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Preparation, Characteristics, Toxicity, and Efficacy Evaluation of the Nasal Self-Assembled Nanoemulsion Tumor Vaccine In Vitro and In Vivo
Published on: September 28, 2022
Targeted and Self-Adjuvated Nanoglycovaccine Candidate for Cancer Immunotherapy
Rui Freitas1,2,3,4,5, Eduardo Ferreira1,2, Andreia Miranda1,2,3,4,5
1Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal.
Abstract:
Advanced-stage solid primary tumors and metastases often express mucin 16 (MUC16), carrying immature glycans such as the Tn antigen, resulting in specific glycoproteoforms not found in healthy human tissues. This presents a valuable approach for designing targeted therapeutics, including cancer glycovaccines, which could potentially promote antigen recognition and foster the immune response to control disease spread and prevent relapse. In this study, we describe an adjuvant-free poly(lactic-co-glycolic acid) (PLGA)-based nanoglycoantigen delivery approach that outperforms conventional methods by eliminating the need for protein carriers while exhibiting targeted and adjuvant properties. To achieve this, we synthesized a library of MUC16-Tn glycoepitopes through single-pot enzymatic glycosylation, which were then stably engrafted onto the surface of PLGA nanoparticles, generating multivalent constructs that better represent cancer molecular heterogeneity. These glycoconstructs demonstrated affinity for Macrophage Galactose-type Lectin (MGL) receptor, known to be highly expressed by immature antigen-presenting cells, enabling precise targeting of immune cells. Moreover, the glycopeptide-grafted nanovaccine candidate displayed minimal cytotoxicity and induced the activation of dendritic cells in vitro, even in the absence of an adjuvant. In vivo, the formulated nanovaccine candidate was also nontoxic and elicited the production of IgG specifically targeting MUC16 and MUC16-Tn glycoproteoforms in cancer cells and tumors, offering potential for precise cancer targeting, including targeted immunotherapies.
Insights
This study introduces a novel, adjuvant-free nanovaccine using poly(lactic-co-glycolic acid) (PLGA) to deliver MUC16-Tn glycoepitopes. This approach targets cancer cells, activates immune cells, and elicits a specific immune response without adjuvants or protein carriers.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Glycobiology
Background:
- Advanced-stage cancers express MUC16 with immature glycans (Tn antigen), creating unique glycoproteoforms.
- These MUC16 glycoproteoforms are absent in healthy tissues, making them ideal targets for cancer therapeutics.
- Targeted cancer glycovaccines can enhance antigen recognition and immune response to control disease spread and prevent relapse.
Purpose of the Study:
- To develop an adjuvant-free nanodelivery system for MUC16-Tn glycoepitopes.
- To create a multivalent nanovaccine that mimics cancer molecular heterogeneity.
- To evaluate the targeting, immunogenicity, and efficacy of the novel nanovaccine candidate.
Main Methods:
- Synthesized MUC16-Tn glycoepitopes using single-pot enzymatic glycosylation.
- Engrafted glycoepitopes onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles to form multivalent glycoconstructs.
- Assessed nanovaccine targeting of Macrophage Galactose-type Lectin (MGL) receptors on antigen-presenting cells, in vitro cytotoxicity, dendritic cell activation, and in vivo immunogenicity.
Main Results:
- The MUC16-Tn glycoconstructs showed affinity for MGL receptors on immature antigen-presenting cells.
- The nanovaccine candidate exhibited minimal cytotoxicity and induced dendritic cell activation in vitro without adjuvants.
- In vivo studies confirmed the nanovaccine's safety and its ability to elicit specific IgG production against MUC16 and MUC16-Tn in cancer cells and tumors.
Conclusions:
- An adjuvant-free PLGA-based nanoglycoantigen delivery system was successfully developed.
- The nanovaccine effectively targets MGL-expressing immune cells and elicits a specific anti-cancer immune response.
- This approach offers a promising strategy for targeted cancer immunotherapies, including glycovaccines.
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