Physicochemical Properties and Hematocompatibility of Layered Double Hydroxide-Based Anticancer Drug Methotrexate Delivery System

Abstract

A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property.

Multifunctional Layered Double Hydroxides for Drug Delivery and Imaging

“…Oh et al generated LDH nanoparticles intercalated with MTX using the ion exchange approach to address the safety and stability of MTX-LDH in blood vessel settings [ 66 ]. Before the in-vivo study, colloidal characteristics were examined by measuring the zeta potential and hydrodynamic diameter of MTX-LDH under simulated plasma conditions.…”

Blood Compatibility of Drug–Inorganic Hybrid in Human Blood: Red Blood Cell Hitchhiking and Soft Protein Corona

“…Despite the growing interest in LDH as a DDS, there has been only limited information on the hematocompatibility of LDH. We recently reported that LDH itself demonstrated negligible blood cell damage regardless of the particle size surface charge [18] and that LDH did not seriously denature the plasma proteins [11,19]. Other research also reported that surface modification of LDH with polysulfobetaine had excellent blood compatibility [20,21].…”

“…They are known to stabilize biologically unstable drug molecules to protect them [1], enhance the solubility of less soluble drugs [2,3], release the incorporated moiety in a controlled manner [4], effectively internalize into the target cell [5,6], and to have low cytotoxicity [7]. Based on the extensive studies on LDH-based DDS both in vitro and in vivo [8][9][10], recently, it was suggested that delivery of anticancer agents to a target organ was possible in animal models [11][12][13]. Although various injection routes, such as oral [14], intraperitoneal [15], intertumoral [16], intravenous administration [17], etc., have been utilized, most of the studies adopt intravenous administration as a practical and effective method.…”

“…Meanwhile, we previously reported that LDH nanomaterials were fairly inert to red blood cells (RBCs) regardless of the size and surface charge [18], and that LDH could interact with proteins to different degrees depending on the size and surface charge [19]. The drug-incorporated LDH, of which the surface might be partially covered by the drug, would undergo different blood interactions [11].…”

Development of Mesopore Structure of Mixed Metal Oxide through Albumin-Templated Coprecipitation and Reconstruction of Layered Double Hydroxide

“…Interfacial interaction between proteins and LDH have attracted interests in terms of colloidal stability and biological inertness. LDH particles coated with albumin are known to show high dispersibility and biocompatibility physiological condition both in vitro and in vivo [50][51][52]. It is straightforward that this protein could attach on the surface of LDH to separate individual particles.…”