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Abstract Blockade of programmed cell death‐1 (PD‐1) is a transformative immunotherapy. However, only a fraction of patients benefit, and there is a critical need for broad‐spectrum checkpoint inhibition approaches that both enhance the recruitment of cytotoxic immune cells in cold tumors and target resistance pathways. Indoleamine 2, 3‐dioxygenase (IDO) small molecule inhibitors are promising but suboptimal tumor bioavailability and dose‐limiting toxicity have limited therapeutic benefits in clinical trials. This study reports on a nanoformulation of the IDO inhibitor navoximod within polymeric nanoparticles prepared using a high‐throughput microfluidic mixing device. Hydrophobic ion pairing addresses the challenging physicochemical properties of navoximod, yielding remarkably high loading (>10%). The nanoformulation efficiently inhibits IDO and, in synergy with PD‐1 antibodies improves the anti‐cancer cytotoxicity of T‐cells, in vitro and in vivo. This study provides new insight into the IDO and PD‐1 inhibitors synergy and validates hydrophobic ion pairing as a simple and clinically scalable formulation approach.

Abstract Disruption of the cell cycle is among the most effective approach to increase tumour cells’ radio-sensitivity. However, the presence of dose-limiting side effects hampers the clinical use of tyrosine kinase inhibitors targeting the cell cycle. Towards addressing this challenge, we identified a bosutinib nanoformulation within high density lipoprotein nanoparticles (HDL NPs) as a promising radiosensitiser. Bosutinib is a kinase inhibitor clinically approved for the treatment of chronic myeloid leukemia that possesses radiosensitising properties through cell cycle checkpoint inhibition. We found that a remarkably high bosutinib loading (> 10%) within HDL NPs could be reliably achieved under optimal preparation conditions. The radiosensitisation activity of the bosutinib-HDL nanoformulation was first assessed in vitro in UM-SCC-1 head and neck squamous cell carcinoma (HNSCC) cells, which confirmed efficient disruption of the radiation induced G2/M cell cycle arrest. Interestingly, the bosutinib nanoformulation out-performed free bosutinib, likely because of the specific affinity of HDL NPs with tumour cells. The combination of bosutinib-HDL NPs and radiotherapy significantly controlled tumour growth in an immunocompetent murine HNSCC model. The bosutinib-HDL nanoformulation also enhanced the radiation induced immune response through the polarisation of tumour associated macrophages towards proinflammatory phenotypes.

Pluronic based nano-particulate systems are innovative platforms for delivery of anti-cancer agents. These systems due to their pharmacological properties and suitable physicochemical characteristics are great opportunity for development cancer therapeutics. This mini-review tries to provide a more detailed overview on the currently available pluronic based drug delivery systems. In the section 2, pharmacological characteristics of pluronic as a therapeutic polymer are assessed. In section 3, pluronic based formulations for undruggable payloads and surfaced modified targeted delivery systems are analyzed. The combinatorial pluronic based systems are summarized in section 4 and at last but not least the challenges and future prospective are discussed within section 5.