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Photodynamic Therapy with Blended Conducting Polymer/Fullerene Nanoparticle Photosensitizers
Published on: October 28, 2015
Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy
Chi Zhang1, Ziling Zeng1, Dong Cui1
1School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore.
Abstract:
Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPNpro) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPNpro can remotely generate singlet oxygen (1O2) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPNpro is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.
Insights
This study introduces a novel semiconducting polymer nano-PROTAC (SPNpro) for cancer therapy. SPNpro combines phototherapy with targeted protein degradation, activating cancer treatment only when needed to enhance efficacy and reduce side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Immunometabolic interventions target cancer by inhibiting tumor metabolism.
- Current methods like small-molecule inhibitors and genetic modification have limitations including off-target effects and insufficient efficacy.
- Proteolysis targeting chimeras (PROTACs) offer a new approach to protein homeostasis modulation but often exhibit uncontrollable degradation.
Purpose of the Study:
- To develop a novel semiconducting polymer nano-PROTAC (SPNpro) for photo-immunometabolic cancer therapy.
- To create a PROTAC system with activatable degradation triggered by cancer biomarkers.
- To investigate the synergistic effects of phototherapy and targeted protein degradation in cancer treatment.
Main Methods:
- Synthesized a semiconducting polymer nano-PROTAC (SPNpro).
- Utilized NIR photoirradiation to generate singlet oxygen (1O2) for tumor cell eradication and immunogenic cell death (ICD).
- Engineered SPNpro for biomarker-activated (cathepsin B) targeted proteolysis of indoleamine 2,3-dioxygenase (IDO).
Main Results:
- SPNpro demonstrated phototherapeutic capabilities, inducing ICD and enhancing tumor immunogenicity.
- Biomarker-activated PROTAC function specifically degraded immunosuppressive IDO in vivo.
- IDO degradation blocked tryptophan catabolism, promoting effector T-cell activation and enhancing antitumor immunity.
- The combined approach effectively inhibited tumor growth and metastasis.
Conclusions:
- SPNpro offers a polymer platform for advanced PROTAC-based cancer therapy.
- Activatable protein degradation combined with phototherapy provides a synergistic approach to cancer treatment.
- This strategy enhances antitumor T-cell immunity and controls tumor progression and metastasis.
