Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, No.17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, No.17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, China; NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China; National Engineering Research Center for Biomaterials & College of Biomedical Engineering, Sichuan University, Chengdu, China.
Acta Biomater. 2022 Jun;145:122-134. doi: 10.1016/j.actbio.2022.03.050. Epub 2022 Apr 2.
The dense stroma that acts as a physical and biological barrier in the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) leads to the failure of chemotherapeutic drug delivery. Cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mainly constitute the refuge for cancer cells in PDAC. Herein, a CAF targeting drug delivery system (TDDS) based on RBC vesicles partial protection (RBC-Fn-NP) was established and investigated for reprogramming stroma, as well as enhancing tumor penetration and antitumor efficacy in PDAC. RBC vesicles were firstly used for partial protection of peptide from external influences. The exposed FnBPA5 peptide showed high affinity with both CAFs and the major components as collagen I and relaxed-fibronectin of ECM. Retinoic acid (RA) could disturb Golgi of CAFs, resulting in the reduction of protein secretion from the headstream. As expected, the strategy of RBC vesicles protected FnBPA5 targeting and RA-induced protein reduction was confirmed to reprogram the dense stroma and improve the penetration of Doxorubicin (Dox) in PDAC. RBC-Fn-NP inhibited tumor growth in both Pan02-orthotopic bearing model and Pan02-subcutaneous mice model. Hence, these partial ligand shielding nanoparticles offer a multifunctional and efficient approach to overcome penetration barriers and enhance the antitumor efficacy of chemotherapy in PDAC. STATEMENT OF SIGNIFICANCE: A partial ligand shielding nanoparticle platform (RBC-Fn-NP), which has the function of an RBC vesicle "shell" and thetargeting properties of a "core" to achieve superior therapeutic effects against PDAC, was established. The targeted ligand was modified on the surface of the nanoparticles instead of the RBC membranes. Three-dimensional PDAC stroma-rich spheroids were established to evaluate the penetration and tumor stroma remodeling. The targeting properties of FnBPA5 peptide, the effect of RA-induced Golgi disruption on the reduction of protein secretion, and the incomplete "camouflage" of the RBC vesicles were confirmed both in vitro and in vivo. As expected, our nanoplatform may provide a promising strategy for remolding dense stroma and enhancing the permeability in PDAC.
在胰腺导管腺癌 (PDAC) 的肿瘤微环境 (TME) 中，密集的基质充当物理和生物屏障，导致化疗药物输送失败。癌相关成纤维细胞 (CAF) 和细胞外基质 (ECM) 主要构成 PDAC 中癌细胞的避难所。在此，建立了一种基于 RBC 囊泡部分保护 (RBC-Fn-NP) 的 CAF 靶向药物递送系统 (TDDS)，用于重编程基质，并增强 PDAC 中的肿瘤穿透和抗肿瘤疗效。首先使用 RBC 囊泡来部分保护肽免受外部影响。暴露的 FnBPA5 肽与 CAF 以及 ECM 的主要成分胶原 I 和松弛型纤维连接蛋白均具有高亲和力。维甲酸 (RA) 可扰乱 CAF 的高尔基体，导致蛋白分泌减少。不出所料，RBC 囊泡保护 FnBPA5 靶向和 RA 诱导的蛋白减少的策略被证实可重编程密集的基质并改善 PDAC 中多柔比星 (Dox) 的穿透。RBC-Fn-NP 抑制了 Pan02 原位荷瘤模型和 Pan02 皮下小鼠模型中的肿瘤生长。因此，这些部分配体屏蔽纳米粒子提供了一种多功能且有效的方法来克服穿透障碍并增强 PDAC 中化疗的抗肿瘤疗效。
声明：建立了一种具有 RBC 囊泡“壳”功能和“核”靶向特性的部分配体屏蔽纳米颗粒平台 (RBC-Fn-NP)，可实现对 PDAC 的卓越治疗效果。靶向配体修饰在纳米颗粒表面而不是 RBC 膜上。建立了富含三维 PDAC 基质的球体来评估穿透和肿瘤基质重塑。在体外和体内均证实了 FnBPA5 肽的靶向特性、RA 诱导的高尔基体破坏对蛋白分泌减少的影响以及 RBC 囊泡的不完全“伪装”。正如预期的那样，我们的纳米平台可能为重塑致密基质和增强 PDAC 中的通透性提供了一种有前途的策略。
