LBPO.CH01 · 化学 · Late-Breaking

前沿的无药靶向抗癌疗法：智能叶酸偶联共聚物本征性地失活YAP/TAZ-HIPPO癌蛋白并遏制胰腺癌进展与转移

Cutting-edge, drug-free targeted cancer therapeutic: Smart folate-conjugated copolymer intrinsically disables the YAP/TAZ-HIPPO oncoproteins and abrogates pancreatic cancer progression and metastasis

编号 LB022 展板 2 时间 4/19 02:00–05:00 区域 Section 51 主讲 Reza Bayat Mokhtari, MS;PhD

分会场 Late-Breaking Research: Chemistry

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作者与单位 Authors & Affiliations

Reza Bayat Mokhtari¹, Nicole Mendonza², Daniel Leon Moshe³, Yunfan Li⁴, Daniella Ghokasian³, Razieh Salahandish⁵, Narges Baluch⁶, Myron R. Szewczuk⁷

¹Association of Clinical Immunology and Cancer Research(ACICR), and California Comprehensive Allergy and Food Institute, P.C. (CalCafi, P.C.), San Diego, CA,²Department of Chemistry and Chemical Engineering, Royal Military College of Canada, Kingston, ON, Canada,³Faculty of Health Sciences, Queen’s University, Kingston, ON, Canada,⁴Faculty of Arts and Science, Queen’s University, Kingston, ON, Canada,⁵Laboratory of Advanced Biotechnologies for Health Assessments (Lab-HA), Biomedical Engineering Program, Lassonde School of Engineering, York University, and Department of Electrical Engineering and Computer Science (EECS), Lassonde School of Engineering, Toronto, ON, Canada,⁶Department of Immunology and Allergy, Rady Children’s Hospital, San Diego, CA,⁷Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

摘要 Abstract

中文摘要

背景：胰腺导管腺癌（PDAC）由内源性化疗耐药和适应性生存通路所驱动，其中包括Hippo/YAP轴和缺氧信号通路。全身性细胞毒治疗因严重毒性和不良的肿瘤穿透性而受限。近期进展提示，功能化纳米结构可具备超越惰性载体作用的内在生物学活性。我们假设超灵敏纳米生物传感的精准性可被重新用于治疗干预和体内示踪。方法：合成了一种350 kDa叶酸功能化两亲性交替共聚物（FA-DABA-SMA），并在PANC-1人胰腺癌的RAG2×Cgamma双突变异种移植模型中将其作为“无药”纳米疗法进行测试。小鼠每周接受FA-DABA-SMA静脉单药治疗，并与姜黄素和未治疗对照进行比较。通过肿瘤体积和转移负荷评估疗效。机制分析采用免疫组织化学和免疫荧光，以评估Hippo通路效应分子（YAP、TAZ）、增殖（Ki67）和缺氧信号（HIF-1alpha、VEGF、CA9）。结果：FA-DABA-SMA相较对照实现了69%的肿瘤缩小（p < 0.001），优于姜黄素，并遏制了肝和肺转移。多价叶酸受体结合将Hippo效应分子（YAP/TAZ）滞留于胞质中，阻止其核转位。治疗使缺氧生存机制崩溃并抑制了血管生成拟态（CD31/CD34）。结论：FA-DABA-SMA是一种新型本征纳米疗法，可在无细胞毒性载荷的情况下失活PDAC生存通路，支持将其作为一种无毒的临床候选药物用于转移预防加以转化。

查看英文原文 English abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by intrinsic chemoresistance and adaptive survival pathways, including the Hippo/YAP axis and hypoxic signaling. Systemic cytotoxic therapy is limited by severe toxicity and poor tumor penetration. Recent advances suggest functionalized nanostructures can possess intrinsic biological activity beyond serving as inert carriers. We hypothesized that the precision of ultrasensitive nano-biosensing could be repurposed for therapeutic intervention and in vivo tracking. Methods: A 350 kDa folate-functionalized amphiphilic alternating copolymer (FA-DABA-SMA) was synthesized and tested as a "drug-free" nanotherapeutic in a RAG2×Cgamma double-mutant xenograft model of PANC-1 human pancreatic cancer. Mice received weekly intravenous FA-DABA-SMA monotherapy, compared to curcumin and untreated controls. Efficacy was assessed by tumor volume and metastatic burden. Mechanistic analysis used immunohistochemistry and immunofluorescence to evaluate Hippo pathway effectors (YAP, TAZ), proliferation (Ki67), and hypoxic signaling (HIF-1alpha, VEGF, CA9). Results: FA-DABA-SMA achieved 69% tumor reduction versus controls (p < 0.001), outperforming curcumin, and abrogated liver and lung metastases. Multivalent folate receptor engagement sequestered Hippo effectors (YAP/TAZ) in the cytoplasm, preventing nuclear translocation. Treatment collapsed hypoxic survival machinery and suppressed vasculogenic mimicry (CD31/CD34). Conclusions: FA-DABA-SMA is a novel intrinsic nanotherapeutic disabling PDAC survival pathways without cytotoxic cargo, supporting translation as a non-toxic clinical candidate for metastasis prevention.

利益披露 Disclosure

R. Bayat Mokhtari, None.. N. Mendonza, None.. D. Moshe, None.. Y. Li, None.. D. Ghokasian, None.. R. Salahandish, None.. N. Baluch, None.. M. R. Szewczuk, None.

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