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

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 

会议名称：《2012年中国药学大会暨第十二届中国药师周》

会议日期：2012年

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

关 键 词：Tumor interstitial fluid pressure Intratumoral delivery Combination therapy Imatinib Doxorubicin Sterically stabilized liposome 

摘      要：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.