Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique, UMR 7039, Université de Lorraine, Campus Sciences, Boulevard des Aiguillette, 54506, Vandoeuvre-lès-Nancy, France.
Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 54519, Vandoeuvre-lès-Nancy, France.
J Nanobiotechnology. 2021 Jan 6;19(1):3. doi: 10.1186/s12951-020-00743-x.
Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs).
Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10 g, 0.07 × 10 g, and 1.3 × 10 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs.
The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.
尽管纳米颗粒（NPs）具有很高的临床应用前景，但 NPs 从实验室到临床的转化相对缓慢。共培养 3D 球体模拟了肿瘤细胞和基质成分（如癌相关成纤维细胞（CAF）和细胞外基质）的 3D 排列，重现了头颈部鳞状细胞癌（HNSCC）的微环境。在本研究中，我们研究了富含基质的肿瘤微环境如何影响三种已在欧盟获得批准的光敏剂替莫泊芬（mTHPC）的脂质纳米制剂的摄取、渗透和光动力效率：Foslip（mTHPC 常规脂质体）、药物-环糊精-脂质体（mTHPC-DCL）和细胞外囊泡（mTHPC-EVs）。
共培养富含基质的 3D HNSCC 球体中的胶原蛋白表达与单个球体中 CAF（MeWo 细胞）的数量相关。mTHPC 负载评估表明，Foslip、mTHPC-DCL 和 mTHPC-EVs 分别封装了 0.05×10^g、0.07×10^g 和 1.3×10^g 的 mTHPC 纳米囊泡。mTHPC NPs 在球体中的中渗透深度分别为 47.8µm（Foslip）、87.8µm（mTHPC-DCL）和 49.7µm（mTHPC-EVs），与基质成分的百分比无关。在富含基质的共培养球体中，Foslip 和 mTHPC-DCL 的细胞摄取率显著更高，并随着培养基中血清的添加而增加。重要的是，我们观察到在用脂质纳米粒子处理的单核培养和共培养球体中，PDT 效果没有显著差异。总体而言，在所有类型的球体中，mTHPC-EVs 的总细胞摄取量和 PDT 效率均优于其他 NPs。
基质微环境强烈影响 NPs 的摄取，而渗透和 PDT 效果对基质成分的存在不太敏感。由于极高的载药能力，mTHPC-EVs 优于其他脂质纳米囊泡。本研究的结果增加了我们对基质成分如何影响 NPs 进入肿瘤的理解。
