Study On The Self-assembled Systems Of The Anti-HIV Bolaamphiphilic Prodrug

Self-assembled drug delivery systems (SADDS) were prepared from amphi-philic conjugates of hydrophilic drugs and lipids through self-assembling into ordered highly dispersing aggregates such as micelles, vesicles, hexagosomes and cubosomes in the aqueous media. The amphiphilic nature of SADDS leads to strong affinity and permeability with biomembranes. Meanwhile, the property of high dispersion leads to targeting of the MPS. SADDS could delivery themselves into targets in vivo. The unique advantages of SADDS over the microparticlate carriers were high drug loads, no drug leakage and sustained degradation at targets.On the basis of SADDS, a novel drug delivery system called self-assembled systems of bolaamphiphilc prodrugs (SASBP) was designed in this paper. SASBP were the new advance of SADDS. They were prepared from bolaamphiphilic molecules of a hydrophobic skeleton and two water-soluble groups on both ends through self-assembling into ordered highly dispersing aggregates in aqueous media. Besides the advantages of SADDS, SASBP also has the unique merit that the "cocktail" therapy in vivo is achieved by this technology.In this paper, the antiviral drugs - zidovudine (3'-azido-3'-deoxythymidine, AZT) and didanosine (2',3'-dideoxyinosine, DDI) were selected as the model drugs. AZT and DDI were lipophilic derivated and then self-assemblies of zidovudine phosphoryl-deoxycholic didanosine amphipathic prodrugs (ZPDD) were prepared. The main contents were described in details as follows:1. Synthesis and characteristics of anti-HIV bolaamphiphilic prodrug.An anti-HIV bolaamphiphilic prodrug was designed and synthesized, that was zidovudine phosphoryl-deoxycholic didanosine (ZPDD). And its purification was identified. The solubility of the prodrug was measured, of which the hydrogen bonding and hydrophobic interaction were the key factors. The lipophilicity of the prodrug increased greatly. Meanwhile, the formation and characterization of its langmuir monolayers were investigated. As a typical bolaamphiphilic prodrug, ZPDD formed the stable monolayer. Because the hydrophobic chain of glyc-deoxycholic acid moieties was rigid, the possible configuration of the monolayer at the air/water interface formed by ZPDD might be stretched.2. Preparation and characteristics of anti-HIV bolaamphiphilic prodrug self-assembled systems.Many methods were used to prepare ZPDD self-assembled systems. A kind of highly dispersed homogeneous suspension system with high concentration was prepared by THF injection method. The mechanism of ZPDD self-assembly system was presumed with transmission electron microscope (TEM) and the size determination. ZPDD molecules self-assembled to monolayer membrane by the hydrophobic interaction of glyc-deoxycholic acid moieties and under the action of the hydrogen bonding of nucleosides, and then formed to the vesicles. The mean particle size of ZPDD self-assembled systems was about 175 nm. The surface Zeta potential was -44.4 mV.3. Physical stability of anti-HIV bolaamphiphilic prodrug self-assembled systems.Physical stability was investigated through heating, high pressure, centrifugation (≤10000 rpm) and storing at room temperature. The results indicated the content of ZPDD decreased sharply when ZPDD self-assembled systems were heated and under high pressure. However, ZPDD self-assemblies were stable to a great extent through high speed centrifugation and storing at room temperature. Self-assembled systems of high concentration (>10 mg/mL) could redisperse easily with water.4. Chemical stability of anti-HIV bolaamphiphilic prodrug self-assembled systems.Chemical stability of ZPDD self-assembled systems in the buffer solutions of different pH, plasma of different animals and tissue homogenates of mice were all investigated using an assay method of HPLC. Self-assembled systems of ZPDD hydrolyzed quickly in the buffer solution of pH 2.0, but kept stable for a long period in the neutral and weak acid surrounding with t_1/2 more than 1000 h and 61 h, respectively. However, the hydrolysis of ZPDD in the plasma of animals was different. The hydrolysis rate of ZPDD in the plasma of mice and human were faster than that of dogs, monkeys and rats. The degradation rate of ZPDD in liver homogenates of mice was very fast, and the t_1/2 was 3 h. The main degradation products were AZT and DDL But the content of DDI detected was little, because DDI degraded to hypoxanthine. The results indicated that the prodrug could degrade to the active compound-AZT and DDI efficiently, which could delay the release in vivo.5. Pharmacodynamics of anti-HIV bolaamphiphilic prodrug self-assembled systems.Antiviral action of ZPDD self-assembled systems was investigated, which the EC50 in the MT4 cells infected by HIV-1IIIB was 5 nmol/L, and it was the same as AZT. The results indicated that the prodrug could degrade to the active compound-AZT and DDI efficiently, which could play a part in pharmacodynamic action.6. Pharmacokinetics and tissue distribution of anti-HIV bolaamphiphilic prodrug self-assembled systems.After single bolus of iv., po. and ip. administration to mice, ZPDD self-assembled systems were eliminated quickly from the blood circulation, and t_1/2 were 18, 16 and 28 min, respectively. It was suggested that ZPDD self-assembled systems had some longevity in the blood. It attributed to the lymph and macrophage system, especially lymph node, thymus, spleen, liver, lung targeting and sustained releasing effects. The bioavailabilities of ZPDD self-assembled systems with po. and ip. administration to mice were 30.8 % and 86.5 %, respectively. The concentration of AZT was high, but the content of the other parent drug - DDI detected was little. However, the contents difference of AZT and DDI wasn't statistically significant. The results indicated that ZPDD self-assembled systems could target to the lymphatics and macrophage system, it could degrade to the active compound efficiently in the targeting tissues and played a part in antiviral action. Although the bioavailabilities of po. and ip. administration were low, the pharmacodynamic action didn't have distinguished difference.A highly dispersed, homogeneous and stable self-assembled systems of zidovudine phosphoryl-deoxycholic didanosine (ZPDD) was prepared in this paper. A nano-size, ordered structure formed under the action of hydrophobic interaction and hydrogen bonding was proved. The self-assembled systems were uptaken by lympholeukocyte and monocyte macrophage quickly in mice and degraded sustainedly into AZT and DDL ZPDD self-assembled systems could make the "cocktail" therapeusis come true in vivo and played an important part in the antiviral action.