| Self-assembly drug delivery systems (SADDS) are the micelle-or vesicle-like and highly dispersedaggregates prepared from amphiphilic drugs or prodrugs through self-assembling in aqueous media． Theadvantages of SADDS include high drug loading, no drug leakage, good stability, high targeting, andcontrolled release．Zidovudine (AZT), an anti-HIV nucleoside analogue, was selected as the model drug in thisstudy．5′-cholesteryl-phosphoryl zidovudine (CPZ) was obtained by the lipophilic derivation of AZT, andCPZ pharmacosomes were prepared． And both internal and external feature of CPZ pharmacosomes wereassessed． The primary details included:1． Synthetize and properties of5′-cholesteryl-phosphoryl zidovudineThe synthetic route of CPZ was devised and prepared, and its structure was identified． And thesolubility of CPZ in different solvents and the traits of Langmuir monolayer were estimated． Thelipophilicity of the prodrug CPZ increased greatly in comparison with AZT, and this hydrophobic effectbecomes the pivotal role which affect the dissolvability of CPZ． Moreover, CPZ can formed the stablemonolayer at the water/air interface as a typical amphipathic prodrug．2． Preparation and characteristics of CPZ SADDSCPZ SADDS were synthetized by Vortex injection method with Tetrahydrofuran (THF) as solventand ultrapure water as dispersed medium, which visualize as uniform atomization appearance． And Theshape, Zeta potential and partical size of CPZ SADDS were determined by transmission electronmicroscopy(TEM) and laser granulometry． The Result Indicates that CPZ SADDS take on the uniformsize of spherical vesicles structure, with130nm of mean grain size,-35．4mV of Zeta potential andexcellent stability．3． The Stabilization of the physics of CPZ SADDSThe Stabilization of the physics of CPZ SADDS involve under various situations, such as hightemperature and high pressure, centrifugal sedimentation and so on． The Study revealed that high temperature and high pressure and centrifugal sedimentation and have no influence on the configuration ofCPZ SADDS． Even after long-term storage at room temperature, CPZ SADDS can still remain stable,only with a little precipitate separate out at the bottom, but recover to the original state once shake up．4． Chemical Durability of CPZ SADDSThe Chemical Durability of CPZ SADDS refer to under different conditions, for instance, different pHof buffer, mice various organizations of the homogenate, and animal plasma． The results display, thestability of CPZ SADDS were bad and degraded fast under acidic buffer, such as pH1．0and pH2．0, withthe half-time(t1/2)18．78h and50．2h respectively． While under pH5．0and pH7．4, CPZ SADDS revealrelatively stable, with the t1/2117．5h and154．0h respectively． While under pH9．0and pH12．0, CPZSADDS show stable, with t1/2866．3h and1155．0h separately． CPZ SADDS degraded slower in theplasma of rat and monkey, with t1/2256．7h and364．7h． CPZ SADDS degraded quickly in mouse livertissue homogenate, with t1/21．5h． However, it was slower in spleen and lung homogenates of mice, whichwere6．0h and24．7h, respectively．5． Pharmacokinetics and tissue distribution of CPZ SADDSThe CPZ SADDS possess distinct mononuclear phagocyte targeting, so they distribute fast tomacrophage-rich tissues and organs (such as Lung, liver and spleen．) after i．v． administration of singlebolus to mormal KM mice, with scatter t1/2α6．2min and removal t1/2β178．8min discretely．6． Extrinsic pharmacodynatics of CPZ SADDSThe study revealed that CPZ SADDS exert better antiviral activity than the positive control ofAZT． The anti-HIV activity of CPZ SADDS was evaluated on the MT4cell line infected by HIV． Thehalf effective concentrations (EC50) of CPZ self-assemblies and zidovudine were0．5and5n mol/lrespectively when HIV, cells and CPZ were added simultaneously． However, it was0．1and5n mol/l ifCPZ self-assemblies was added one hour in advance．In this paper, CPZ SADDS were synthetized, and it was clarified that hydrogen bond and hydrophobiceffect prompt CPZ to form nanoscale, stable and sequential construction． CPZ SADDS targeted to andwere uptaked by monocyte macrophage quickly in mice． It demonstrated good inhibition effect on HIV in vitro．... |
PDF Full Text Request