Sakhare Kalyani, Bhattacharya Dwaipayan, Dhiman Chhavi, Erukulla Priyanka, Bhattacharya Srija, Ansari Aasia, Khandelia Piyush, Eanti Anjaneyulu, Banerjee Rajkumar, Narayan Kumar Pranav
Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad PIN 500078, India.
Department of Oils, Lipid Science & Technology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India.
Biomed Mater. 2025 Sep 24;20(5). doi: 10.1088/1748-605X/ae05a3.
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).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.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 theandexpression, 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.
靶向糖皮质激素受体（GR）可诱导癌细胞中的糖异生，可能破坏其糖酵解依赖性和酸性肿瘤微环境（TME），从而创造一个能量上不利的状态，并通过损害酸反流机制降低耐药性。基于这一原理，我们开发了一种GR介导的脂质体共递送系统D1XP-p53，它携带肿瘤抑制基因p53和化疗药物紫杉醇，以克服传统抗癌疗法的局限性，并评估野生型p53是否能增强紫杉醇对口腔鳞状细胞癌（OSCC）的抗癌活性。研究表明，D1XP-p53选择性降低了OSCC细胞的活力，并显著抑制了它们的迁移、侵袭和增殖。机制研究显示，当口腔癌细胞用D1XP-p53处理时，BAX/BCL2比值上调，表明内在凋亡途径被激活。D1XP-p53的疗效在使用MOC2和FaDu细胞系的3D球体模型中得到进一步验证，在该模型中它显著降低了球体形成能力并上调了E-钙黏蛋白表达，表明其在增强抗癌活性和减轻细胞迁移方面的潜在作用。使用带有MOC2细胞的OSCC小鼠模型进行的实验表明，用D1XP-p53处理的小鼠肿瘤体积显著减小，通过苏木精和伊红（H&E）染色及生物分布分析评估，全身毒性最小。考虑到肿瘤相关巨噬细胞、癌症干细胞和生长因子等TME成分在肿瘤进展和转移中的关键作用，我们进一步评估了我们的递送系统D1XP-p53对这些成分的影响。我们观察到，在小鼠中用D1XP-p53处理显著上调了M1/M2比值，并降低了 和 的表达，表明该递送系统在调节TME成分方面的潜在作用。这些发现共同表明，GR靶向共递送系统D1XP-p53增强了抗癌活性并调节了TME，为侵袭性口腔癌提供了一种有前景的多模式治疗方法。
