[Show abstract][Hide abstract] ABSTRACT: Self-assembled nanostructures were obtained through injecting cholesteryl-succinyl didanosine (CSD) solutions in tetrahydrofuran (THF) into water. The incorporation of THF leads to CSD flexible bilayers. Spherical vesicles of CSD initially formed based on hydrophobic interaction and transformed to short nanotubes with THF leaving. A large proportion of THF led to formation of long flexible nanoribbons, also transforming to short nanotubes after removing THF because of rigid bilayers recovering. Cholesteryl-adipoyl didanosine (CAD) only formed spherical vesicles due to its long and flexible tails. A triblock copolymer, poloxamer 188 (P188) could insert into CSD monolayers at the air/water interface. P188 stabilized CSD nanoparticulate systems by incorporation and adsorption. The optimal formulation of nanoparticulate systems was identified and the appropriate ratio of CSD/P188 and CSD concentration in injected solutions were the keys. A highly concentrated system had a narrow size distribution, allowing heat sterilization at 100 degrees C, and resisting aggregation under high gravity accelerations in spite of the low zeta potential of -18.5 mV. A gel-liquid crystalline phase transition at 47 degrees C occurred. The system may become promising self-assembled drug delivery systems (SADDS) for anti-HIV therapy.
Journal of Colloid and Interface Science 11/2008; 326(1):275-82. DOI:10.1016/j.jcis.2008.07.014 · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Self-assembled drug delivery systems (SADDS) are defined as the self-assemblies of amphiphilic prodrugs, integrating prodrugs, molecular self-assembly and nanotechnology for drug targeting and controlled release. Cholesteryl-succinyl didanosine (CSD) and cholesteryl-adipoyl didanosine (CAD) nanoparticulate systems in water were previously prepared and optimized. In this paper, the in vitro and in vivo behavior of them was investigated. Precipitation occurred when they were mixed with acid solutions due to rapid production of hypoxanthine and subsequent disruption of supramolecular structures. They showed pH-dependent degradation and kept relatively stable in the neutral pH range. CSD is more stable than CAD due to the shorter spacer and poloxamer protection. CSD showed different degradation rates in various plasma with the descending order of rat, mouse, rabbit, dog and human. The half-life (t(1/2)) of CSD is 9 days in rat plasma, and 5.9 days in rat liver homogenates. CAD has a faster degradation than CSD though the t(1/2) in rat liver homogenates is long to 23 h. CSD nanoparticulates showed no significant anti-HIV effect in MT4 cell model because of very slow degradation. CSD nanoparticulates showed the distribution t(1/2) of 7.6 min after bolus intravenous (i.v.) administration to rats, and the site-specific distribution in liver, lung and spleen with the high t(1/2) of 10 days in liver. The factors affecting achievement of successful SADDS are discussed.
International Journal of Pharmaceutics 11/2008; 368(1-2):207-14. DOI:10.1016/j.ijpharm.2008.10.009 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Self-assembled drug delivery systems (SADDS) are defined as the self-aggregates of amphiphilic prodrugs. Prodrug, molecular self-assembly and nanotechnology are involved in SADDS manufacturing. But the knowledge of the self-assembly of amphiphilic prodrugs and the formation rules of SADDS is very limited. In this paper, five cholesteryl derivatives of antiviral nucleoside analogues were synthesized, involving antiviral acyclovir, didanosine and zidovudine, and the different acyl linkers, succinyl, adipoyl and phosphoryl. The derivatives are typical amphiphiles with nucleosides as polar heads and long-chained lipids as hydrophobic tails. The derivatives showed the similar soluble behavior, and the solubility highly depended on the types of solvents. Two forces, hydrogen bonding and hydrophobic interaction in alcohol solutions could improve the derivatives dissolving. However, the molecular self-assembly of derivatives could prefer to happen in the noncompetitive solvents including chloroform and tetrahydrofuran (THF) based on the intermolecular hydrogen bonding between nucleobase moieties, which could greatly increase their solubility. The derivatives formed nanosized vesicles based on hydrophobic interaction after injecting their THF solutions into water. The volume ratios of polar heads and hydrophobic tails of amphiphiles could determine the vesicle size, and the amphiphiles with large ratios would prefer to form small vesicles. The self-assembled vesicles would likely become SADDS.
International Journal of Pharmaceutics 03/2008; 350(1-2):330-7. DOI:10.1016/j.ijpharm.2007.08.037 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Self-assembled drug delivery systems (SADDS) were designed in the paper. They can be prepared from the amphiphilic conjugates of hydrophilic drugs and lipids through self-assembling into small-scale aggregates in aqueous media. The outstanding characteristic of SADDS is that they are nearly wholly composed of amphiphilic prodrugs. The self-assembled nanoparticles (SAN) as one of SADDS had been prepared from the lipid derivative of acyclovir (SGSA) in the previous paper. They were further studied on the properties and the in vitro/in vivo behavior in this paper. The SAN kept the physical state stable upon centrifugation or some additives including some inorganic salts, alkaline solutions, surfactants and liposomes except for HCl solution, CaCl(2) solution and animal plasma. Autoclave and bath heat for sterilization hardly influenced the SAN. However, gamma-irradiation strongly destroyed the structure of SAN and SGSA was degraded. SGSA in SAN showed good stability in weak acidic or neutral buffers although it was very sensitive to alkaline solutions and carboxylester enzymes, the half-lives (t(1/2)) of which in the buffer at pH 7.4, the alkaline solution at pH 12.0, pig liver carboxylester enzyme solution, rabbit plasma, and rabbit liver tissue homogenate were 495, 21, 4.7, 25 and 8.7 h, respectively. Compared with SGSA in a disordered state, the specific bilayer structures of SAN could protect SGSA from hydrolysis through hiding the sensitive ester bonds. The SAN showed hemolytic action because the amphiphilic SGSA could insert into rabbit erythrocyte membranes. Both the high concentration of SGSA in samples and the long incubation time improved hemolysis. No hemolysis was observed if the additional volume of the SAN was less than 10% of rabbit whole blood in spite of the high concentration of SGSA. Plasma proteins could interfere the interaction between the SAN and erythrocytes by binding the SAN. The in vitro antiviral activity of acyclovir SAN was limited possibly because of the weak hydrolysis of SGSA in Vero cells, and the SAN showed a little cell toxicity possible due to the amphiphilicity of SGSA. A macrophage cell line of QXMSC1 cells showed uptake of the SAN but not significantly. The SAN were rapidly removed from blood circulation after bolus iv administration to rabbits with the very short distribution t(1/2) (1.5 min) and the elimination t(1/2) (47 min). The SAN were mainly distributed in liver, spleen and lung after iv administration, and SGSA was eliminated slowly in these tissues (t(1/2), about 7 h). It would appear that the nanosized SAN were trapped by the mononuclear phagocyte system. SADDS including SAN combine prodrugs, molecular self-assembly with nanotechnology, and hopefully become novel drug delivery approaches.
International Journal of Pharmaceutics 03/2006; 309(1-2):199-207. · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The long-chain alkyl derivatives of a nucleoside analogue-acyclovir were prepared in the paper. One is stearyl-glycero-succinyl-acyclovir (SGSA) with a single 18-carbon length (C18) alkyl chain. Another is dioctadecyl-aspartate-succinyl-acyclovir (DASA) with double C18 alkyl chains. They were prepared by the esterification of succinyl-acyclovir with the lipids, and sodium salts of them were also prepared. Guanine moieties and alkyl moieties bring the derivatives intermolecular hydrogen bonding and hydrophobic interaction in water separately. The forces are influenced by the number of alkyl chains and the charged state, and determine the solubility and the self-assembly behavior of the derivatives. The double alkyl-chain derivatives (DASA and DASA-Na) formed rigid Langmuir monolayers on air/water surface, while the single alkyl chain derivatives (SGSA and SGSA-Na) did not. However, cholesterol (Chol) could assist SGSA to form rigid monolayers through inserting into the alkyl chains of SGSA to mimic the second alkyl chain. SGSA self-aggregates in water were prepared by the injection method with tetrahydrofuran as solvent. Cuboid-like shape and nanoscale size demonstrated that SGSA self-aggregates were self-assembled nanoparticles. Shape, particle size, zeta potential and phase transition of the nanoparticles were characterized. And they showed an average size of 83.2 nm, a negative surface charge of -31.3-mV zeta potential and a gel-liquid crystalline phase transition of 50.38 degrees C. The formation mechanism of self-assembled nanoparticles was analyzed. Hydrophobic interaction of alkyl chains improves SGSA molecules to form bilayers, and then cuboid-like nanoparticles were obtained by layer-by-layer aggregation based on inter-bilayers hydrogen bonding. However, the charged guanine moieties make SGSA-Na lose the function of hydrogen bonding so that SGSA-Na only forms vesicles in water based on hydrophobic interaction. Strong hydrophobicity and wide-open rigid double alkyl chains of DASA and DASA-Na restrict self-assembly in water media, and no homogeneous suspensions were obtained. Therefore, the molecular self-assembly behavior of the long-chain alkyl derivatives of nucleoside analogues on water surface or in water media is determined by the number of alkyl chains and the charged state.