A promising self-nanoemulsifying adjuvant with plant-derived saponin D boosts immune response and exerts an anti-tumor effect

Objectives The low immunogenicity of tumor antigens and unacceptable toxicity of adjuvants has hindered the application and development of tumor vaccines. Hence, we designed a novel anti-tumor vaccine composed of a plant-derived immunostimulant molecular nanoadjuvant (a self-nanoemulsifying system, SND) and the antigen OVA, to reinvigorate the immune response and inhibit tumor progression. Methods In this study, this novel nanoadjuvant with Saponin D (SND) was designed and prepared by low-energy emulsification methods. Several important characteristics of the SND, including morphology, size, polymer dispersity index (PDI), zeta potential, and stability, were estimated, and the cytotoxicity of the SND was evaluated by MTT assay. Additionally, the immune response in terms of antibody titer levels and cellular immunity were evaluated in vivo after immunization with the vaccine, and the preventative and therapeutic effects of this novel vaccine against tumors were estimated. Finally, the antigen release profile was determined by IVIS imaging and by in vivo assay. Results This SND nanoadjuvant had good characteristics including the average particle size of 26.35 ± 0.225 nm, narrow distribution of 0.221 ± 1.76, and stability zeta potential of -12.9 ± 0.83 mV. And also, it had good stability (size, PDI, zeta potential, antigen stability) and low toxicity in vitro and in vivo, and delayed antigen release in vivo. The humoral immune response (IgG, IgG1, IgG2a, and IgG2b) and cellular immune level (cytokines of splenocytes including IFN-γ, IL-4, IL-1β andIL-17A) were both improved greatly after injected immunization at 0, 14, 28 days with the novel nanoadjuvant and antigen OVA. Importantly, this novel nanoadjuvant combined with OVA might lead to the induction of the prevent and treatment efficacy in the E.G7-OVA tumor-bearing mice. Conclusions These results suggested that this novel nanoadjuvant encapsulated natural plant immunostimulant molecular OPD could be a good candidate of tumor vaccine adjuvant for reinvigorating the immune response and powerfully inhibiting tumor growth effect.

[1]  Yujie Chen,et al.  Discovering hematoma-stimulated circuits for secondary brain injury after intraventricular hemorrhage by spatial transcriptome analysis , 2022, bioRxiv.

[2]  Ji Zhou,et al.  Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects , 2022, International journal of molecular sciences.

[3]  N. Peppas,et al.  Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy , 2022, Science advances.

[4]  A. Ghaemi,et al.  Recombinant COVID-19 vaccine based on recombinant RBD/Nucleoprotein and saponin adjuvant induces long-lasting neutralizing antibodies and cellular immunity , 2022, Frontiers in Immunology.

[5]  Xuesong Liu,et al.  A lipophilic chitosan-modified self-nanoemulsifying system influencing cellular membrane metabolism enhances antibacterial and anti-biofilm efficacy for multi-drug resistant Pseudomonas aeruginosa wound infection. , 2022, Biomaterials advances.

[6]  Catherine J. Wu,et al.  Cancer vaccines: Building a bridge over troubled waters , 2022, Cell.

[7]  Nicolas Liaudet,et al.  IFN-γ–dependent tumor-antigen cross-presentation by lymphatic endothelial cells promotes their killing by T cells and inhibits metastasis , 2022, Science advances.

[8]  D. Irvine,et al.  A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity , 2021, Science Immunology.

[9]  O. Ahmed,et al.  Rp-HPLC Determination of Quercetin in a Novel D-α-Tocopherol Polyethylene Glycol 1000 Succinate Based SNEDDS Formulation: Pharmacokinetics in Rat Plasma , 2021, Molecules.

[10]  Zhiming Hu,et al.  A novel self-assembled epitope peptide nanoemulsion vaccine targeting nasal mucosal epithelial cell for reinvigorating CD8+ T cell immune activity and inhibiting tumor progression. , 2020, International journal of biological macromolecules.

[11]  Judy MacArthur Clark,et al.  Guidelines for the ethical review of laboratory animal welfare People’s Republic of China National Standard GB/T 35892‐2018 [Issued 6 February 2018 Effective from 1 September 2018] , 2020, Animal models and experimental medicine.

[12]  G. Shahnaz,et al.  Formulation and evaluation of hyaluronic acid-based mucoadhesive self nanoemulsifying drug delivery system (SNEDDS) of tamoxifen for targeting breast cancer. , 2020, International journal of biological macromolecules.

[13]  Haijun Yu,et al.  Molecular imaging for cancer immunotherapy: Seeing is believing. , 2020, Bioconjugate chemistry.

[14]  C. Leclerc,et al.  IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8+ T-cell responses , 2020, Oncoimmunology.

[15]  Zhuang Liu,et al.  Local biomaterials-assisted cancer immunotherapy to trigger systemic antitumor responses. , 2019, Chemical Society reviews.

[16]  Haijun Yu,et al.  Engineering Nanoparticles to Reprogram the Tumor Immune Microenvironment for Improved Cancer Immunotherapy , 2019, Theranostics.

[17]  Xiaoyu Liang,et al.  Nano-, micro-, and macroscale drug delivery systems for cancer immunotherapy. , 2019, Acta biomaterialia.

[18]  Yaping Li,et al.  Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy , 2019, Acta Pharmacologica Sinica.

[19]  M. Smyth,et al.  Cancer immunoediting and resistance to T cell-based immunotherapy , 2018, Nature Reviews Clinical Oncology.

[20]  Yuzhi Du,et al.  Development of a safety and efficacy nanoemulsion delivery system encapsulated gambogic acid for acute myeloid leukemia in vitro and in vivo , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[21]  Li-Chen Gao,et al.  Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine , 2018, Journal of Nanobiotechnology.

[22]  M. Rong,et al.  Synergistic effect of dual targeting vaccine adjuvant with aminated β-glucan and CpG-oligodeoxynucleotides for both humoral and cellular immune responses. , 2018, Acta biomaterialia.

[23]  X. Mao,et al.  An immunopotentiator, ophiopogonin D, encapsulated in a nanoemulsion as a robust adjuvant to improve vaccine efficacy. , 2018, Acta biomaterialia.

[24]  Helen Y Wang,et al.  Immune targets and neoantigens for cancer immunotherapy and precision medicine , 2016, Cell Research.

[25]  J. Moon,et al.  Designer vaccine nanodiscs for personalized cancer immunotherapy , 2016, Nature materials.

[26]  Yiping Yang,et al.  Cancer immunotherapy: harnessing the immune system to battle cancer. , 2015, The Journal of clinical investigation.

[27]  Zhuojing Luo,et al.  Ophiopogonin D: A new herbal agent against osteoporosis. , 2015, Bone.

[28]  Zhong-yu Hu,et al.  Advances in aluminum hydroxide-based adjuvant research and its mechanism , 2015, Human vaccines & immunotherapeutics.

[29]  Xiaoping Zhao,et al.  A metabonomic study of cardioprotection of ginsenosides, schizandrin, and ophiopogonin D against acute myocardial infarction in rats , 2014, BMC Complementary and Alternative Medicine.

[30]  Min Beom Heo,et al.  Polymer nanoparticles for enhanced immune response: combined delivery of tumor antigen and small interference RNA for immunosuppressive gene to dendritic cells. , 2014, Acta biomaterialia.

[31]  Ashutosh Kumar Singh,et al.  Engineering vaccines and niches for immune modulation. , 2014, Acta biomaterialia.

[32]  Gregory L. Szeto,et al.  Structure-based programming of lymph-node targeting in molecular vaccines , 2014, Nature.

[33]  L B Nash,et al.  Seeing is believing , 2013, BDJ.

[34]  T. Gajewski,et al.  Cancer immunotherapy , 2012, Molecular oncology.

[35]  P. Livingston,et al.  Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer , 2011, Expert review of vaccines.

[36]  Lisa Menegatos,et al.  Building a Bridge over Troubled Waters: Transgressor Communication after Committing a Hurtful Event , 2010 .

[37]  F. Pijpers,et al.  Therapeutic cancer vaccines , 2005, Nature Reviews Drug Discovery.

[38]  F. Ennis,et al.  Three double-blind, randomized trials evaluating the safety and tolerance of different formulations of the saponin adjuvant QS-21. , 2001, Vaccine.

[39]  H. Matsuda,et al.  Adjuvant and Haemolytic Activities of 47 Saponins Derived from Medicinal and Food Plants , 2000, Biological chemistry.

[40]  寛 大岩.  早期関節リウマチ：brief overview , 2018 .

[41]  Sakurai Kazuo,et al.  Immunization with antigenic peptides complexed with beta-glucan induces potent cytotoxic T-lymphocyte activity in combination with CpG-ODNs , 2017 .

[42]  G. Prendergast,et al.  Cancer Vaccines: A Brief Overview. , 2016, Methods in molecular biology.

[43]  Michael Y. Gerner,et al.  Supplementary Text and Figures to In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity , 2015 .

[44]  K. Calman,et al.  Immunological Aspects of Cancer Chemotherapy , 1980 .