Mitochondria-Targeting Polymer Micelle of Dichloroacetate Induced Pyroptosis to Enhance Osteosarcoma Immunotherapy

Abstract

Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.

Induction of pyroptotic cell death as a potential tool for cancer treatment

“…In addition, the immune checkpoint (PD1/PD-L1) increased the oncolytic effect of rAAV-GSDMD NT , stimulating antitumor immunity [96]. In a melanoma model, intradermal injection with active caspase-1 and antigen DNA resulted in pyroptosis, increasing adoptively transferred T cell migration to the tumors [95] (Fig. 3).…”

“…Several pyroptosis pathways related to mitochondrial modulation can induce PD-L1 secretion [95], through the maturation of DCs and recruiting CD4 and CD8 T + cells, enhancing antitumor efficacy in combination with immunotherapy [96].…”

Hypoxia-Triggered Bioreduction of Poly(N-oxide)–Drug Conjugates Enhances Tumor Penetration and Antitumor Efficacy

“…Hypoxia is highly associated with treatment resistance, increased metastasis, and thus poor prognosis. − However, hypoxia provides an opportunity for tumor-selective therapy, − including hypoxia-activated prodrugs, , hypoxia-activated gene therapy, , and recombinant anaerobic bacteria, and inhibiting the hypoxia-inducible factor-1 transcription factor. , Hypoxia-activated prodrugs such as AQ4N − and tirapazamine , are featured with a hypoxia-responsive moiety of N -oxide. Under hypoxia, N -oxides can be reduced into tertiary amines through the catalysis of cytochrome P450 (CYP450) enzymes that are highly overexpressed in the hypoxia regions of many solid tumors, − leading to the intratumoral generation of active drugs or fluorophores for tumor-selective therapy or imaging. − To our surprise, N -oxide-based polymers, poly­( N -oxide)­s, have not been explored as hypoxia-responsive bioreducible polymers that can carry drugs into the interior of tumors to improve their antitumor efficacy, although poly­( N -oxide)­s have recently been studied as unique zwitterionic polymers that are not sticky to proteins but reversibly bind to cell membranes for drug delivery. − …”

Enhanced mild-temperature photothermal therapy by pyroptosis-boosted ATP deprivation with biodegradable nanoformulation

“…As mitochondria are the energy source of cells and produce ATP, their dysfunction might inhibit the cellular ATP supply. The increased ROS and less cellular ATP lever are also considered to contribute to the loss of function for HSPs [ 22 , 23 ]. It is envisaged that the induction of pyroptosis through targeted modulation of mitochondria could be beneficial for effective mild PTT via the inhibition of HSPs.…”