| Nowadays, gastric carcinoma is one of the most common malignant tumors of alimentary tract that harm people severely. At present, operative resection is the major therapeutic method of the gastric carcinoma, but the five-year survival rate was very low after operation. Because of the lack of special clinical manifestations, biochemical and immune monitoring marks, most patients are in the middle or late period of the tumor before it is definitely diagnosed, losing the best opportunity to be operated. Among nonoperative therapeutic methods, systemic chemotherapy is often used, but the effect is poor and the toxicity to the body is serious. Recently, the development of activated carbon particles adsorbing mitomycin C (MMC) offers a new method to treat the advanced gastric carcinoma, which has achieved much better therapeutic effect. This method possesses a good prospect in clinical use because of the advantages of active carbon nanoparticles, such as its high adsorption and desorption of MMC, lymphatic targeting property, high selectivity, low toxicity, and so on.ACNP were prepared in our lab. The diameter and morphology of ACNP were studied by atomic force microscopy and transmission electron microscopy. The results showed that the average diameter of ACNP was 299±187 nm. Mostof ACNP were nearly round and its surface was smooth. Animal experiment proved that the toxicity and local irritating effect of ACNP were lower than that of activated carbon micro- particles (ACMP).There was no any inflammation and tissue conglutination in the abdomen of mice after ACNP were injected and existed in the peritoneal cavity for three months. As a standard dose drug delivery formulation, ACNP can be easy used in clinic with no contamination and can well standardize clinical use and avoid the side effects caused by the irregularities and the larger particle diameter of ACMP.The purpose of the chemotherapy with ACNP adsorbing MMC was to change the distributing of MMC in body and the characteristics of pharmaco-kinetics. ACNP- MMC can enhance anticancer efficacy and reduce the toxicity of MMC to the body. But the detailed pharmacokinetics data of intraperitoneal chemotherapy with ACNP-MMC has not been obtained up to now. Doctors haven' t enough patients and it is not possible that the human tissues is used as experimental examples.Comparative pharmacokinetics of free MMC and ACNP-MMC in rat blood and the distribution in rat tissues were conducted using high performance liquid chromatography (HPLC) after MMC and MMC-ACNP were injected in the peritoneal cavity to afford theoretical evidences for the clinical use of ACNP-MMC as a new neoplasm and lymph system targeting dosage formulation. At the same time, the in vivo behavior, distribution, migration and excretion of ACNP, the drug delivery carrier, are studied with pathological light and electron microscopic methods.The results show ACNP-MMC has perfect pharmacokinetics properties include short-time low plasma drug concentration and high drug concentration in intra-abdominal tissues. This can reinforce the effect of the anticancer drug and reduce the toxicity to system.The concentration-time profile in blood of rats was best fitted to one-compartment model with first order absorption after three dosage (2mg/kg^ 4mg/kg, 8mg/kg) of MMC and ACNP-MMC, the main pharmacokinetics (PK) parameters of free MMC were: tl/2 were 15.157,17.146 and 15. 697min, the I?,, of the three dosages were 10 min all the same, Cmax were 0.068,0.303 and 0.429 mg/1, AUC were 2.561, 10.817 and 17.276 mg/L ? min. The main PK parameters of ACNP-MMC were: tl/2 were 11. 845, 48. 336 and 27. 081 min, Tmax were 10. 00, 20. 00 and 20. 00 min, Cmax were 0. 050, 0. 047? 0. 090mg/l, AUC were 1. 476, 3. 321 and 0. 238 mg/L ? min.MMC 4mg/kg IP distributed rapidly to intra-abdominal organs after administration and reached Cmax in 10 min. The peritoneum and great epiploon showed much higher concentration. There should be no space between punctuation mark and the word before it with exception of parenthesis. There are plenty of such kind mistakes. Correct all of them. Lymph node of intestine, diaphragm, liver and stomach followed in turn. The concentration in tissues decreased to very low level within 2 hour after administration. ACNP-MMC, like the situation of MMC, reached Cmax rapidly in abdominal tissues in 2 hour after ip, but the concentration could be kept at high level until 48 hour. All of the data were statistically calculated by SAS software and analyzed with a two-factor analysis of variance between groups. The difference between the MMC group and ACNP-MMC group and between the corresponding intra-abdominal organs were statistically.significant(p<0.001). The peritoneum, great epiploon and diaphragm show much higher MMC concentration. These tissues were the sites activated carbon particles can reach easily as well as tumour cells. All these results showed ACNP-MMC to be a new kind of lymph system- and neoplasm- targeting dosage formulation, which has advantages over other formulations, such as high concentration in and high selectivity for the intra-abdominal tissuesand low toxicity to system.The results of pharmacokinetics show high drug concentration in intra-abdominal tissues can be kept more than 48 hour. At the same time, the drug concentration in blood was very low or even not to be detectable. The Cmax of MMC in blood in the high dosage group of ACNP-MMC was not higher than 100u g/L, lower than the plasma levels of 400p g/L, which is the inhibitory concentration to marrow. The drug concentration in blood of the high dosage group of MMC was higher than fore-mentioned toxicological concentration. The MMC concentration in the great epiploon and lymph node of intestine in group of MMC decreased to very low level within 2 hour after administration. At 2 hour, the MMC concentration in the same tissues in group of ACNP-MMC was 4-100 times of that in MMC group. Its anticancer effect can persist more than 48 hour. The characteristics of ACNP-MMC pharmacokinetics show the advantages, such as high concentration, high selectivity, better chemotherapy and low toxicity, over other methods.Experiments with ACNP intraperitoneal administration show that ACNP have obvious lymph-tissue-targeting effects. The lymph-targeting effect is obtained by the diameter of ACNP. ACNP and tumor cells can be sequestered in the same sites, which shows the advantages of targeting intraperitoneal chemotherapy with ACNP-MMC. Anatomic and pathological examinations of the mice showed no exudation, edema, organization and encapsulaton in peritoneal tissues and internal organs. There were no inflammation and conglutination in peritoneal cavity. These results showed that ACNP have good compliance with animal tissues and low toxicity to system as a drug carrier.The experiments with intravenous carbon nanoparticles (CNP) including ACNP showed that they can be excreted by some ways, such as biliary canal, urinary duct and the goblet cells in intestinal epithelium. It is the first... |
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