| At present, cancer is one of serious diseases leading cause of death. Worldwide, cancer causes more deaths than AIDS, tuberculosis and malaria combined. It is estimated that there were more than 12 million new cancer cases in 2007 worldwide. The corresponding estimates for total cancer deaths in 2007 are 7.6 million (about 20,000 cancer deaths a day). By 2050, the global burden is expected to grow to 27 million new cancer cases and 17.5 million cancer deaths simply due to the growth and aging of the population. The National Institutes of Health estimate overall costs for cancer in 2007 at $206.3 billion: $78.2 billion for direct medical costs (total of all health expenditures); $17.9 billion for indirect morbidity costs (cost of lost productivity due to illness); and $110.2 billion for indirect mortality costs (cost of lost productivity due to premature death).However, most of anticancer agents are utilized limitedly in clinic because of the severe side effects. Liposome is one of the significant progresses in tumor treatment. Liposomal antineoplastic agents can increase therapeutic effect and reduce toxicity. They are characterized by delayed-releasing and tumor targeting. Anticancer drugs encapsulated in liposomes accumulate preferentially in solid tumors due to the leakiness of tumor microvessels and the release of the drugs from liposomes. Despite these advantages, liposomal drugs have not yet led to a significant improvement in the clinical outcome in cancer treatment. The lack of improvement is likely to be due to the low concentration of free drugs in tumor tissues, although the total concentration of drugs (i.e., free plus liposome-associated drugs) may not be low. To significantly kill tumor cells, free drugs must achieve an adequately high concentration in tumor. In general, the concentration depends on the difference between the rate of drug release from liposomes and the rate of drug clearance through the microcirculation. Thus, one can either reduce the clearance rate or increase the release rate to increase the local concentration of free drugs.Long-circulating thermosensitive liposome is a new kind of liposome. When antineoplastic are encapsulated in liposome, not only decrease the clearance of RES, but also increase the free drugs release at the tumor site. As a result the therapeutic effect is improved.Objective: In this study, we selected the platinum anticancer agent carboplatin as the model drug. The carboplatin long-circulating thermosensitive liposomes were prepared and the quality was evaluated.Content and methods: The formulation and preparation process were studied and evaluated with particle size distribution and encapsulation efficiency. The optimized formulation was scaled-up and repeated, in order to evaluate reproducibility and feasibility of industrialization. The stability of dilution and filtration were studied. The release behavior of the drug from liposomes at 42℃and the release rate at different temperature were studied in vitro. The rate of tumor inhibition was evaluated with the established Lewis lung cancer model mice by i.v. CLTL.Results: The optimal formulation of CLTL was obtained by orthogonal experiment. The encapsulation efficiency, particle size and Span of liposomes prepared by scaling-up process were above 90%, 100.93nm±2.59nm and 0.39±0.03, respectively. The stability of dilution and filtration were fine and establishing the foundation of sterilization and clinic. CLTL is very stable stored in refrigerator at 4℃. Most drugs release from the liposomes in 60 seconds at 42℃in vitro. The rate of tumor inhibition indicated that CLTL could improve treatment efficacy effectively.Conclusion: The preparation technique was stable and repeatable. The results demonstrated that CLTL is temperature-sensitive remarkably and could increase the release rate to increase the local concentration of free drugs. |
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