Antitumor efficacy following the intracellular and interstitial release of liposomal doxorubicin
- 作者：Amey Bandekar ; Shrirang Karve ; Min-Yuan Chang ; Qingshan Mu ; Jimmy Rotolo ; Stavroula Sofou ; ss1763@rci.rutgers.edu
- 关键词：pH-triggered liposomes ; Targeted liposomal chemotherapy ; Doxorubicin ; Anti-HER2/neutargeting
- 刊名：Biomaterials
- 出版年：2012
- 期刊代码：7_01429612
- 类别：ms
- 出版时间：June, 2012
- 卷：33
- 期：17
- 页码：4345-4352
- 文件大小：626 K
摘要
pH-triggered lipid-membranes designed from biophysical principles are evaluated in the form of targeted liposomal doxorubicin with the aim to ultimately better control the growth of vascularized tumors. We compare the antitumor efficacy of anti-HER2/neu pH-triggered lipid vesicles encapsulating doxorubicin to the anti-HER2/neu form of an FDA approved liposomal doxorubicin of DSPC/cholesterol-based vesicles. The HER2/neu receptor is chosen due to its abundance in human breast cancers and its connection to low prognosis. On a subcutaneous murine BT474 xenograft model, superior control of tumor growth is demonstrated by targeted pH-triggered vesicles relative to targeted DSPC/cholesterol-based vesicles (35%vs. 19%decrease in tumor volume after 32 days upon initiation of treatment). Superior tumor control is also confirmed on SKBR3 subcutaneous xenografts of lower HER2/neu expression. The non-targeted form of pH-triggered vesicles encapsulating doxorubicin results also in better tumor control relative to the non-targeted DSPC/cholesterol-based vesicles (34%vs. 41%increase in tumor volume). Studies in BT474 multicellular spheroids suggest that the observed efficacy could be attributed to release of doxorubicin directly into the acidic tumor interstitium from pH-triggered vesicles extravasated into the tumor but not internalized by cancer cells. pH-triggered liposome carriers engineered from gel-phase bilayers that reversibly phase-separate with lowering pH, form transiently defective interfacial boundaries resulting in fast release of encapsulated doxorubicin. Our studies show that pH-triggered liposomes release encapsulated doxorubicin intracellularly and intratumorally, and may improve tumor control at the same or even lower administered doses relative to FDA approved liposomal chemotherapy.