(183j) Layer-By-Layer Nanoparticle Delivery of Synergistic Nucleic Acid Therapy for Ovarian Cancer

Advanced high-grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5-year survival rates of only 25–30% due to late-stage diagnosis and the limitations of current chemotherapies. The primary standard of care consists of tumor removal surgery followed by platinum-based chemotherapy. However, patients often develop resistance to chemotherapies, leading to shortened disease-free intervals, increased risk of metastasis, and worsened prognosis. In particular, the metastatic distribution of HGSOC makes it challenging to reach tumors via systemic drug delivery.

Given that many phenotypes of ovarian cancer (OC) are caused by underlying genetic mutations, small interfering ribonucleic acid (siRNA) therapies have emerged as promising solutions for OC by targeting the underlying mutations with high specificity and high efficiency, with low toxicity compared to systemic chemotherapy. However, bare siRNA is unstable and immunogenic and thus requires a well-engineered delivery system. Layer-by-layer nanoparticles (LbL NPs) are a drug delivery platform in which a charged NP core is layered with alternating charged polymers via electrostatic attraction, enabling the incorporation of complex polymers without the need for complex chemical conjugation techniques. LbL NPs enable broad therapeutic opportunities: by incorporating functional polymers, LbL NPs better avoid liver clearance than existing NPs and selectively target tumors without affecting healthy cells,² which in turn reduces drug resistance, improves treatment efficacy, and decreases systemic toxicity. Thus, LbL NPs delivering siRNA therapies targeting multiple tumor proliferation or chemotherapy resistance pathways are a promising solution to improving patient outcomes. In this work, we screened and discovered synergistic siRNA combinations targeting multiple tumor proliferation and chemotherapy resistance pathways, providing a novel therapeutic opportunity.

Previous research demonstrates that LbL NP surface chemistry plays a critical role in governing pharmacokinetics, with particular surface chemistries demonstrating improved tumor targeting abilities, thereby decreasing toxicity associated with systemic drug administration. However, the mechanisms of how surface chemistry affects function and uptake in cancer cells have yet to be elucidated. By modulating the surface polymers, we further optimized the LbL NPs to selectively traffick siRNAs to tumors while reducing off-target effects to healthy cells. By engineering LbL NPs to deliver combination siRNA therapies, we show improved treatment efficacy and decreased systemic toxicity in an in vivo murine model of HGSOC, demonstrating a promising solution to improving patient outcomes.