Table4_Nanotechnological synergy of mangiferin and curcumin in modulating PI3K/Akt/mTOR pathway: a novel front in ovarian cancer precision therapeutics.XLSX

Background: Ovarian cancer, colloquially termed the “silent killer” among gynecological malignancies, remains elusive due to its often-asymptomatic progression and diagnostic challenges. Central to its pathogenesis is the overactive PI3K/Akt/mTOR signaling pathway, responsible for various cellular functions, from proliferation to survival. Within this context, the phytochemical compounds mangiferin (derived from Mangifera indica) and curcumin (from Curcuma longa) stand out for their potential modulatory effects. However, their inherent bioavailability challenges necessitate innovative delivery systems to maximize therapeutic benefits.
Objective: This study seeks to synergize the merits of nanotechnology with the therapeutic properties of mangiferin and curcumin, aiming to bolster their efficacy against ovarian cancer.
Methods: Employing specific nanotechnological principles, we engineered exosomal and liposomal nano-carriers for mangiferin and curcumin, targeting the PI3K/Akt/mTOR pathway. Molecular docking techniques mapped the interactions of these phytochemicals with key proteins in the pathway, analyzing their binding efficiencies. Furthermore, molecular dynamics simulations, spanning 100 nanoseconds, verified these interactions, with additional computational methodologies further validating our findings. The rationale for the 100 nanoseconds time span lies in its sufficiency to observe meaningful protein-ligand interactions and conformational changes. Notably, liposomal technology provided an enhancement in drug delivery by protecting these compounds from degradation, allowing controlled release, and improving cellular uptake.
Results: Our computational investigations demonstrated notable binding affinities of mangiferin and curcumin: PI3K at −11.20 kcal/mol, Akt at −15.16 kcal/mol, and mTOR at −10.24 kcal/mol. The adoption of exosome/liposome-mediated delivery significantly amplified the bioavailability and cellular uptake of these nano-formulated compounds, positioning them as potential stalwarts in ovarian cancer intervention. A brief explanation of exosome/liposome-mediated delivery involves the use of these vesicles to encapsulate and transport therapeutic agents directly to the target cells, enhancing drug delivery efficiency and minimizing side effects.
Conclusion: Addressing ovarian cancer’s intricacies, dominated by the erratic PI3K/Akt/mTOR signaling, mandates innovative therapeutic strategies. Our pioneering approach converges nanotechnological liposomal delivery with mangiferin and curcumin’s natural efficacies. This confluence, validated by computational insights, heralds a paradigm shift in ovarian cancer treatment. As our findings underscore the collaborative potential of these phytochemicals, it beckons further exploration in translational studies and clinical applications, ensuring the best intersection of nature and technology for therapeutic advantage.

背景：卵巢癌作为妇科恶性肿瘤中俗称的"沉默杀手"，因其常呈无症状进展且诊断难度极大，至今仍难以实现有效管控。其发病机制的核心为过度激活的PI3K/Akt/mTOR信号通路，该通路调控细胞增殖、存活等多种核心生理功能。在此背景下，源自芒果（Mangifera indica）的芒果苷（mangiferin）与源自姜黄（Curcuma longa）的姜黄素（curcumin）这两种植物化学物，因其潜在的通路调控作用而备受关注。但二者固有的生物利用度缺陷，亟需创新型药物递送系统以最大化其治疗收益。
研究目标：本研究旨在将纳米技术的优势与芒果苷、姜黄素的治疗特性相结合，以提升二者对抗卵巢癌的临床疗效。
研究方法：本研究基于特定纳米技术原理，构建了用于负载芒果苷与姜黄素的外泌体（exosome）和脂质体（liposome）纳米载体，靶向PI3K/Akt/mTOR信号通路。采用分子对接技术，解析了这两种植物化学物与通路中关键蛋白的相互作用，并定量分析其结合效率。此外，通过时长100纳秒的分子动力学模拟验证了上述相互作用，并辅以其他计算方法进一步佐证研究结果。选择100纳秒模拟时长的依据在于，该时长足以观察到具有生物学意义的蛋白质-配体相互作用及构象变化。值得注意的是，脂质体技术可通过保护上述化合物免于降解、实现可控释放并提升细胞摄取效率，从而显著优化药物递送效果。
研究结果：本研究的计算分析结果显示，芒果苷与姜黄素展现出显著的蛋白结合亲和力：与PI3K的结合能为−11.20 kcal/mol，与Akt为−15.16 kcal/mol，与mTOR为−10.24 kcal/mol。采用外泌体/脂质体介导的递送方式，可显著提升上述纳米制剂的生物利用度与细胞摄取能力，使其有望成为卵巢癌干预治疗的潜在中坚力量。外泌体/脂质体介导的递送机制简述为：利用这类囊泡包裹治疗性药物并直接靶向递送至靶细胞，从而提升药物递送效率并降低毒副作用。
研究结论：卵巢癌的复杂病理特征以PI3K/Akt/mTOR信号通路异常激活为核心，对此亟需开发创新型治疗策略。本研究的开创性思路将纳米脂质体递送技术与芒果苷、姜黄素的天然治疗活性相结合。经计算分析验证的这一融合策略，有望为卵巢癌治疗带来范式革新。本研究结果凸显了这两种植物化学物的协同治疗潜力，也呼吁开展更多转化研究与临床应用探索，以实现天然产物与纳米技术的最优结合，获取最佳治疗收益。