基于瘤内基质重塑的肿瘤靶向递药系统增效策略研究

Tumor-targeting drug delivery system (TTDDS) is raised as a novel strategy for cancer care. However, the clinical response of TTDDS remains palliative. The insufficient intratumor concentration of TTDDS induced by high level of tumor-stroma is considered as one of primary reasons for compromised effect. Thus, to explore the penetration profiles of TTDDS in tumor stroma and increased its intratumor level is a promising mean to improve clinical outcomes. For shortage of applicable models to mimic real microenvironment in vivo or in vitro, the penetration behaviors of TTDDS remain unclear. Thus, we developed a novel 3D fibroblast-cancer cell co-culture model and a patient-derived xenograft (PDX) model, which were abundant of stroma in previous study. Then we disclosed that high level of tumor-stroma was a negatively prognosis factor of patients treated with TTDDS, which may probably be attributed to the impaired accumulation of TTDDS in tumor induced by high-density stroma collage. Subsequently, we remodeled the intratumor-stroma, enhanced intratumor accumulation and ultimately improving the antitumor effect of TTDDS by Rosiglitazone (RSG, one of approved anti-diabetic agents). In this project, we intend to disclose the penetration of TTDDS on tumor stroma based on the PDX, 3D co-culture model and samples from patients, then, reduce stroma collagen-level to facilitate the permeability and anti-tumor effect of TTDDS by RSG. Our results will disclose the penetration behaviors of TTDDS in tumor tissues and demonstrate the stroma-remodeling effect of RSG and its role in intratumor-accumulation enhancing and antitumor-response improving of TTDDS.

靶向纳米载药系统作为近年肿瘤治疗领域的热点备受关注，然而其临床疗效普遍不及预期，肿瘤基质所致瘤内渗透障碍极可能是关键原因。但是由于缺少适宜基质研究模型，纳米递药系统的瘤内渗透过程尚不明确。项目组临床分析发现肿瘤基质是纳米递药系统的不良预后因素，通过构建患者来源移植瘤模型（PDX）还原瘤内微环境，发现基质胶原阻碍纳米载体瘤内渗透，进而利用上市药品罗格列酮（RSG）可下调基质水平促进纳米递药系统渗透提升疗效。基于此，本研究将聚焦肿瘤微环境，采用临床样本、PDX模型和原代肿瘤成纤维细胞-肿瘤细胞三维共培养模型，研究肿瘤基质对纳米递药系统瘤内渗透的阻碍作用及其治疗耐受相关性，探讨RSG的重塑肿瘤基质促纳米载体瘤内渗透作用及关键调控机制，明确其增效作用及临床价值。成果不仅将率先从瘤内渗透动力学的全新角度诠释耐药机制，更为基于基质重塑的新兴肿瘤治疗策略提供支持，丰富肿瘤靶向递药系统理论体系。

以聚乙二醇修饰的多柔比星脂质体（PLD）为代表的抗肿瘤靶向制剂，通过长循环和实体瘤的高通透性和滞留效应（EPR效应）产生被动肿瘤靶向作用以实现增强抗肿瘤效果的目的。然而，实体瘤尤其是消化道肿瘤存在显著的瘤内结缔组织化现象，致密的基质，阻隔药物从血管向肿瘤细胞渗透，同时增加瘤内压增加药物扩散的阻力，尤其对于大分子的PLD作用更为显著。因此，明确基质对PLD渗透及疗效的影响，探索重塑基质减少基质增加药物渗透实现增效的可行性。.本研究完成肿瘤基质对纳米递药系统的瘤内渗透及抗结肠癌作用的影响研究，明确肿瘤基质胶原对纳米载药体系结肠癌瘤内深部渗透、富集效率的影响。同时，针对积雪草酸和罗格列酮重塑结肠癌基质作用及其化疗增效的调控机制开展实验，明确了两药对结直肠癌基质的重塑作用，以及对PLD抗肿瘤效应的增敏作用。.同时基于肿瘤基质对血液灌注和药物瘤内渗透作用的阻碍作用重构血管与灌注相关肿瘤预后因子。项目组定义并测定了药物瘤内渗透距离及其与患者预后的相关性，进而依据距离定义了有效灌注血管，改进经典灌注相关肿瘤预后标记物微血管密度（MVD）大大提高了MVD预测效率；以基质面积调整血管面积形成复合预后因子（SnMVA）大大提高了MVA的预测效率；同时考虑到收到基质压迫所改变的血管形态变化对于灌注的影响，探索了破碎微血管和变形微血管的纵横比与肿瘤患者预后的相关性，提示除了微血管因素以外，基质也是影响肿瘤患者生存的重要因素。研究成果发表SCI论文5篇，含中国科学院分区I区论文1篇，申请国家发明专利1项。.研究成果率先从体内外及临床层面明确肿瘤基质与纳米载体治疗耐受的相关性，进而阐明肿瘤基质重塑作为纳米载体增效策略的可行性与临床价值。同时患者渗透距离的研究也首次定义和测量了药物瘤内渗透距离，为后续研究的深入提供了数据支持。更重要的是将从瘤内渗透障碍这一全新角度诠释肿瘤治疗耐受，为以肿瘤基质重塑为方向的新兴肿瘤治疗策略提供理论支持，丰富肿瘤靶向递药系统理论体系。