Synthesis and Characterization of Thallium-Texaphyrin Nanoparticles and Their Assessment as Potential Delivery Systems for Auger Electron-Emitting 201Tl to Cancer Cells.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Pharmaceutics Pub Date : 2025-01-06 Epub Date: 2024-12-16 DOI:10.1021/acs.molpharmaceut.4c00873
Katarzyna M Wulfmeier, Miffy H Y Cheng, Zhongli Cai, Samantha Y A Terry, Vincenzo Abbate, Philip J Blower, Gang Zheng, Raymond M Reilly
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引用次数: 0

Abstract

Thallium-201 is an Auger electron-emitting radionuclide with significant potential for targeted molecular radiotherapy of cancer. It stands out among other Auger electron emitters by releasing approximately 37 Auger and Coster-Kronig electrons per decay, which is one of the highest numbers in its category. It has also a convenient half-life of 73 h, a stable daughter product, established production methods, and demonstrated high in vitro radiotoxicity. However, its full potential in targeted radiotherapy remains unexplored, primarily due to the lack of available efficient chelators for [201Tl]Tl+ or [201Tl]Tl3+. This study aims to assess texaphyrin for macrocycle chelation of [201Tl]Tl3+. Texaphyrins are known for effective binding of trivalent metals with similar ionic radii, such as indium and gadolinium. Optimization of [201Tl]Tl+ to [201Tl]Tl3+ oxidation and subsequent chelation with texaphyrin-lipid conjugate were assessed using thin-layer chromatography. The formation and stability of nonradioactive Tl-texaphyrin-lipid complexes were confirmed by UV-Vis spectroscopy and ultrahigh performance liquid chromatography-mass spectrometry. [201Tl]Tl/Tl-texaphyrin-lipid nanoparticles (nanotexaphyrins) were assembled by using a microfluidic system, and their morphology and stability were evaluated by using dynamic light scattering and transmission electron microscopy. The uptake of these nanotexaphyrins in lung cancer and ovarian cancer cells was evaluated using both radioactive and nonradioactive methods. The conversion of [201Tl]Tl+ to [201Tl]Tl3+ in 0.25 M HCl achieved an average yield of 91.8 ± 3.1%, while the highest radiolabeling yield of the texaphyrin-lipid with [201Tl]Tl3+ was 25.5 ± 4.5%. Tl-texaphyrin-lipid conjugates were stable at room temperature for at least 72 h. These conjugates were successfully assembled into homogeneous nanotexaphyrins with an average hydrodynamic diameter of 147.4 ± 1.4 nm. Throughout a 72 h period, no changes in size or polydispersity of the synthesized nanoparticles were observed. [201Tl]Tl-nanotexaphyrins were synthesized with an average radiochemical purity of 77.4 ± 10.3% and a yield of 5.1 ± 4.4%. The release of [201Tl]Tl+ from [201Tl]Tl-nanotexaphyrins in phosphate-buffered saline exhibited a time- and temperature-dependent pattern, with a faster release observed at 37 °C than at room temperature. Additionally, the uptake of Tl-nanotexaphyrins and [201Tl]Tl-nanotexaphyrins in cancer cells was similar to that of unbound Tl+ and [201Tl]Tl+. This is the first time that texaphyrins have been investigated as chelators for radiothallium. Although [201Tl]Tl-nanotexaphyrins were found to be thermodynamically and kinetically unstable, we successfully synthesized stable texaphyrin-lipid complexes with natTl3+. This opens up opportunities for further refinements in the nanotexaphyrin-lipid structure to enhance [201Tl]Tl3+ stability and prevent its reduction to a 1+ oxidation state. Future research should consider further modifications to the texaphyrin structure or using texaphyrins without the lipid component.

纳米铊- texaphyrin的合成、表征及其作为俄格电子发射201Tl向癌细胞传递系统的评价。
铊-201是一种俄歇电子发射放射性核素,在癌症靶向分子放疗中具有重要的潜力。它在其他俄歇电子发射器中脱颖而出,每次衰变释放大约37个俄歇和科斯特-克朗格电子,这是其类别中最高的数字之一。它的半衰期为73小时,是一个稳定的子产物,具有成熟的生产方法,并具有较高的体外放射毒性。然而,由于缺乏有效的[201Tl]Tl+或[201Tl]Tl3+螯合剂,其在靶向放疗中的全部潜力仍未得到充分开发。本研究旨在评估texaphyrin对[201Tl]Tl3+的大环螯合作用。众所周知,Texaphyrins能有效结合具有相似离子半径的三价金属,如铟和钆。采用薄层色谱法对[201Tl]Tl+对[201Tl]Tl3+的氧化及随后与texaphyrin-脂质偶联物的螯合进行了优化。通过紫外可见光谱和超高效液相色谱-质谱分析证实了非放射性tl -texaphyrin-脂类复合物的形成和稳定性。[201Tl]利用微流控系统组装了Tl/Tl-texaphyrin-脂质纳米颗粒(nanotexaphyrins),并利用动态光散射和透射电镜对其形貌和稳定性进行了评价。使用放射性和非放射性方法评估肺癌和卵巢癌细胞对这些纳米葡萄素的摄取。[201Tl]Tl+在0.25 M HCl中转化为[201Tl]Tl3+的平均产率为91.8±3.1%,而[201Tl]Tl3+对texaphyrin-脂质的放射性标记率最高为25.5±4.5%。l-texaphyrin-脂质偶联物在室温下至少稳定72小时。这些偶联物成功组装成均匀的纳米texaphyrin,平均水动力直径为147.4±1.4 nm。在72小时内,没有观察到合成的纳米颗粒的大小或多分散性的变化。[201Tl]Tl-nanotexaphyrins的平均放射化学纯度为77.4±10.3%,产率为5.1±4.4%。[201Tl]Tl-nanotexaphyrins中的[201Tl]Tl+在磷酸盐缓冲盐水中的释放表现出时间和温度依赖模式,在37℃下的释放速度比室温下更快。此外,肿瘤细胞对Tl-nanotexaphyrins和[201Tl]Tl-nanotexaphyrins的摄取与未结合的Tl+和[201Tl]Tl+相似。这是第一次研究texaphyrins作为放射性铊的螯合剂。虽然[201Tl]Tl-nanotexaphyrins在热力学和动力学上不稳定,但我们成功地用natTl3+合成了稳定的texaphyrins -脂质复合物。这为进一步改进纳米葡萄蛋白脂质结构提供了机会,以增强[201Tl]Tl3+的稳定性并防止其还原为1+氧化态。未来的研究应考虑进一步修改texaphyrin的结构或使用不含脂质的texaphyrin。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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