Umar Sheriff, Welch Xavier, Obichere Chihurumanya, Carter-Cooper Brandon, Samokhvalov Alexander
Department of Chemistry, Morgan State University, 1700 East Cold Spring Lane, Baltimore, MD 21251, USA.
Translational Laboratory Shared Services (TLSS), The University of Maryland School of Medicine's & Greenebaum Comprehensive Cancer Center, 22 S. Greene Street, Baltimore, MD 21201, USA.
Nanomaterials (Basel). 2024 Sep 29;14(19):1571. doi: 10.3390/nano14191571.
6-thioguanine (6-TG) is an antimetabolite drug of purine structure, approved by the FDA for the treatment of acute myeloid lesukemia, and it is of interest in treating other diseases. The interaction of drugs with matrices is of interest to achieving a delayed, sustained, and local release. The interaction of 6-TG with an aluminum metal-organic framework (Al-MOF) DUT-4 is studied using a novel experimental approach, namely, mechano-chemistry by liquid-assisted grinding (LAG). The bonding of 6-TG to the DUT-4 matrix in the composite (6-TG)(DUT-4) was studied using ATR-FTIR spectroscopy and XRD. This interaction involves amino groups and C and N atoms of the heterocyclic ring of 6-TG, as well as the carboxylate COO and (Al)O-H groups of the matrix, indicating the formation of the complex. Next, an in vitro delayed release of 6-TG was studied from composite powder versus pure 6-TG in phosphate buffered saline (PBS) at 37 °C. Herein, an automated drug dissolution apparatus with an autosampler was utilized, and the molar concentration of the released 6-TG was determined using an HPLC-UV analysis. Pure 6-TG shows a quick (<300 min) dissolution, while the composite gives the dissolution of non-bonded 6-TG, followed by a significantly (factor 6) slower release of the bonded drug. Each step of the release follows the kinetic pseudo-first-order rate law with distinct rate constants. Then, a pharmaceutical shaped body was prepared from the composite, and it yields a significantly delayed release of 6-TG for up to 10 days; a sustained release is observed with the 6-TG concentration being within the therapeutically relevant window. Finally, the composite shows a time-dependent (up to 9 days) stronger inhibition of leukemia MV-4-11 cell colonies than 6-TG.
6-硫鸟嘌呤（6-TG）是一种嘌呤结构的抗代谢药物，已获美国食品药品监督管理局（FDA）批准用于治疗急性髓系白血病，并且在治疗其他疾病方面也受到关注。药物与基质的相互作用对于实现延迟、持续和局部释放具有重要意义。采用一种新颖的实验方法，即液相助磨机械化学法（LAG），研究了6-TG与铝基金属有机框架（Al-MOF）DUT-4的相互作用。使用衰减全反射傅里叶变换红外光谱（ATR-FTIR）和X射线衍射（XRD）研究了6-TG在复合物（6-TG）（DUT-4）中与DUT-4基质的结合情况。这种相互作用涉及6-TG杂环的氨基以及C和N原子，还有基质的羧酸盐COO和（Al）O-H基团，表明形成了复合物。接下来，研究了在37℃下，复合物粉末中的6-TG与纯6-TG在磷酸盐缓冲盐水（PBS）中的体外延迟释放情况。在此，使用了带有自动进样器的自动药物溶出装置，并通过高效液相色谱-紫外分析（HPLC-UV）测定释放的6-TG的摩尔浓度。纯6-TG显示出快速（<300分钟）溶解，而复合物则先释放未结合的6-TG，随后结合药物的释放显著减慢（慢6倍）。释放的每个步骤都遵循具有不同速率常数的动力学伪一级速率定律。然后，由该复合物制备了一种药物成型体，它能使6-TG显著延迟释放长达10天；在6-TG浓度处于治疗相关范围内时观察到持续释放。最后，与6-TG相比，该复合物对白血病MV-4-11细胞集落的抑制作用呈现出时间依赖性（长达9天）且更强。
