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In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Engineering Dual-Responsive Prodrug-MOFs as Immunogenic Cell Death Initiator for Enhancing Cancer Immunotherapy
Xiaochun Hu1,2, Ruihao Li1, Jie Liu1
1Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Department of Comprehensive Cancer Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P. R. China.
Abstract:
In recent years, the anticancer effects of disulfiram, a clinical drug for anti-alcoholism, are confirmed. However, several defects limit the clinical translation of disulfiram obviously, such as Cu(II)-dependent anticancer activity, instability, and non-selectivity for cancer cells. Herein, a phosphate and hydrogen peroxide dual-responsive nanoplatform (PCu-HA-DQ) is reported, which is constructed by encapsulating disulfiram prodrug (DQ) and modifying hyaluronic acid (HA) on copper doping metal-organic frameworks (PCu MOFs). PCu-HA-DQ is expected to accumulate in tumor by targeting CD-44 receptors and enable guidance with magnetic resonance imaging. Inside the tumor, Cu(DTC)2 will be generated in situ based on a dual-responsive reaction. In detail, the high concentration of phosphate can induce the release of DQ, after that, the intracellular hydrogen peroxide will further mediate the generation of Cu(DTC)2 . In vitro and in vivo results indicate PCu-HA-DQ can induce the apoptosis as well as immunogenic cell death (ICD) of tumor cells distinctly, leading to enhanced immune checkpoint inhibitor (ICI) efficacy by combining the anti-programmed death-1 antibody. This work provides a portable strategy to construct a dual-responsive nanoplatform integrating tumor-targeted ability and multi-therapy, and the designed nanoplatform is also an ICD inducer, which presents a prospect for boosting systemic antitumor immunity and ICI efficacy.
Insights
This study introduces a novel dual-responsive nanoplatform (PCu-HA-DQ) that targets tumors and enhances anticancer therapy. It effectively induces cancer cell death and boosts the efficacy of immune checkpoint inhibitors.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Disulfiram shows anticancer potential but faces limitations like copper dependence, instability, and poor cancer cell selectivity.
- Existing nanoplatforms require improvement for targeted delivery and combination therapies in cancer treatment.
Purpose of the Study:
- To develop a dual-responsive nanoplatform (PCu-HA-DQ) for targeted cancer therapy and enhanced immune checkpoint inhibitor (ICI) efficacy.
- To overcome disulfiram's limitations by creating a system that releases active compounds specifically within tumors.
Main Methods:
- Constructed a nanoplatform by encapsulating disulfiram prodrug (DQ) in copper-doped metal-organic frameworks (PCu MOFs) and modifying with hyaluronic acid (HA).
- Utilized CD-44 receptor targeting for tumor accumulation and magnetic resonance imaging guidance.
- Investigated dual-responsive release of DQ triggered by phosphate and hydrogen peroxide, leading to in situ generation of Cu(DTC)2.
Main Results:
- PCu-HA-DQ demonstrated effective tumor targeting and accumulation via CD-44 receptor interaction.
- The nanoplatform successfully induced apoptosis and immunogenic cell death (ICD) in tumor cells both in vitro and in vivo.
- Combined therapy with anti-programmed death-1 antibody significantly enhanced ICI efficacy.
Conclusions:
- The developed dual-responsive nanoplatform offers a promising strategy for integrated tumor-targeted therapy and multi-modal treatment.
- PCu-HA-DQ acts as an effective ICD inducer, highlighting its potential to enhance systemic antitumor immunity and ICI effectiveness.
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