Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment

Abstract

Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor-microenvironment-activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual-responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction-activatable homodimer of NLG919 for inactivating indoleamine 2,3-dioxygenase 1, which is a key regulator for ITM. Upon tumor-acidity-triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione-mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO-1-mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

“…During tumor progression, tumor microenvironment (TME) promotes the aggressiveness of tumors and prevents tumors from being subjected to external invasion . Recently, many researchers have focused on the means of TME regulation to accomplish a better antitumor effect, including in situ production of O 2 to reduce the polarization of M2 macrophages and tumor metastasis, neutralization of tumor pH to sensitize chemotherapy, and inhibition of the overexpressed enzymes in TME to limit metastasis .…”

Immunomodulatory Nanosystems

“…[130,131] These clinical researches confirmed their great therapeutic potential as antitumor agents. [56,126,[132][133][134] In this section, we overview the recent developments in the use of engineered nanoparticles to enhance cancer immunotherapy. [67] To achieve precise and controlled drug delivery, smart nanoparticles with more complex structures and specific drug release properties are also being produced according to the hallmarks of TME, such as weak acidic pH (6.5-6.8), high level of glutathione and hydrogen peroxide (H 2 O 2 ), and disorder of proteinases production, such as matrix metalloproteinase-2 (MMP-2).…”

“…[226] Chemotherapy combined with immunotherapy can well relieve the toxicities and also improve its treatment effect. [26,126,228] For example, the TLR9 agonist CpG was loaded into a nanodepot platform (NDP) composed of cationic liposomes and thiolated hyaluronic acid (HA). At the same time, immunoregulatory agents provide a preferable environment to ensure the highly efficient antigen presentation and the activation of APCs and cytotoxic T cells.…”

“…Reproduced with permission [126]. A) Self-assembly of ASPN from stimuli-responsive OXA prodrug and NLG919 prodrug.…”

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

“…[1][2][3] Chemotherapy is the major approach for clinical therapy of the advanced or metastatic TNBC tumors. [45][46][47] Meanwhile, PTX, delivered with ISPN to combat ITM by specifically killing the regulatory T cells (T regs ). [4][5][6] In past few years, immunotherapy, in particular, immune checkpoint blockade (ICB) on the surface of cell membrane, release high mobility group box 1 (HMGB1), and secrete adenosine triphosphate (ATP) for priming antitumor immune response.…”