Self-assemblies of 5'-cholesteryl-ethyl-phosphoryl zidovudine.

Anti-HIV prodrugs are recently focused on due to their ability of self-assembly, macrophage targeting, and enhanced antiviral effects. Here, an amphiphilic prodrug of zidovudine, an anti-HIV nucleoside analogue, 5'-cholesteryl-ethyl-phosphoryl zidovudine (CEPZ) was synthesized. CEPZ showed some unique physicochemical properties. The solubility of CEPZ in the noncompetitive solvents chloroform and tetrahydrofuran (THF) was very high based on the hydrogen bonds between zidovudine groups, though CEPZ was sparing soluble in alcohols and almost insoluble in water. The typical amphiphilic property of CEPZ was demonstrated according to the Langmuir monolayers at the air/water interface. The LogP of CEPZ was high to 13.78, indicating the high hydrophobicity of amphiphilic CEPZ similar to phospholipids. Homogenous and stable self-assemblies were formed with the mean size of 128.7nm and the zeta potential of -35.4mV after injecting the CEPZ-in-THF solution into water. Hydrophobic interaction between the cholesteryl moieties of CEPZ could drive molecular self-assembly and lead to the formation of spherical vesicles. CEPZ self-assemblies showed strong stability even under high temperature and gravity probably due to the high surface charge. CEPZ was very slowly degraded in neutral solutions (e.g., pH 7.4), but fast in acid solutions (e.g., pH 5.0) and some tissue homogenates. CEPZ was quickly eliminated from the circulation and distributed into the mononuclear phagocyte system (MPS) including the liver, spleen and lung after bolus intravenous administration of CEPZ self-assemblies to mice. The MPS targeting effect of CEPZ self-assemblies makes them become a promising self-assembled drug delivery system to eradicate the HIV hidden in the macrophages.

Magnetic resonance imaging of osteosarcoma using a bis(alendronate)-based bone-targeted contrast agent.

Magnetic resonance (MR) is currently used for diagnosis of osteosarcoma but not well even though contrast agents are administered. Here, we report a novel bone-targeted MR imaging contrast agent, Gd2-diethylenetriaminepentaacetate-bis(alendronate) (Gd2-DTPA-BA) for the diagnosis of osteosarcoma. It is the conjugate of a bone cell-seeking molecule (i.e., alendronate) and an MR imaging contrast agent (i.e., Gd-DTPA). Its physicochemical parameters were measured, including pKa, complex constant, and T1 relaxivity. Its bone cell-seeking ability was evaluated by measuring its adsorption on hydroxyapatite. Hemolysis was investigated. MR imaging and biodistribution of Gd2-DTPA-BA and Gd-DTPA were studied on healthy and osteosarcoma-bearing nude mice. Gd2-DTPA-BA showed high adsorption on hydroxyapatite, the high MR relaxivity (r1) of 7.613mM-1s-1 (2.6 folds of Gd-DTPA), and no hemolysis. The MR contrast effect of Gd2-DTPA-BA was much higher than that of Gd-DTPA after intravenous injection to the mice. More importantly, the MR imaging of osteosarcoma was significantly improved by Gd2-DTPA-BA. The signal intensity of Gd2-DTPA-BA reached 120.3% at 50min, equal to three folds of Gd-DTPA. The bone targeting index (bone/blood) of Gd2-DTPA-BA in the osteosarcoma-bearing mice was very high to 130 at 180min. Furthermore, the contrast enhancement could also be found in the lung due to metastasis of osteosarcoma. Gd2-DTPA-BA plays a promising role in the diagnoses of osteosacomas, including the primary bone tumors and metastases.