Biomedical Engineering, and Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
Biomaterials. 2012 Jun;33(17):4345-52. doi: 10.1016/j.biomaterials.2012.02.039. Epub 2012 Mar 17.
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.
我们根据生物物理原理设计了 pH 触发脂质膜，并以靶向脂质体多柔比星的形式进行评估，旨在最终更好地控制血管化肿瘤的生长。我们将载有阿霉素的抗 HER2/neu pH 触发脂质体与 FDA 批准的基于 DSPC/胆固醇的载多柔比星脂质体的抗 HER2/neu 形式进行比较。选择 HER2/neu 受体是因为它在人类乳腺癌中丰富，并且与低预后相关。在皮下 BT474 异种移植模型中，与靶向 DSPC/胆固醇脂质体相比，靶向 pH 触发脂质体显示出对肿瘤生长的更好控制（治疗开始后 32 天，肿瘤体积分别减少 35%和 19%）。在 HER2/neu 表达较低的 SKBR3 皮下异种移植中，也证实了更好的肿瘤控制。载有阿霉素的 pH 触发非靶向脂质体也导致更好的肿瘤控制，与非靶向 DSPC/胆固醇脂质体相比（肿瘤体积分别增加 34%和 41%）。在 BT474 多细胞球体中的研究表明，观察到的疗效可能归因于从 pH 触发脂质体中直接释放阿霉素进入酸性肿瘤间质，该脂质体外渗到肿瘤中但未被癌细胞内化。由凝胶相双层组成的 pH 触发脂质体载体在 pH 降低时可逆地相分离，形成瞬态缺陷的界面边界，导致包封的阿霉素快速释放。我们的研究表明，pH 触发脂质体可在细胞内和肿瘤内释放包封的阿霉素，并可能以相同甚至更低的给药剂量改善肿瘤控制，与 FDA 批准的脂质体化疗相比。
