title: The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin.
abstract: Interstitial fluid pressure (IFP) in tumor is much higher than that in normal tissue and it constitutes a great obstacle for the delivery of chemodrugs, which makes it a potential target for cancer therapy. In this study, imatinib, a molecular targeting drug, was loaded in sterically stabilized liposomes (SSL-IMA) to reduce the tumor IFP, in an attempt to deliver more liposomal doxorubicin (SSL-DOX) into tumor tissue. In a mouse B16 melanoma model, intravenous injection of 20 mg/kg SSL-IMA achieved the most reduction of tumor IFP and the effect lasted for at least 50 h with the least hematotoxicity. However, intragastric administration of 100 mg/kg free IMA did not decrease the tumor IFP significantly. Mechanisms of the reduction of tumor IFP by SSL-IMA were proved to be the inhibition of PDGF receptor beta, the inhibition of tumor fibroblasts as well as the anti-angiogenesis effect of SSL-IMA. Then it was demonstrated by in vivo imaging that the decrease of tumor IFP by SSL-IMA led to a more and longer intratumoral distribution of the lipid vehicles. The improved delivery was proved again in the anti-tumor study. The combination of SSL-IMA and SSL-DOX inhibited tumor growth and induced apoptosis of tumor cells the most, at a low dose in which neither SSL-DOX nor SSL-IMA showed obvious anti-tumor efficacy. Since no synergy against B16 cells was found between SSL-IMA and SSL-DOX, it was clear that the improved combinational therapy was basically due to the decrease of tumor IFP by SSL-IMA. In conclusion, reducing tumor IFP by SSL-IMA seems to be a promising strategy to potentiate chemotherapies.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Fan
authors.forename: Wenwen
authors.initials: W
authors.lastname: Du
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Fengying
authors.initials: F
authors.lastname: Fu
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.forename: Hounan
authors.initials: H
authors.lastname: Wu
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D045604:Extracellular Fluid / Q000187:drug effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008081:Liposomes / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta