High Capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of Lung Adenocarcinoma

Abstract

About 40% of the NSCLC patients have Stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti-PD1 checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our novel poly(2-oxazoline) (POx) based nanomicellar formulation of Resiquimod, an imidazoquinoline TLR 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti-PD1 immune checkpoint blockade therapy as well as platinum-based chemotherapy, which is the mainstay of treatment for NSCLC. Investigation of the in vivo immune status following Resiquimod PM (POx micellar formulation of Resiquimod) treatment showed that Resiquimodbased stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of anti-tumor CD8 + immune response. Our study demonstrates the promise of optimally delivered and nano-formulated Resiquimod as a new immunomodulating therapeutic strategy for the treatment of metastatic NSCLC.Due to the superior toxicity profile and synergistic effect of C 6 CP/AZD7762 and C 6 CP/VE-822 combinations, they were identified as lead candidates for in vivo study.

The future of poly(2-oxazoline)s

“…Amphiphilic ABA triblock copoly(2-oxazoline) micelles have been developed by Jordan, Luxenhofer and Kabanov who demonstrated their potential as excellent carriers for various hydrophobic drugs, enabling very high drug loading. [116] These systems have been further developed, amongst others, for treatment of ovarian and breast cancer through codelivery of cisplatin and paclitaxel, [117] as well as for lung adenocarcinoma through immunotherapy with resiquimod, [118] which were both demonstrated to be effective in in vivo using mice models. More recently, Kabanov and coworkers also reported the use of such ABA triblock copoly(2-oxazoline)s as stabilizer for a Remdesivir formulation for aerosol treatment of COVID-19.…”