Liposomes As Drug Carriers Targeting To Lymphatic Metastatic Tumors

Lymphatic metastasis is one of the main reasons that lead to the failure of treatment of malignant tumor. Drug-entrapped liposomes with proper size can be transported into lymphatic system following topical administration, which provides a rationale for precaution and therapy of primary or metastatic lymphatic tumors. However, the clinical practice of topical injection of liposome as a vehicle for drug targeting to the lymphatic system is hampered by the tissue damage mainly due to the injection site residue and normal lymph nodes accumulation of liposomal antitumor drugs. In the present study, the strategies for solving above two problems are based on the ideas of "pressure compensation" and "presaturation of macrophages".The factors that influence the lymphatic uptake of liposomes, such as particle size, surface charge and surface modification with PEG, were investigated. The pharmacokinetic profiles of liposomes at injection site, in lymph nodes and in blood were also studied. The particle size is the most important factor that influences the lymphatic uptake of liposomes. The smaller the liposomes are, the more they were taken up into the lymphatic system. As the liposome size decreased, the mean time for liposome clearance from the injection site was prolonged and the amount of liposomes accumulated in lymph nodes and circulating into blood increased. Modified with phosphatidylserine, which bears anion, the amount of liposome residues at injection site decreased. On the contrary, the cationic modification of the lipid membrane made no profit to the lymphatic uptake of liposomes.The effect of dextran or its derivative solutions to liposome stabilization were inspected. And also the possibility of enhancing lymphatic uptake of liposomes from the injection site by administering liposomes together with dextran or its derivative solutions was studied, for the reason that the solution could increase the topical osmotic pressure. The results showed that both the liposome size and drug encapsulation ratio did not change in the dextran solution with a concentration below 25%. With the strategy of pressure compensation, the injection site residue ratio of liposomes decreased from 20% to 10%.The influence of molecular weight and surface charge of dextrans on the effect ofenhancing liposome uptake was inspected, too. The lymphatic liposome uptake was enhanced with the increase of the molecular weight of dextrans. Cationic dextran (DEAE-Dx) increased liposome uptake more than anionic (CM-Dx) and neutral dextran. The pharmacokinetic studies also showed a faster clearance rate of liposomes from topical site following administration with DEAE-Dx.The influence of dxtran and its derivatives on the liposome accumulation in lymph nodes was studied by detecting the amount of liposomes in popliteal lymph nodes. The uptake of liposomes in lymph nodes could be inhibited by dextran and its derivatives. The AUC of liposomes in popliteal lymph node decreased by 73.49%, 45.48% and 9.51% respectively, when liposomes were administered together with DEAE-Dx, CM-Dx and neutral Dx. The result indicated that cationic dextran could help decrease liposome accumulation in lymph nodes.The influence of dextran and its derivatives on the in vitro macrophage uptake of liposomes was carried out with RAW264.7. The results showed that the uptake of liposomes declined while the concentration of Dx increased, which indicated that one reason for the reduction of liposome accumulation in lymph nodes after Dx was applied might be that Dx and its derivatives could inhibit the macrophage uptake of liposomes, which is one of the most important ways for liposome uptake in lymph nodes. The dissociation constant of the interaction between liposomes and macrophage cells was 1.14 and 0.34 times respectively applied with DEAE-Dx and Dx, while the dissociation constant was not affected when CM-Dx was applied. The fluorescent micrograph of Dx and macrophage cells showed that only the fluorescent intensity on cell surface boosted with the increase of Dx concentration, which indicated that the role of Dx to decrease the liposome uptake in lymph nodes might be due to the twining of the Dx molecules on the surface of macrophage cells.Doxorubicin-entrapped liposomes were prepared by film-hydration and gradient method. The formulation and the preparation techniques were optimized using single factor experiments. Lipid compositions, temperature, gradient and the inner water phase were the main factors that might influence the encapsulation ratio and drug content of liposomes. The encapsulation ratio of liposomal doxorubicin increased with accrescence of the gradient and temperature. Increasing the membrane stability could...