Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznańskiego 2, 61-614 Poznań, Poland.
NanoBioMedical Centre, Adam Mickiewicz University, Wszechnicy Piastowskiej 3, 61-614 Poznań, Poland.
J Mater Chem B. 2024 Nov 27;12(46):12017-12029. doi: 10.1039/d4tb01684j.
Self-assembled lipid nanoparticles containing Gd-chelating lipids are a new type of positive magnetic resonance imaging contrast agents (MRI CAs). High molecular weight imposes reduced molecular reorientation () and corresponding longer reorientation correlation times (), finally resulting in overall high relaxivity () of such contrast agents. Therefore, we report nanoassemblies based on two types of amphiphile molecules: glyceryl monooleate (GMO) as a matrix embedded with DTPA-bis(stearylamide) and its gadolinium salt (DTPA-BSA-Gd) as a Gd-chelating lipid, stabilized by surfactant Pluronic F127 molecules. The loading of DTPA-BSA-Gd into the GMO matrix was investigated at low (5% w/w) and high (30, 40, 50% w/w) contents. Small angle X-ray scattering (SAXS), cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS) results show that although the nanoassembly of both amphiphile molecules within the nanoparticle is disturbed in terms of the formed phases, this composition ensures their colloidal stability. In nanoparticles with low DTPA-BSA-Gd contents, the assembly results in a cubic diamond phase that is co-existing with a fraction of liposomes. For high DTPA-BSA-Gd contents, swelling of the structure occurs such that the initially formed primitive cubic phase transforms toward a lamellar phase in the nanoassemblies. Results from inductively coupled plasma mass spectrometry (ICP-MS) indicate that for almost all systems, the loading efficiency (LE) of DTPA-BSA-Gd is high (reaching up to approx. 85%), and the nanoassembly provides strong entrapment of Gd ions, which are then efficiently uptaken by cells. Moreover, the higher the surfactant content, the higher the LE. The viability studies demonstrate that the prepared nanoassemblies preserve high biocompatibility towards both cancer (HeLa) and normal cells (MSU 1.1). Nuclear magnetic resonance relaxometry studies (NMR relaxometry) followed by MRI on the prepared nanoassembly dispersions proved that the formation of GMO@DTPA-BSA-Gd nanoassemblies, considered as high molecular weight CAs, results in high relaxivity parameters (, = 19.72 mM s for 2GMO-40DTPA-10F127) that are superior to commercially developed ones (, Magnevist or Gadovist). These comprehensive studies imply that a high degree of internal ordering of nanoassemblies with a higher content of Gd-chelating lipid is not a decisive factor in determining the increase in relaxivity, thus confirming their potential as positive MRI CAs.
自组装含钆螯合脂质的脂质纳米颗粒是一种新型的正磁共振成像对比剂（MRI CA）。高分子量会降低分子的重定向（）和相应的更长的重定向相关时间（），最终导致此类对比剂的整体高弛豫率（）。因此，我们报告了基于两种类型的两亲分子的纳米组装体：甘油单油酸酯（GMO）作为基质，嵌入 DTPA-双（硬脂酰胺）及其镓盐（DTPA-BSA-Gd）作为镧系元素螯合脂质，由表面活性剂 Pluronic F127 分子稳定。在低（5%w/w）和高（30、40、50%w/w）含量下研究了 DTPA-BSA-Gd 载入 GMO 基质的情况。小角 X 射线散射（SAXS）、低温透射电子显微镜（cryo-TEM）和动态光散射（DLS）结果表明，尽管两种两亲分子的纳米组装体在形成的相中受到干扰，但这种组成确保了它们的胶体稳定性。在 DTPA-BSA-Gd 含量低的纳米颗粒中，组装导致立方金刚石相与部分脂质体共存的相。对于高 DTPA-BSA-Gd 含量，结构发生肿胀，使得最初形成的原始立方相在纳米组装体中向层状相转变。电感耦合等离子体质谱（ICP-MS）的结果表明，对于几乎所有系统，DTPA-BSA-Gd 的载药效率（LE）都很高（最高可达约 85%），纳米组装体提供了对 Gd 离子的有效包封，然后这些 Gd 离子被细胞有效摄取。此外，表面活性剂含量越高，LE 越高。细胞活力研究表明，所制备的纳米组装体对癌细胞（HeLa）和正常细胞（MSU 1.1）均保持高生物相容性。制备的纳米组装体分散体的磁共振弛豫率研究（NMR 弛豫率）和随后的 MRI 证明，GMO@DTPA-BSA-Gd 纳米组装体的形成被认为是高分子量 CA，导致高弛豫率参数（，= 19.72 mM s 对于 2GMO-40DTPA-10F127），优于商业开发的（，Magnevist 或 Gadovist）。这些综合研究表明，具有更高含量镧系元素螯合脂质的纳米组装体的高度内部有序性不是决定弛豫率增加的决定性因素，从而证实了它们作为正磁共振成像 CA 的潜力。
