Ghasemizadeh Aria, Wan Lili, Hirose Aiko, Diep Jacqueline, Ewert Kai K, Safinya Cyrus R
Materials Department, University of California, Santa Barbara, California 93106, USA.
Biomolecular Science and Engineering, University of California, Santa Barbara, California 93106, USA.
bioRxiv. 2024 Aug 3:2024.08.01.606138. doi: 10.1101/2024.08.01.606138.
Paclitaxel (PTX) is one of the most widely utilized chemotherapeutics globally. However, the extremely poor water solubility of paclitaxel necessitates a mechanism of delivery within blood. Fluid lipid PTX nanocarriers (lipids in the chain-melted state) show promise as PTX delivery vectors, but remain limited by their solubility of PTX within the membrane. To improve pharmacokinetics, membrane surfaces are typically coated with polyethylene glycol (PEG). Recent work has demonstrated the generation of a population of micelles within fluid lipid formulations containing a 2kDa PEG-lipid at a 10 mol% ratio. Driven by the positive curvature of the PEG-lipid (i.e. area of head group > area of tails), micelle-containing formulations were found to exhibit significantly higher uptake in cancer cells, cytotoxicity, and antitumor efficacy compared to formulations containing solely liposomes. Here, we describe the custom synthesis of a library of high-curvature micelle-inducing PEG-lipids and examine the effects of PEG chain length, chain branching (single- or double-PEG-lipid), and cationic charge on PTX solubility and cytotoxicity. We examined PEG-lipids at standard (10 mol%) and high (100-x mol%, where x=PTX mol%) formulation ratios. Remarkably, all formulations containing the synthesized high-curvature PEG-lipids had improved PTX solubility over unPEGylated formulations and commercially available DOPE-5k. The highest PTX solubility was found within the 100-x mol% PEG-lipid micellar formulations, with particles made from 2k (two PEG2k chains) encapsulating 13 mol% PTX for up to 24 h. The pancreatic cancer cell line PC3 exhibited higher sensitivity to formulations containing PEG-lipid at 100-x mol%, the most potent of which being formulations made from 2k (IC50 = 14 nM). The work presented here suggests formulations employing high-curvature PEG-lipids, particularly the double-PEG-lipid 2k, hold great potential as next-generation PTX delivery systems owing to their high PTX solubility, enhanced cell cytotoxicity, and ability for precision targeting by affixation of ligands to the PEG molecules.
紫杉醇（PTX）是全球应用最广泛的化疗药物之一。然而，紫杉醇极差的水溶性使其需要一种在血液中的递送机制。流体脂质PTX纳米载体（处于链熔融状态的脂质）有望成为PTX递送载体，但仍受限于PTX在膜内的溶解度。为改善药代动力学，膜表面通常用聚乙二醇（PEG）进行包被。最近的研究表明，在含有10 mol%比例的2kDa PEG - 脂质的流体脂质制剂中会产生一群胶束。受PEG - 脂质正曲率（即头部基团面积>尾部面积）驱动，发现含胶束的制剂与仅含脂质体的制剂相比，在癌细胞摄取、细胞毒性和抗肿瘤疗效方面显著更高。在此，我们描述了一系列高曲率胶束诱导型PEG - 脂质库的定制合成，并研究了PEG链长、链分支（单PEG - 脂质或双PEG - 脂质）和阳离子电荷对PTX溶解度和细胞毒性的影响。我们在标准（10 mol%）和高（100 - x mol%，其中x = PTX mol%）制剂比例下研究了PEG - 脂质。值得注意的是，所有含有合成的高曲率PEG - 脂质的制剂相比未PEG化的制剂和市售的DOPE - 5k，PTX溶解度都有所提高。在100 - x mol%的PEG - 脂质胶束制剂中发现了最高的PTX溶解度，由2k（两条PEG2k链）制成的颗粒可包封13 mol%的PTX长达24小时。胰腺癌细胞系PC3对含有100 - x mol% PEG - 脂质的制剂表现出更高的敏感性，其中最有效的是由2k制成的制剂（IC50 = 14 nM）。本文介绍的工作表明，采用高曲率PEG - 脂质的制剂，特别是双PEG - 脂质2k，因其高PTX溶解度、增强的细胞毒性以及通过将配体附着于PEG分子进行精准靶向的能力，作为下一代PTX递送系统具有巨大潜力。
