Tailoring micellar nanocarriers for pemetrexed in breast cancer: design, fabrication and <i>in vitro</i> evaluation

<b>Aim:</b> To investigate the pemetrexed encapsulated polymeric mixed micelles (PMMs) against breast cancer treatment. <b>Methods:</b> We meticulously optimized the formulation and conducted extensive characterizations, including photon correlation spectroscopy for micellization, advanced analytical techniques and <i>in vitro</i> cell line assessments. <b>Results:</b> The PMM exhibited favorable characteristics, with a spherical morphology, hydrodynamic particle size of 19.58 ± 0.89 nm, polydispersity index of 0.245 ± 0.1, and a surface charge of -9.70 ± 0.61 mV. Encapsulation efficiency and drug payload reached 96.16 ± 0.37% and 4.5 ± 0.32%, respectively. Cytotoxicity analysis indicated superior efficacy of the PMM over the drug solution. <b>Conclusion:</b> The PMM formulation exhibited controlled release of the drug, and demonstrated enhanced cytotoxicity against breast cancer cells, highlighting its therapeutic promise. Breast cancer is a profoundly complex malignancy characterized by extensive genetic and clinical diversity, displaying a wide array of clinicopathological and morphological attributes and demonstrating variable responses to various therapeutic modalities. In this investigation, we delved into the intricate realm of medical science by examining the ternary amalgamation of Pluronic F127, Pluronic F68 and D-α-tocopheryl PEG 1000 succinate to encapsulate pemetrexed within a composite of polymeric mixed micelles. Pemetrexed, a pharmacological agent, operates as an antimetabolite, effectively inhibiting critical enzymes such as thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, which play pivotal roles in DNA synthesis. The meticulously prepared formulation underwent a process of optimization, followed by exhaustive characterization studies. The micellization phenomena were subjected to meticulous scrutiny using photon correlation spectroscopy. We employed advanced analytical techniques including Fourier transform infrared spectroscopy, differential scanning calorimetry, powder x-ray diffraction, 1D proton nuclear magnetic resonance (NMR) spectroscopy, one-dimensional selective rotating-frame Overhauser effect NMR spectroscopy and 2D proton–proton rotating-frame Overhauser effect NMR spectroscopy to elucidate the intricate interplay between the formulation's excipients and the therapeutic agent. We conducted rigorous assessments of drug and formulation dissolution behavior, along with <i>in vitro</i> studies on MCF-7 cell lines, to ascertain the formulation's efficacy against breast cancer. Our <i>in vitro</i> drug-release investigation unveiled a sustained release profile, outperforming the drug solution, with release kinetics adhering to the Higuchi model. NMR spectroscopy confirmed the presence of noncovalent interactions between the drug and the polymer components of the formulation. Our comprehensive cytotoxicity analysis demonstrated that the meticulously developed formulation exhibits superior efficacy compared with the unadulterated drug solution. The culmination of these findings unequivocally suggests that the polymeric mixed micelles represent a promising paradigm in the realm of drug-delivery systems, holding great potential for the treatment of breast cancer.

**研究目的：** 本研究旨在探究包载培美曲塞的聚合物混合胶束（polymeric mixed micelles，PMMs）用于乳腺癌治疗的效果。
**研究方法：** 我们对制剂处方进行了精细化优化，并开展了全面的表征工作，包括用于胶束形成表征的光子相关光谱法（photon correlation spectroscopy）、先进分析技术以及体外细胞系评价实验。
**研究结果：** 该PMM展现出优良的理化特性：呈球形形貌，流体力学粒径为19.58±0.89 nm，多分散指数（polydispersity index）为0.245±0.1，表面电荷为-9.70±0.61 mV。包封率与载药量分别可达96.16±0.37%与4.5±0.32%。细胞毒性分析显示，该PMM的抗肿瘤效果优于游离药物溶液。
**研究结论：** 该PMM制剂可实现药物的控释，并对乳腺癌细胞展现出更强的细胞毒性，凸显了其治疗应用前景。

乳腺癌是一种极为复杂的恶性肿瘤，具有广泛的遗传与临床异质性，呈现多样的临床病理与形态学特征，且对不同治疗手段的响应存在显著差异。本研究中，我们以泊洛沙姆F127（Pluronic F127）、泊洛沙姆F68（Pluronic F68）与D-α-生育酚聚乙二醇1000琥珀酸酯（D-α-tocopheryl PEG 1000 succinate）三元复配作为载体，将培美曲塞包载于聚合物混合胶束体系中。培美曲塞是一种抗代谢类抗肿瘤药物，可有效抑制胸苷酸合酶、二氢叶酸还原酶以及甘氨酰胺核糖核苷酸甲酰转移酶等关键酶的活性，这些酶在DNA合成过程中发挥核心作用。

我们对精心制备的制剂处方进行了优化，随后开展了全面的表征研究。通过光子相关光谱法对胶束形成过程进行了细致的表征分析，并采用多种先进分析技术，包括傅里叶变换红外光谱（Fourier transform infrared spectroscopy）、差示扫描量热法（differential scanning calorimetry）、粉末X射线衍射（powder x-ray diffraction）、一维质子核磁共振（nuclear magnetic resonance, NMR）光谱、一维选择性旋转坐标系奥氏核效应NMR光谱以及二维质子-质子旋转坐标系奥氏核效应NMR光谱，以阐明制剂辅料与治疗药物之间复杂的相互作用。同时，我们对药物与制剂的溶出行为进行了严格评价，并开展了MCF-7细胞系的体外实验，以评估该制剂抗乳腺癌的活性。

体外释药实验结果显示，该制剂具有持续释药特性，释药行为优于游离药物溶液，其释药动力学符合希戈奇（Higuchi）模型。核磁共振光谱分析证实，该制剂中药物与聚合物载体之间存在非共价相互作用。全面的细胞毒性分析结果表明，我们精心开发的该制剂的抗肿瘤活性优于纯药物溶液。上述研究结果明确表明，聚合物混合胶束是一种极具前景的药物递送系统载体，在乳腺癌治疗领域具有巨大的应用潜力。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于乳腺癌治疗中培美曲塞的纳米载体研究，通过设计、优化和表征聚合物混合胶束（PMMs）来封装药物。研究结果显示，PMMs具有小尺寸、高封装效率和增强的细胞毒性，体外实验证实其能控制药物释放并优于药物溶液，展现出作为药物递送系统的治疗潜力。