Research Spotlight | For Triple-Negative Breast Cancer

2020-11-05Author:adminpraise:0

The team of Professor Zhiping Zhang recently explored an alterable nanoparticle-enabled method for synergistic elicitation and promotion of immunogenic cell death (ICD) to achieve effective antitumor and antimetastatic for Triple-negative breast cancer (TNBC) therapy.

Congratulations to researchers for publishing the latest articles in the top-level journal "Advanced Functional Materials". It is a great honor for Elabscience's products to contribute to this great scientific research achievement. Elabscience is determined to be strict with itself and be the most loyal partner of scientific research scholars!

Fundamental Information:

Title: Transformable Nanoparticle-Enabled Synergistic Elicitation and Promotion of Immunogenic Cell Death for Triple-Negative Breast Cancer Immunotherapy

Journal: Advanced Functional Materials

IF16.836 (2019)

Institution of the first author: HuaZhong University of Science and Technology, Wuhan, China

Institution of the corresponding author: HuaZhong University of Science and Technology, Wuhan, China

Elabscience® Products Cited:

Cat. No

Application

Detection target

Species

Tested sample

E-EL-H1554

ELISA

Human HMGB-1

Human

Cell culture supernatant

Background of the Research:

Triple-negative breast cancer (TNBC) proved to be a lethal breast carcinoma with an incidence rate of ≈10–15%. Due to several factors, there are no approved targeted therapies for TNBC discovered yet. Only treatment options remains chemotherapy with side effects, and metastasis etc. Researchers are trying hard to develop targeted therapeutic strategies like immunotherapy and immune-chemotherapy for the treatment of TNBC. Treatment with immune checkpoint inhibitors (ICIs), is a recent discovery through which malignant tumors could be effectively cured by targeting immune cells. The combination therapy of atezolizumab and nab-paclitaxel (nanoparticle albumin-bound paclitaxel) can significantly enhance the anticancer activity of atezolizumab in phase III clinical trial. This indicates that nanoenabled chemotherapy may be a promising synergistic therapy strategy can enhance tumor-specific antigen release and inducing antitumor responses to ICIs, thus, improving the tumor immunogenicity during the process of cancer immunotherapy.

Chemotherapy provokes antitumor immunity either by inducing immunogenic cell death (ICD) and/or by disrupting immune escape of tumor cells. ICD induced by antitumor chemotherapy is characterized by calreticulin (CRT) exposure on the surface of dying cells as well as the subsequent ATP secretion and high-mobility group box 1 (HMGB-1) release. Cisplatin (Pt) have antitumor immunostimulatory effects when used as a neoadjuvant chemotherapy agent for TNBC, but it has no ICD effect mainly owing to the lack of CRT exposure. Adjudin (ADD), a derivative of lonidamine, has shown a potential antitumor activity through a caspase-3 (Cas-3) dependent apoptosis pathway and by increasing intracellular ROS level. The combination of Pt and ADD exhibited synergistic antitumor effect against A549 cell lines. However, their combinational therapy for TNBC and immune activities on tumor suppression were rarely investigated. Peptide-based sequentially responsive and structure-transformable nanoparticles (NPs) in a matrix metalloproteinases-9 overexpressed tumor model have shown that it is possible to introduce smart-design features for achieving CAPIR cascade. Therefore, structural transformable NPs can be used for contemporaneous delivery of ADD and Pt in support of TNBC immunotherapy on promotion of ICD response by amplifying ROS cascade.

Experimental Design:

Schematic illustration of structural conversion and synergistic immunotherapy mechanisms of transformable NPs (Fig a, Fig b).

  • A multiresponsive peptide-based prodrug platform with sequentially structure-transformable property for codelivery of Pt and ADD is reported in this study.
  • In order to observe the release of HMGB-1, different mediums (containing Pt, ADD, Pt-ADD, 1-NPs, Blank-NFs, 2-NPs) were used in the experiment (with MMP-2 pre-treatment 8 h) cultured 4T1 cells for 24 hours, cell fluid was collected, HMGB-1 concentration was quantitatively analyzed with ELISA, and western blot was carried out to further verify whether the injection of nanoparticles causes ICD reaction in TNBC tumor cells.

Research Findings:

1. The nanoparticles can sequentially respond to matrix metalloproteinases-2, pH, and glutathione to achieve structural transformation with the advantages of optimal size change, efficient drug delivery, and well-controlled release.

2. Cisplatin and adjudin can synergistically amplify reactive oxygen species (ROS) cascade and eventually increase the formation of hydrogen peroxide and downstream highly toxic ROS like •OH, which can elicit ICD response by mechanisms of endoplasmic reticulum stress, apoptotic cell death, and autophagy.

3. WKYMVm can further promote anti-TNBC immunity by activation of formyl peptide receptor 1 to build stable interactions between dendritic cells and dying cancer cells.

4. 3-NPs showed the best therapeutic effect in orthotopic 4T1 tumor model with the highest inhibitory rate of 93.1% and around 2.7-fold increase of overall survival benefit.

5. The nanoparticles achieve significant primary tumor regression and pulmonary metastasis inhibition as well as a remarkable survival benefit, with boosting of the innate and adaptive anti-TNBC immunity.

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