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The reduction of tumor interstitial fluid pressure by liposomal imatinib to improve the intratumor delivery of liposomal doxorubicin and their combination therapy

The reduction of tumor interstitial fluid pressure by liposo...

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2012年中国药学大会暨第十二届中国药师周

作者： Yuchen Fan a,b,Wenwen Du a,b,Bing He a,b,Fengying Fu c,Lan Yuan d,Hounan Wu d,Wengbing Dai b,Hua Zhang b,Xueqing Wang b,Jiancheng Wang b,Xuan Zhang b,Qiang Zhang a,b, a State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China b Department of Pharmaceutics,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China c Department of Physiology and Pathophysiology,Peking University Health Science Center,Beijing 100191,China d Medical and Healthy Analytical Center,Peking University,Beijing 100191,China

interstitial fluid pressure （IFP） in tumor is much higher than that in normal tissue and appears a great obstacle for the delivery of chemodrugs,which makes it a potential target for cancer *** this study,imatinib,a molecular targeting drug,was loaded in sterically stabilized liposomes （SSL-IMA） to reduce tumor IFP,in an attempt to deliver more liposomal doxorubicin （SSL-DOX） into tumor *** a mouse B16 melanoma model,intravenous injection of 20 mg/kg SSL-IMA achieved the most reduction of tumor IFP lasting for at least 50 hours with the least hematotoxicity,whereas intragastric administration of 100 mg/kg free IMA did not decrease tumor IFP *** mechanisms of IFP reduction in tumor by SSL-IMA were proved to be related with the inhibition of PDGF receptor beta,the inhibition of tumor fibroblasts as well as the anti-angiogenesis effect of *** it was demonstrated by in vivo imaging that the decrease of tumor IFP by SSL-IMA led to a more and longer intra-tumor distribution of the lipid *** improved delivery was proved again in the anti-tumor *** 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 antitumor *** no synergy was found between SSL-IMA and SSL-DOX,it was clear that the improved combination therapy was basically due to the decrease of tumor IFP by *** conclusion,reducing tumor IFP by SSL-IMA seems to be a promising strategy to potentiate chemotherapies.

关键词： tumor interstitial fluid pressure Intratumoral delivery Combination therapy Imatinib Doxorubicin Sterically stabilized liposome

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