Tumor microenvironment-responsive micelles assembled from a prodrug of mitoxantrone and 1-methyl tryptophan for enhanced chemo-immunotherapy

Abstract

Mitoxantrone (MX) can induce the immunogenic-cell death (ICD) of tumor cells and activate anti-tumor immune responses. However, it can also cause high expression of indole amine 2, 3-dioxygenase (IDO) during ICD, leading to T-cell apoptosis and a weakened immune response. An IDO inhibitor, 1-methyl tryptophan (1-MT), can inhibit the activity of IDO caused by MX, resulting in enhanced chemo-immunotherapy. Here, MX-1-MT was connected by ester bond which could be broken in an acidic tumor microenvironment. MX-1-MT was combined with polyethylene glycol (PEG) via a disulfide bond which could be reduced by glutathione overexpressed in tumors, thereby accelerating drug release at target sites. Folic acid-modified distearoyl phosphoethanolamine-polyethylene glycol (DSPE-PEG-FA) was introduced to form targeting micelles. The micelles were of uniform particle size, high stability, and high responsiveness. They could be taken-up by drug-resistant MCF-7/ADR cells, displayed high targeting ability, and induced enhanced cytotoxicity and ICD. Due to 1-MT addition, micelles could inhibit IDO. In vivo studies demonstrated that micelles could accumulate in the tumor tissues of nude mice, resulting in an enhanced antitumor effect and few side-effects.

Applications and prospects of microneedles in tumor drug delivery

“…127 Immunosuppressants include immune checkpoint inhibitors such as anti-CTLA-4 antibody, 128 anti-PD-1 antibody, 129 anti-PD-L1 antibody, 130 and IDO inhibitors such as 1-MT. 131,132 Immunomodulators include GM-CSF, 133,134 astragalus, 135,136 TLR agonists 137,138 and tumor vaccines. 138,139 Li et al 126 implanted porous PLGA microneedles encapsulating CAR-T cells into the tumor bed or the resection cavity after surgery; CAR-T cells in the microneedles were released into the tumor tissue uniformly and maintained activity.…”

Probing the Impact of Surface Functionalization Module on the Performance of Mitoxantrone Prodrug Nanoassemblies: Improving the Effectiveness and Safety

“…Chemotherapy stands as a principal approach in cancer treatment, but it has major drawbacks due to the limited tumor specificity of the most chemotherapeutic drugs, which cause severe side effects. − One such drug is mitoxantrone (MTO), a broad-spectrum anthraquinone antitumor agent that inhibits DNA synthesis. , Although MTO exhibits powerful therapeutical efficiency, its clinical application is still severely restricted by the serious side effects such as bone marrow suppression and gastrointestinal injury. , There exists a compelling urgency to design a novel drug delivery system for MTO, with the goals of improving safety while ensuring a powerful therapeutic efficiency. In order to achieve this purpose, many nanodelivery systems have been developed to deliver MTO in order to target tumor tissues through the EPR effect. − However, the low solubility of MTO in both water and organic solvents makes it difficult to encapsulate into nanocarriers. Furthermore, nanocarriers are usually loaded with MTO through physical encapsulation, which is easy to leak MTO during blood circulation.…”