Meher Niranjan, Bidkar Anil P, Wadhwa Anju, Bobba Kondapa Naidu, Dhrona Suchi, Dasari Chandrashekhar, Mu Changhua, Fong Cyril O Y, Cámara Juan A, Ali Umama, Basak Megha, Bulkley David, Steri Veronica, Fontaine Shaun D, Zhu Jun, Oskowitz Adam, Aggarwal Rahul R, Sriram Renuka, Chou Jonathan, Wilson David M, Seo Youngho, Santi Daniel V, Ashley Gary W, VanBrocklin Henry F, Flavell Robert R
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
National Institute of Pharmaceutical Education and Research, Lucknow, India.
Mol Cancer Ther. 2025 Jan 2;24(1):141-151. doi: 10.1158/1535-7163.MCT-24-0024.
The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed starPEG40kDa with or without talazoparib (TLZ), a potent PARP inhibitor, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four copis of TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous (s.c.) xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared with CT26, a known EPR-high cell line. MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545 and moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 s.c. xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in s.c. and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.
增强的通透性和滞留(EPR)效应控制着纳米药物在肿瘤中的被动摄取,并可能为癌症治疗提供高肿瘤载药量和延长的滞留时间。然而,EPR介导的肿瘤摄取和分布因癌症表型而异。因此,我们假设一种配套的PET成像替代物可能有益于EPR介导的治疗性药物递送。我们基于四臂starPEG40kDa开发了两种89Zr放射性标记的纳米载体,分别含有或不含有他拉唑帕尼(TLZ,一种有效的PARP抑制剂),作为PEG-TLZ4治疗支架的替代物。对于PET成像,通过用去铁胺B(DFB)取代PEG-TLZ4上的一个或所有四个TLZ拷贝,将PEG-DFB4和PEG-DFB1-TLZ3用89Zr进行放射性标记。放射性标记的纳米药物[89Zr]PEG-DFB4和[89Zr]PEG-DFB1-TLZ3在前列腺癌皮下(s.c.)异种移植物(22Rv1、LTL-545和LTL-610)和22Rv1转移模型中进行了体内测试。将它们的EPR介导的肿瘤摄取和渗透与已知的EPR高细胞系CT26进行了比较。MicroPET/CT图像、器官生物分布和计算的动力学参数显示,CT26和LTL-545摄取高,而LTL-610和22Rv1摄取中等至低。MicroPET/CT和高分辨率放射自显影图像显示纳米载体渗透到高通透性的CT26中,但在LTL-545、LTL-610和22Rv1皮下异种移植物和转移瘤中观察到外周积累不均匀。肿瘤切片的CD31染色显示CT26肿瘤中血管发育均匀,而其他异种移植物中存在异质性。[89Zr]PEG-DFB4和[89Zr]PEG-DFB1-TLZ3在皮下和转移瘤模型中的积累和分布相似。两种纳米载体都可以测量肿瘤模型的被动摄取异质性。尽管存在异质性,但前列腺癌异种移植物的EPR较低。这些starPEG纳米载体可用作PET成像替代物,以预测药物递送和疗效。
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