Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG–PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APT_EDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.

中文翻译：

---

大小可切换纳米系统在促纤维间质中的渗透级联用于改进胰腺癌治疗

胰腺导管腺癌细胞（PDAC）被致密的细胞外基质（ECM）包围，极大地限制了治疗药物的获取，导致对化疗的临床反应不佳。转化生长因子-β1 (TGF-β1) 信号传导在促纤维增生基质的构建中起着至关重要的作用，并为 PDAC 治疗提供了潜在的靶点。为了克服病理障碍，我们开发了一种尺寸可切换的纳米系统，该系统基于封装在脂质体中的 PEG-PLGA 纳米球，用于联合递送 vactosertib (VAC)、TGF-β1 受体激酶抑制剂和细胞毒性药物紫杉醇 (TAX)。通过用肽对脂质体进行表面修饰，APT _EDB，该纳米系统可以锚定在 PDAC 基质中丰富的肿瘤相关纤连蛋白上，并通过释放封装的载有 TAX 的纳米球以及脂质体塌陷后的 VAC 来减小其大小。VAC 对 ECM 增生的抑制使 TAX 除了体积小外，还可以更容易地接近癌细胞，从而比游离药物的组合更有效地缩小胰腺肿瘤异种移植物。这种尺寸可切换的纳米系统能够以固定剂量组合顺序递送药物并简化给药，并提供令人鼓舞的药物渗透级联方法，以增强具有致密促纤维增生基质的癌症的化疗。