| Objective: Adriamycin (ADR) is a broad spectrum anthracycline antineoplastic agent that is extensively used to treat patients with hepatocellular carcinoma (HCC) and lymphomas. The drug can produced widely biological effects with its cytotoxicity. Unfortunately, intravenous adminis- tration (i.v.) of high-dose ADR is often associated with serious side-effects, such as myelosuppression, immunosup- pression, and dose-cumulative cardiotoxicity. These drawbacks have limited the clinical application of ADR for a long time. As a result, a promising approach to increase the efficacy and to lower side-effects of antineoplastic drugs is their binding to drug delivery systems such as nanopar- ticles, liposomes, and polymeric micelles.Since liposomes has been successful development and approved on 1990s, more researchers at home and abroad began to pay a high value on nanoparticles. Many studies showed that nanoparticles is a promising system for the targeting and controlling release of anticancer drugs. Obviously, binding ADR to HSA nanoparticles is a reasonable approach since it allows the drug concentration to be increased at the desired site. It can also prolong the drug release and lower its cardiotoxicity by intravenous injection.Method: The preparative method of the HSA nanoparticles was determined by preliminary experiments. Adopting the single factor tests were practiced for the identification of factors affecting adriamycin-loaded HSA nanoparticles. And then four factors and three levels orthogonal design was employed to select the optimal prescription and preparation technology, taking nanoparticle size and size distribution, drug loading and the entrapment efficiency of nanoparticles as indexes. For the colloid solution of nanoparticle is an unstable system, the particles in solution will concentrate together and a part of drugs will seep out after a long time store. So freeze drying technology is necessary to apply to elevate its stability.Using the scanning electron microscope, the shape and surface of the nanoparticles were observed. The particle size distribution was measures by particle size analyzer.Drug release from adriamycin-loaded HSA nanopar- ticles was evaluated by means of a dynamic dialysis technique. And the release data were analyzed with traditional models to study the release mechanism.The stability test:the freeze drying adriamycin HSA nanoparticles were stored at 4℃, then the permanent stability was investigated by determination of its appearance,redispersibility and envelopment rate at different times.Pharmacokinetics study in vivo:The acute toxicity test carried out using animal model of mice. Mice were grouped randomly and administered different dosages of adriamycin solutions and adriamycin-loaded HSA nanoparticles by intravenous injection, and then comparing their toxicity by observing the dead rate of each group and their LD50.SD rats were used for the study of pharmacokinetics and body distribution. After the administration of adriamycin solution and nanoparticles, a RP-HPLC method with ultraviolet detection was developed for the determination of adriamycin in rat plasma and tissues at different times. The pharmacokinetic parameters were calculated by 3p87 program. The body distribution of rats was investigated to evaluate targeting of adriamycin-loaded nanoparticles.Result: On the basis of preliminary experiments,the HSA nanoparticles was prepared by a desolvation technique. The optimal formulation and process were defined from the orthogonal experiment. The nanoparticles are globular, with a smooth surface and narrow size distribution at 200-400 nm.The accumulative release behavior of adriamycin- loaded nanoparticles in vitro was in accord with Weibull equation and the correlation coefficient were as follows: ln[-ln(1-Q)]=0.3275lnt-3.0779, r=0.9918. The release curve indicates that there is no burst release on the nanoparticles.The result of stability study displays that the freeze drying nanoparticles have a good stability at 4℃and with a condition of air tight.Pharmacokinetics study in vivo:The result of acute toxicity test showed that the LD50 of nanoparticles is 27.81 mg/kg compared of 10.48 mg/kg of free drug. Pharmaco- kinetic behavior of adriamycin solution and nanoparticles were conformed to three compartment model. Pharmacokinetic characteristic of adriamycin-loaded HSA nanoparticles in rats displayed a sustained-release of adriamycin can be achived by loading it into nanoparticle system. Body distribution of adriamycin in tissues shows that nanoparticles has the ability to passively accumulate in target tissues such as liver. At the same time, a great decrease can be seen in heart by the administration of nanoparticles, which comes to a purpose of lowering the cardiotoxicity of adriamycin.Conclusions: Nanoparticles prepared by desolvation and subsequent cross linking of human serum albumin (HSA) represent promising carriers for drug delivery. Particle size is a crucial parameter, in particular for the in vivo behavior of nanoparticles after intravenous injection. The data can be useful for the further study of nanoparticles loading of anticancer drugs.
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