Abstract Introduction: Inflammation plays a key role in all stages of ovarian cancer (OC), starting from tumorigenesis to progression and therapy resistance, till metastasis and recurrence. Toll-like receptors (TLRs) are pathogen-related receptors that initiate inflammatory responses. Pathogen-Associated Molecular Pattern (PAMPs), such as LPS released from pathogens, or DAMPs (Damage-Associated Molecular Pattern) released from dead cells, stimulate TLRs expressed on immune and OC cells. These stimulations activate signaling pathways such as NF-kB and STAT-3 to secrete pro-inflammatory protumor cytokines (e.g., IL-6), leading to tumor progression. Targeted therapy, such as PARP inhibitors (e.g., Olaparib), is used to treat OC patients. However, multiple resistance mechanisms have been attributed to Olaparib, including the activation of NF-kB and STAT3 oncogenic signaling. We have developed a library of immunomodulatory Telodendrimer (TD) nanoparticles that can also be used as drug delivery systems. Here, we speculate that dual-functional TD that acts as a TLR2/4 antagonist and a nanocarrier for Olaparib can control inflammation and the resulting tumor progression, as well as sensitize the tumor to Olaparib. Results and Methods: As an immunomodulator, TD specifically inhibits TLR2 and TLR4 activation using reporter HEK cells overexpressing TLR2 and TLR4, respectively. TD also inhibits TLR2/4 activation by DAMPs prepared via sonication of OC cells in these HEK cells and also inhibits the consequent proinflammatory cytokines (TNF-α and IL-6) secreted by THP-1 human differentiated macrophages using ELISA. In OC cell lines, TD suppresses IL-6 levels secreted in an autocrine manner, and when cells are stimulated with LPS (TLR4 agonist), DAMPs, and in immune-OC coculture using ELISA, by inhibiting NF-kB and STAT-3 phosphorylation shown by western blot. Consequently, it controls OC proliferation enhanced by LPS, LTA (TLR2 agonist), DAMPs, and the inflammatory secretome of macrophages (conditioned media of THP-1 differentiated macrophages stimulated with LPS) using MTS. Interestingly, TD directly impedes the migration of OC cells demonstrated by scratch assay. In vivo, TD alone restricts tumor progression in mice injected i.p. with ID8-luc OC cells, reflected by decreased bioluminescence signal. It also decreases the plasma levels of TNF-α and IL-6 in ID-8-luc OC bearing mice injected i.p. with LPS using ELISA. As a nanocarrier for Olaparib TD(OLA), the loading is characterized by studying the particle size and stability by dynamic light scattering (DLS) and the release profile by UV-Vis. TD(OLA) shows a small and stable particle size with sustained release compared to Olaparib alone. TD(OLA) preferentially sensitizes OC cells compared to Olaparib as monotherapy and in combination with TD. Conclusion: The dual function of TD as an immunomodulator and a nanocarrier for Olaparib can control the inflammation, inhibit tumor progression and migration, and sensitize OC cells to treatment. Citation Format: Hadil A. Gadelrab, Changying Shi, Dandan Guo, Rinki Agarwal, Sandra Orsulic, Juntao Luo. Multi-functional telodendrimer nanodrug: Nanocarrier for ovarian cancer treatment and immunomodulator to control inflammation and sensitize the tumor abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B021.
Gadelrab et al. (Wed,) studied this question.