The Investigation Of Slow-release PLGA-Gemcitabine Microsphere In Treatmentment Of Pancreatic Cancer

Object To study the acute toxicity and pharmacokinetics of slow-release PLGAGemcitabine microsphere and its antitumor effect on xenograft pancreatic tumor ir mice.Method Acute toxicity study: slow-release Gemcitabine was injected subcutaneously to healthy nude mice or to the tumor tissue of tumor bearing nude mice respectively. Up and down procedure was used to determine the LD₅₀. Pharmacokinetical study: tumor-bearing nude mice were randomly divided into two groups, receiving interstitial chemotherapy and systematic chemotherapy respectively. The half time(t_1/2), area under the curve(AUC) and peak concentration(T_max) were determined. Drug effect study: 80 tumor-bearing nude mice were randomly divided into eight groups for different treatments. Group A1: intratumor injection ot PLGA-Gemcitabine microsphere, 5mg/kg; Group A2: intratumor injection ot PLGA-Gemcitabine microsphere, 2.5mg/kg; Group A3: intratumor injection ot PLGA-Gemcitabine microsphere, 1.25mg/kg; Group B: intratumor injection of gemcitabine, 5 mg/kg; Group C: intraperitonium injection of gemcitabine, 5mg/kg; Group D, intratumor injection of PLGA-5-Fu microsphere, 5mg/kg; Group E: intratumor injection of PLGA, 5 mg/kg; Group F: control. On the days of 0, 4, 8, 12, 16, 20, 24 after the drug injection, health condition and the size of the tumor were observed. At the end of the experiment, the weight of the tumor was monitered, the tumor expression of VEGF was measured in A1, A2, A3 and control group.Results: Acute toxicity study of slow-release PLGA-Gemcitabine microsphere: the LD₅₀ of slow-release PLGA-Gemcitabine microsphere on healthy nude mice and tumor bearing nude mice are 256.30mg/Kg and 8.91mg/Kg respectively. Pharmacokinetic study: Interstitial chemotherapy has longer half time, larger area under the curve, higher peak concentration compared with systematic chemotherapy. There were statistical differences of these three pharmacokinetic parameters between the two groups. Drug effect study: the group received PLGA-Gemcitabine microsphere could effectively restrain the tumor compared with other groups, furthermore, the antitumor effects was dose dependent. During the period of treatment no side effects were observed.Conclusion Since the mice could not tolerant a high dose of slow-release PLGA-Gemcitabine microsphere, the dose of slow-release PLGA-Gemcitabine microsphere should be reduced in clinical practice. Interstitial chemotherapy could prolong the regional active time and improve the regional concentration of chemotherapeutic drugs. Interstitial chemotherapy can effectively reduce the expression of VEGF and restrain the growth of the tumor.