment.
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