New materials for cancer vaccine immunotherapy

New materials for cancer vaccine immunotherapy. In this paper, a detailed analysis is made based on the advantages and challenges of tumor nano-vaccine applied to tumor immunotherapy.

Nano Biomaterials

In recent years, cancer immunotherapy has become a key means of clinical cancer treatment. It effectively inhibits tumor development and metastasis by activating the body’s immune system, identifying and killing specific tumor cells.

As a member of immunotherapy, tumor vaccines transport tumor-associated antigens and immune-activating adjuvants to lymph node tissues, and are taken up and processed by corresponding antigen-presenting cells to activate T cell-mediated anti-tumor immune responses. However, traditional tumor vaccines have a series of shortcomings, such as low antigen loading efficiency, poor targeting transport ability to lymph nodes, and weak lysosomal escape ability, so the preclinical and clinical efficacy evaluations are not good.

Faced with these problems and challenges, the application of nano-biomaterial carriers to tumor vaccine delivery has gradually become a research hotspot. Nano-biomaterials can not only achieve efficient loading of antigens and adjuvants through electrostatic interactions, hydrophobic interactions, and covalent binding, but also can achieve targeted accumulation in lymph node tissues and antigens based on their physical or chemical characteristics. Presents high-efficiency release within the cell.

In view of the important research progress made in the field of tumor nano-vaccine in recent years and the related work of the research group, researcher Yu Haijun, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, reviewed related research on cancer vaccine immunotherapy based on nano-biomaterials.

This article summarizes the tumor nano-vaccine based on antigen peptide/adjuvant, tumor nano-vaccine based on nucleic acid molecule, tumor nano-vaccine based on biomimetic materials, and tumor nano-vaccine applied to tumor immune microenvironment regulation. The latest research progress.

First, this article introduces a series of multifunctional nano-biomaterials such as stimulus-responsive polymers, The wide application of modular self-assembled nanocarriers and self-adjuvant vaccine delivery materials in the delivery of antigen peptides/adjuvants to lymph nodes provides an effective solution for overcoming the problems of low delivery efficiency of traditional tumor vaccines to lymph nodes and poor lysosomal escape ability. Strategy.

Secondly, the development of nucleic acid-based tumor vaccines has injected new power into immunotherapy. Nano-biomaterials represented by lipid-based nanocarriers have shown great potential in the targeted delivery of nucleic acid molecules, which can efficiently encapsulate nucleic acid molecules. It effectively shields the degradation of nucleases and promotes the cytoplasmic release of nucleic acid molecules.

In addition, the introduction of exogenous nanomaterials can potentially induce the occurrence of immune rejection. This article further discusses the research progress of biomimetic nano-vaccine based on biomimetic materials in tumor immunotherapy. Various types of cell membrane materials, internal Source-derived nano-delivery vectors provide important support for the development of biomimetic tumor nano-vaccine, and provide an effective strategy for the realization of personalized and precise tumor treatment.

Finally, this article analyzes in detail the advantages and challenges of tumor nano-vaccine applied to tumor immunotherapy, focusing on the many challenges and potential solutions that current tumor nano-vaccine faces in clinical transformation, which will be the rationalization of tumor nano-vaccine in the future. Design and development provide certain ideas and insights.

Hydrogels

Recently, Academician Chen Xuesi of Changchun Institute of Applied Chemistry, Chinese Academy of Sciences and associate researcher Song Wantong jointly published an article entitled “Supramolecular Assembled Programmable Nanomedicine As In Situ Cancer Vaccine for Cancer Immunotherapy” on “Adv. Mater.”

In this article, the author uses the programmable immune activation nanomedicine (PIAN) assembled by supramolecular, which can be used to complete multiple steps sequentially after intravenous injection and trigger a powerful anti-tumor immune response in situ. Programmable nano-drugs are constructed by supramolecular assembly of interactions among PPCD, CpG/PAMAM-TK-Ad, and mPEG TK-Ad. After intravenous injection and accumulation in the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes the dissociation of PIAN and releases PPCD (mediates tumor cell killing and antigen release) and CpG/PAMAM (mediates antigen capture and transfer to the draining tumor Lymph nodes).

This leads to activation of antigen presenting cells, antigen presentation and a strong anti-tumor immune response. Combined with anti-PD-L1 antibody, PIAN can cure 40% of mice in colorectal cancer models. This article provides a new method of cancer in situ vaccine for cancer immunotherapy.

Schematic diagram of the preparation of programmable immune activation nanomedicine (PIAN) for immune activation and tumor suppression. PIAN is prepared through a one-step supramolecular assembly process through β-cyclodextrin (β-CD)/adamantane (Ad) host-guest interaction. After using PIAN, PIAN will accumulate in the tumor tissue and dissociate to release PPCD and CpG/PAMAM. PPCD induces tumor cell death and antigen release, while CpG/PAMAM captures antigen and promotes antigen uptake and dendritic cell (DC) activation. Finally, activated DC induce effector T cells to further kill tumor cells.

Figure 1. The preparation route of the assembled components and the characterization of the assembly results of the programmable immune activated nanomedicine (PIAN). (A–c) Preparation process of PIAN assembly components: PPCD, mPEG-TK-Ad and CpG/PAMAM-TK-Ad. Use dynamic light scattering (d) and zeta potential (e) to determine the size of each component; (f) After incubation with different concentrations of hydrogen peroxide, the diameter of PIAN changes with time; (g) PIAN, PIAN and 0.1× A transmission electron microscope image of 10-3 M hydrogen peroxide incubated at 25 °C for 24 hours. The size of the particles decreases rapidly. When the concentration of hydrogen peroxide increases, PIAN rapidly dissociates.

Figure 2. Evaluation of cell uptake, in vitro cytotoxicity and dendritic cell (DC) activation. (A) Cy5 labeled Cy5-PPCD was incubated with CT26 cells at 37 °C for 1, 3 or 6 hours, and the internalization level in the cells was analyzed by flow cytometry. (B) Confocal laser scanning microscope images of Cy5-PPCD cells taken by CT26 cells after 1, 3, and 6 hours of incubation. (C, d) After 24 hours of incubation, Pt(IV)-COOH and PPCD had in vitro growth inhibitory activity on CT26 cells (c) and B16F10 cells at different Pt concentrations (n=5). These results show that from PIAN The dissociated PPCD is rapidly internalized into tumor cells and effectively inhibits the growth of tumor cells, resulting in the release of tumor antigens. (e) After incubating for 1 h at 37 °C, bone marrow-derived dendritic cells (BMDC) were used to analyze the internalization level of free Cy5-OVA and Cy5-OVA/PAMAM cells by flow cytometry. (F) Schematic diagram of BMDC activation experiment. (G) Flow cytometry analysis of the stimulation of BMDC after different treatments (n=3). Antigen represents CT26 tumor lysate. (H) BMDC secreted TNF-α and IL-6 levels after different treatments (n = 3). These results indicate that PPCD exerts tumor cell killing activity by releasing loaded Pt drugs, and CpG/PAMAM helps DC Absorb protein antigens and promote DC activation together with the captured antigens.

Figure 3. Programmable immune activation nanomedicine (PIAN) enhances the accumulation of cytotoxic drugs in tumor tissues, and enhances the entry and retention of immune adjuvants in tumor draining lymph nodes (TdLNs). (A, b) Two types of Cy5-labeled PIAN (PIAN-C/Cy5(a) and PIAN-P/Cy5(b) are prepared. PolyPPCD and PAMAM-TK-Ad are both labeled with Cy5. ( c) Ex vivo fluorescence images and quantitative analysis results of excised tumors and major organs obtained from CT26 tumor-bearing mice 4 and 24 hours after PIAN-C/Cy5 injection (n=3 mice per group) ( (N=3 mice per group). (d) Retention of released PPCD in tumor tissue and schematic diagram of released CpG/PAMAM excretion to TdLN. (e) 4 and 24 hours after PIAN-C/Cy5 injection ( n=3 mice per group), in vitro fluorescence images of TdLN obtained from mice bearing CT26 tumors. (f) 4 and 24 hours after PIAN-P/Cy5 injection, from CT26 bearing tumors Ex vivo fluorescence image of excised TdLN obtained by mice (n=3 mice per group). (g) Dendritic cells (DC) (CD11c, green) and 4′,6-dimidyl-2-benzene were used The results of the TdLN (24 hours after PIAN-P/Cy5 injection) section stained with the base indole (nucleus, blue). These findings indicate that once PIAN reaches the tumor tissue, the released PPCD will exert an anti-tumor effect, and CpG/PAMAM drains into the lymph nodes to activate DC.

Figure 4. The ability of programmable immune activation nanomedicine (PIAN) in CT26 model to inhibit tumors and immune activation in vivo. (A) The treatment plan of phosphate buffered saline (PBS), pt, PEG@PPCD or PIAN in CT26 tumor model. (B,c) Changes in tumor volume (b) and body weight (c) of mice carrying CT26 after receiving multiple treatments (n=9). (D, e) On the 12th day after receiving multiple treatments, the results of tumor draining lymph nodes (TdLNs) (d) and tumor tissues of CT26 tumor-bearing mice. CD4+ and CD8+ T cells and Results of activated dendritic cells (DC) (both n=4). (F) Results of CD4+ central memory (CM) T cells and CD4+ effector memory (EM) T cells (n=4). (g) Results of CD8+CM T cells and CD8+EM T cells (n=4). (h) Results graph of PIAN and αPD-L1 in PBS, αPD-L1, PIAN, CT26 tumor model. (i–l) Tumor volume after treatment with PBS, αPD-L1, PIAN or PIAN plus αPD-L1 (i), single CT26 tumor growth curve (j), weight (k) and survival curve (n = 5) . These results indicate that the optimized PIAN can effectively activate the immune response and the systemic immune response by stimulating all steps in the immune activation process of at least two cancer types.

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