Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR)—poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously co-administered the nanomedicine with the tumor-penetrating peptide iRGD for enhanced treatment of pancreatic tumor. A FUDR-derived mono-isopropenyl ether was synthesized and underwent self-addition polymerization to afford the hydrophobic poly(FUDR-ketal), which was subsequently co-assembled with amphiphilic DSPE-mPEG into the micellar nanomedicine with size of 12 nm and drug content of 56.8 wt% using nanoprecipitation technique. The acetone-based ketal-linked poly(FUDR-ketal) was triggered by acid to release FUDR to inhibit cell proliferation. In an orthotopic pancreatic tumor model derived from KPC (; ; ) cells that overexpress neuropilin-1 (NRP-1) receptor, iRGD improved penetration of FUDR nanomedicine into tumor parenchyma and potentiated the therapeutic efficacy. Our nanoplatform, along with iRGD, thus appears to be promising for efficient penetration and activation of acid-responsive nanomedicines for enhanced pancreatic cancer therapy.

中文翻译：

---

肿瘤穿透性 iRGD 促进基于聚（氟尿苷缩酮）的纳米药物的渗透，以增强胰腺癌治疗


有效的瘤内渗透对于纳米药物根除胰腺肿瘤至关重要。尽管纳米药物可以进入胰腺肿瘤的血管周围空间，但它们进入远离血管的远端肿瘤细胞仍然是一个艰巨的挑战。在这里，我们合成了氟尿苷（FUDR）的酸激活大分子前药——聚（FUDR-缩酮），设计了FUDR的胶束纳米药物，并将该纳米药物与肿瘤穿透肽iRGD联合静脉给药，以增强对胰腺肿瘤的治疗。合成了 FUDR 衍生的单异丙烯基醚，并进行自加成聚合得到疏水性聚（FUDR-缩酮），随后将其与两亲性 DSPE-mPEG 共组装成尺寸为 12 nm 和药物含量的胶束纳米药物使用纳米沉淀技术获得 56.8 wt%。基于丙酮的缩酮连接的聚(FUDR-缩酮)被酸触发释放FUDR以抑制细胞增殖。在源自过度表达神经毡蛋白-1 (NRP-1) 受体的 KPC (; ; ) 细胞的原位胰腺肿瘤模型中，iRGD 改善了 FUDR 纳米药物对肿瘤实质的渗透并增强了治疗效果。因此，我们的纳米平台与 iRGD 似乎有望有效渗透和激活酸响应纳米药物，以增强胰腺癌治疗。