Environment-responsive dendrobium polysaccharide hydrogel embedding manganese microsphere as a post-operative adjuvant to boost cascaded immune cycle against melanoma.

in Theranostics by Nan Gao, Yiran Huang, Shisuo Jing, Meng Zhang, Ergang Liu, Lu Qiu, Jing Huang, Bahtiyor Muhitdinov, Yongzhuo Huang

TLDR

  • The study developed a special gel that can help the body fight cancer after surgery. The gel is made of a special type of sugar and a metal called Manganese. The gel is designed to release the metal in a way that helps the body's immune system fight cancer. The study tested the gel in mice with cancer and found that it significantly reduced the growth of the cancer and prevented it from spreading. The study also found that the gel worked even better when combined with a special drug called anti-PD1 antibody. The study suggests that the gel could be a promising drug-free strategy for cancer post-operative management.

Abstract

Surgical resection is a primary treatment for solid tumors, but high rates of tumor recurrence and metastasis post-surgery present significant challenges. Manganese (Mn), known to enhance dendritic cell-mediated cancer immunotherapy by activating the cGAS-STING pathway, has potential in post-operative cancer management. However, achieving prolonged and localized delivery of Mnto stimulate immune responses without systemic toxicity remains a challenge.We developed a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn-pectin microspheres (MnP@DOP-Gel). This hydrogel system releases Mn-pectin microspheres (MnP) in response to ROS, and MnP shows a dual effect: promoting immunogenic cell death and activating immune cells (dendritic cells and macrophages). The efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation were assessed in both subcutaneous and metastatic melanoma models in mice, exploring its synergistic effect with anti-PD1 antibody.MnP@DOP-Gel exhibited ROS-responsive release of MnP, which could exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses.experiments showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth.MnP@DOP-Gel represents a promising drug-free strategy for cancer post-operative management. Utilizing this Mn-embedding and ROS-responsive delivery system, it regulates surgery-induced immune responses and promotes sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments.

Overview

  • The study aims to investigate the potential of a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn-pectin microspheres (MnP@DOP-Gel) in cancer post-operative management. The hypothesis being tested is that MnP@DOP-Gel can promote immunogenic cell death and activate immune cells (dendritic cells and macrophages) to initiate a cascade of anti-tumor immune responses, leading to improved surgical cancer treatments. The methodology used for the experiment includes subcutaneous and metastatic melanoma models in mice, and the primary objective is to assess the efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation. The study aims to achieve the following: 1. Develop a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn-pectin microspheres (MnP@DOP-Gel). 2. Assess the efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation in subcutaneous and metastatic melanoma models in mice. 3. Explore the synergistic effect of MnP@DOP-Gel with anti-PD1 antibody in preventing metastasis or abscopal brain tumor growth.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions, specifically the effects of MnP@DOP-Gel alone and in combination with anti-PD1 antibody on residual tumor growth and metastasis in subcutaneous and metastatic melanoma models in mice. The results showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth. The key findings of the study are: 1. MnP@DOP-Gel exhibits ROS-responsive release of MnP, which can exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses. 2. The implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis in subcutaneous and metastatic melanoma models in mice. 3. The combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that MnP@DOP-Gel could be a promising drug-free strategy for cancer post-operative management. The study's findings also highlight the potential of Mn-embedding and ROS-responsive delivery systems in regulating surgery-induced immune responses and promoting sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments. The limitations of the study include the use of subcutaneous and metastatic melanoma models in mice, which may not fully represent human tumors. Future research directions could include the use of human tumor models and the exploration of the efficacy of MnP@DOP-Gel in other types of solid tumors. Additionally, further studies are needed to evaluate the long-term safety and efficacy of MnP@DOP-Gel in humans.
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