Miao Lei, Newby Jay M, Lin C Michael, Zhang Lu, Xu Feifei, Kim William Y, Forest M Gregory, Lai Samuel K, Milowsky Matthew I, Wobker Sara E, Huang Leaf
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, ‡Lineberger Comprehensive Cancer Center, §Departments of Mathematics and Applied Physical Science, ∥Department of Medicine, ⊥Department of Pathology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
ACS Nano. 2016 Oct 25;10(10):9243-9258. doi: 10.1021/acsnano.6b02776. Epub 2016 Sep 28.
The binding site barrier (BSB) was originally proposed to describe the binding behavior of antibodies to cells peripheral to blood vessels, preventing their further penetration into the tumors. Yet, it is revisited herein to describe the intratumoral cellular disposition of nanoparticles (NPs). Specifically, the BSB limits NP diffusion and results in unintended internalization of NPs by stroma cells localized near blood vessels. This not only limits the therapeutic outcome but also promotes adverse off-target effects. In the current study, it was shown that tumor-associated fibroblast cells (TAFs) are the major component of the BSB, particularly in tumors with a stroma-vessel architecture where the location of TAFs aligns with blood vessels. Specifically, TAF distance to blood vessels, expression of receptor proteins, and binding affinity affect the intensity of the BSB. The physical barrier elicited by extracellular matrix also prolongs the retention of NPs in the stroma, potentially contributing to the BSB. The influence of particle size on the BSB was also investigated. The strongest BSB effect was found with small (∼18 nm) NPs targeted with the anisamide ligand. The uptake of these NPs by TAFs was about 7-fold higher than that of the other cells 16 h post-intravenous injection. This was because TAFs also expressed the sigma receptor under the influence of TGF-β secreted by the tumor cells. Overall, the current study underscores the importance of BSBs in the delivery of nanotherapeutics and provides a rationale for exploiting BSBs to target TAFs.
结合位点屏障（BSB）最初是为描述抗体与血管周围细胞的结合行为而提出的，它可阻止抗体进一步渗透到肿瘤中。然而，本文重新探讨了它以描述纳米颗粒（NP）在肿瘤内的细胞分布情况。具体而言，BSB限制NP扩散，并导致位于血管附近的基质细胞意外内化NP。这不仅限制了治疗效果，还会促进不良的脱靶效应。在当前研究中，已表明肿瘤相关成纤维细胞（TAF）是BSB的主要组成部分，特别是在具有基质-血管结构的肿瘤中，TAF的位置与血管对齐。具体来说，TAF与血管的距离、受体蛋白的表达以及结合亲和力会影响BSB的强度。细胞外基质引发的物理屏障也会延长NP在基质中的滞留时间，这可能对BSB有影响。还研究了颗粒大小对BSB的影响。发现用茴香酰胺配体靶向的小（约18 nm）NP具有最强的BSB效应。静脉注射16小时后，TAF对这些NP的摄取比其他细胞高约7倍。这是因为TAF在肿瘤细胞分泌的TGF-β影响下也表达sigma受体。总体而言，当前研究强调了BSB在纳米治疗药物递送中的重要性，并为利用BSB靶向TAF提供了理论依据。
