Effect of Paclitaxel Stereochemistry on X-ray-Triggered Release of Paclitaxel from CaWO4/Paclitaxel-Coloaded PEG-PLA Nanoparticles.
Effect of Paclitaxel Stereochemistry on X-ray-Triggered Release of Paclitaxel from CaWO4/Paclitaxel-Coloaded PEG-PLA Nanoparticles.
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DOI：
10.1021/acs.molpharmaceut.2c00148
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发表时间：
2022-07
影响因子：
4.9
通讯作者：
Kaustabh Sarkar;Sandra E Torregrossa-Allen;B. Elzey;Sanjeev K. Narayanan;M. Langer;G. Durm;You-Yeon Won-Yo
中科院分区：
文献类型：
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作者：
Kaustabh Sarkar;Sandra E Torregrossa-Allen;B. Elzey;Sanjeev K. Narayanan;M. Langer;G. Durm;You-Yeon Won-Yo
对于许多局部晚期肿瘤，化疗-放疗（CT-RT）组合（“放化疗”）目前是护理标准。肿瘤内（IT）基于CT的放化疗有可能克服常规全身CT-RT的局限性（副作用）。为了最大化IT CT-RT的益处，我们的实验室先前已经开发了辐射控制的药物释放制剂，其中抗癌药物紫杉醇（PTX）和放射性发光CaWO 4（CWO）纳米颗粒（NP）与聚（乙二醇）-聚（乳酸）（PEG-PLA）嵌段共聚物（“PEG-PLA/CWO/PTX NP”）共包封。这些PEG-PLA/CWO/PTX NP能够实现PTX的辐射控制释放，并且能够在单次IT注射后产生持续至少一个月的持续治疗效果。本文重点讨论了我们最近发现的PTX的立体化学结构对PEG-PLA/CWO/PTX NP制剂功效的影响。两种不同PTX化合物（来自Samyang Biopharmaceuticals的“PTX-S”和来自Biotang的“PTX-B”）中的立体化学差异通过2D异频/同频NMR、拉曼光谱和圆二色性测量来表征。发现PTX立体化学的差异显著影响它们的水溶性（WS）; PTX-S（WS <4.69 μg/mL）比PTX-B（WS <0.25 μg/mL）的水溶性高约19倍。当作为游离药物使用时，两种PTX化合物在体外显示出相似的癌细胞杀伤性能。然而，细微的立体化学差异显著影响它们从PEG-PLA/CWO/PTX NP的X射线触发的释放动力学;水溶性更高的PTX-S比水溶性更低的PTX-B释放得更快。这种差异表现在IT药代动力学中，并最终表现在体内人肿瘤异种移植研究中用PEG-PLA/CWO/PTX NP + X射线处理的试验动物（小鼠）的存活百分比中;在短时间（<1个月），同时PEG-PLA/CWO/PTX-S NP产生更大的肿瘤抑制作用，而PEG-PLA/CWO/PTX-B NP具有更持久的放射增敏作用。本研究证明了药物的立体化学在基于控释制剂的治疗中的重要性。
For many locally advanced tumors, the chemotherapy-radiotherapy (CT-RT) combination ("chemoradiation") is currently the standard of care. Intratumoral (IT) CT-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT (side effects). For maximizing the benefits of IT CT-RT, our laboratory has previously developed a radiation-controlled drug release formulation, in which anticancer drug paclitaxel (PTX) and radioluminescent CaWO4 (CWO) nanoparticles (NPs) are co-encapsulated with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block copolymers ("PEG-PLA/CWO/PTX NPs"). These PEG-PLA/CWO/PTX NPs enable radiation-controlled release of PTX and are capable of producing sustained therapeutic effects lasting for at least one month following a single IT injection. The present article focuses on discussing our recent finding about the effect of the stereochemical structure of PTX on the efficacy of this PEG-PLA/CWO/PTX NP formulation. Stereochemical differences in two different PTX compounds ("PTX-S" from Samyang Biopharmaceuticals and "PTX-B" from Biotang) were characterized by 2D heteronuclear/homonuclear NMR, Raman spectroscopy, and circular dichroism measurements. The difference in PTX stereochemistry was found to significantly influence their water solubility (WS); PTX-S (WS ≈ 4.69 μg/mL) is about 19 times more water soluble than PTX-B (WS ≈ 0.25 μg/mL). The two PTX compounds showed similar cancer cell-killing performances in vitro when used as free drugs. However, the subtle stereochemical difference significantly influenced their X-ray-triggered release kinetics from the PEG-PLA/CWO/PTX NPs; the more water-soluble PTX-S was released faster than the less water-soluble PTX-B. This difference was manifested in the IT pharmacokinetics and eventually in the survival percentages of test animals (mice) treated with PEG-PLA/CWO/PTX NPs + X-rays in an in vivo human tumor xenograft study; at short times (<1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor-suppression effect, whereas PEG-PLA/CWO/PTX-B NPs had a longer-lasting radio-sensitizing effect. This study demonstrates the importance of the stereochemistry of a drug in a therapy based on a controlled release formulation.