GSH‐Responsive Metal–Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy

Abstract

renal cell carcinoma (RCC), [2] and nonsmall cell lung carcinoma (NSCLC). [3] Through active or passive means, tumor immunotherapy induces the body to produce a tumor-specific immune response which suppresses the tumor progression and prevents the tumor recurrence or metastasis. [4][5][6] Strategies reported for tumor immunotherapy so far mainly involved immune checkpoint blockade (ICB), [7] adoptive cell transfer therapy (ACT), [8] tumor-specific vaccines, [9] and application of small molecular immunemodulating drugs. [10] However, most immunotherapy methods often encounter the great challenge of not being effective enough for many tumors of which a large amount do not respond in the clinic, [11,12] requiring advanced tumor immunotherapy methods to be developed.Among various tumor immunotherapy strategies, inhibition of the indoleamine-2,3-dioxygenase (IDO) is drawing great attention at present because of its critical role in mediating tumor immune evasion, and some inspiring studies were reported. [13][14][15] Admittedly, IDO catalyzes the degradation of amino acid l-tryptophan (Trp) into the metabolite l-kynurenine (Kyn), which suppresses cytotoxic T lymphocytes (CTL) and activates regulatory T (Treg) cells. [16,17] The strong immunomodulatory functions of IDO can be attributed Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8 + T cells and reduce Treg cells to result in highly effective immunotherapy.In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

“…Successful application of magnetically responsive nanoplatforms includes encapsulation/immobilization of therapeutic agents into magnetic-responsive nanoplatforms, injection of the magnetic stimuli-responsive nanoplatforms into the body and taking advantage of external magnetic fields to recruit and activate the magnetic stimuli-responsive nanoplatforms at the lesions of interest [ 384 – 386 ]. Recently, Shuai et al [ 387 ] reported a GSH-responsive MOF to effectively load IDO inhibitor, and NO donor s-nitrosothiol groups for improving antitumor immunotherapy. In this nanoplatform, the high T1 relaxivity endows magnetic resonance (MR) imaging capabilities to detect the in vivo biodistribution of nanoagents.…”

Programming of Regulatory T Cells In Situ for Nerve Regeneration and Long-Term Patency of Vascular Grafts

“…Treg cells have strong immunomodulatory abilities, and their safety and efficiency has have been demonstrated in some a clinical trials [40]. We selected the CRISPR/dCas9 technology to promote TET2 expression to maintain the low methylation levels in the gene encoding a key factor Foxp3 and stabilize Treg cells to control inflammation.…”

Inflammation-Regulated Nanodrug Sensitizes Hepatocellular Carcinoma to Checkpoint Blockade Therapy by Reprogramming the Tumor Microenvironment

“…Drugs and antibodies administered intravenously generally lack tumor specificity, which means that they have a weaker therapeutic effect against the tumors and worse adverse effects on the patients. , In addition, a combination treatment always requires an efficient, precisely timed, and sequenced codelivery of different drugs. The application of nanodrugs for cancer therapy has been gaining mounting interest over the past several years. , Due to the generally leaky vasculature of tumors, nanoparticles can easily enter them through the gaps in the vascular endothelial cells, a mechanism called the enhanced permeability and retention (EPR) effect .…”

“…Drugs and antibodies administered intravenously generally lack tumor specificity, which means that they have a weaker therapeutic effect against the tumors and worse adverse effects on the patients. 23,24 In addition, a combination treatment always requires an efficient, precisely timed, and sequenced codelivery of different drugs. The application of nanodrugs for cancer therapy has been gaining mounting interest over the past several years.…”