Glucocorticoid receptor-mediated delivery of paclitaxel and anticancer gene p53 for oral cancer therapeutics

Targeting glucocorticoid Receptors (GR) induces gluconeogenesis in cancer cells, potentially disrupting their glycolytic dependency and acidic tumor microenvironment (TME), thereby creating an energetically unfavourable state and reducing drug resistance by impairing the acid reflux mechanism. Based on this rationale, we developed a GR-mediated liposomal co-delivery system, D1XP-p53, carrying the tumor suppressor gene, p53, and the chemotherapeutic drug, paclitaxel, to overcome the limitations of conventional anti-cancer therapies and to assess whether wild-type p53 enhances the anti-cancer activity of paclitaxel against Oral Squamous Cell Carcinoma (OSCC).<i>In vitro</i>studies demonstrated that D1XP-p53 selectively decreased the viability of OSCC cells and significantly inhibited their migration, invasion, and proliferation. Mechanistic investigations revealed an upregulation of the BAX/BCL2 ratio when oral cancer cells were treated with D1XP-p53, indicating the activation of intrinsic apoptotic pathways. The efficacy of D1XP-p53 was further validated in 3D spheroid models using MOC2 and FaDu cell lines, where it significantly reduced spheroid-forming ability and upregulated E-cadherin expression, indicating its potential role in enhancing anti-cancer activity and mitigating cellular migration.<i>In vivo</i>experiments using a murine model of OSCC with MOC2 cells showed a marked reduction in tumor volume in mice treated with D1XP-p53, with minimal systemic toxicity as assessed by H&E staining and biodistribution analysis. Considering the crucial role of TME components such as tumor-associated macrophages, cancer stem cells, and growth factors in tumor progression and metastasis, we further evaluated the impact of our delivery system, D1XP-p53, on these elements. We observed that D1XP-p53 treatment in mice significantly upregulated the M1/M2 ratios and decreased the<i>c-myc</i>and<i>SOX2</i>expression, indicating the potential role of the delivery system in modulating the TME components. These findings collectively demonstrate that the GR-targeted co-delivery system, D1XP-p53, enhances anti-cancer activity and modulates the TME, offering a promising multi-modal treatment against aggressive oral cancer.