Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer.
Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer.
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DOI：
10.3390/pharmaceutics14040713
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发表时间：
2022-03-26
期刊：
影响因子：
5.4
通讯作者：
Alani, Adam Wg
中科院分区：
文献类型：
--
作者：
Shah, Vidhi M.;Dorrell, Craig;Al-Fatease, Adel;Allen-Petersen, Brittany L.;Woo, Yeonhee;Bortnyak, Yuliya;Gheewala, Rohi;Sheppard, Brett C.;Sears, Rosalie C.;Alani, Adam Wg
胰腺导管腺癌（PDAC）由于其独特的缺氧生物学特性而成为药物递送的一个未满足的临床挑战。长春碱-N-氧化物（CPD 100）是一种低氧激活的前药（HAP），在氧梯度下选择性转化为其母体化合物长春碱，一种强效细胞毒性剂。该研究评估了微流体配制的脂质体CPD 100（CPD 100 Li）在PDAC中的功效。CPD 100 Li被配制成具有95 nm的尺寸和0.2的多分散指数。CPD 100 Li在3.55 mg/mL浓度下冻干后可稳定储存18个月。CPD 100和CPD 100 Li证实了胰腺癌细胞系在低氧水平下的选择性活化。此外，在3D球状体中，与CPD 100相比，CPD 100 Li显示出更高的渗透和破坏。在患者来源的3D类器官中，与CPD 100相比，CPD 100 Li在低氧诱导因子1 α（HIF 1A）表达更高的类器官中表现出更高的细胞抑制作用。在原位模型中，CPD 100 Li与吉西他滨（GEM）（PDAC的标准治疗）的组合在90天的时间内显示出比单独使用CPD 100 Li更高的疗效。总之，CPD 100 Li在多种细胞模型中的评价为其在PDAC中的临床应用提供了坚实的基础。
Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.
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