Department of Biomedical Engineering and Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
Mol Pharm. 2013 Jan 7;10(1):152-60. doi: 10.1021/mp3002717. Epub 2012 Dec 18.
We investigated the feasibility and efficacy of a drug delivery strategy to vascularized cancer that combines targeting selectivity with high uptake by targeted cells and high bioexposure of cells to delivered chemotherapeutics. Targeted lipid vesicles composed of pH responsive membranes were designed to reversibly form phase-separated lipid domains, which are utilized to tune the vesicle's apparent functionality and permeability. During circulation, vesicles mask functional ligands and stably retain their contents. Upon extravasation in the tumor interstitium, ligand-labeled lipids become unmasked and segregated within lipid domains triggering targeting to cancer cells followed by internalization. In the acidic endosome, vesicles burst release the encapsulated therapeutics through leaky boundaries around the phase-separated lipid domains. The pH tunable vesicles contain doxorubicin and are labeled with an anti-HER2 peptide. In vitro, anti-HER2 pH tunable vesicles release doxorubicin in a pH dependent manner, and exhibit 233% increase in binding to HER2-overexpressing BT474 breast cancer cells with lowering pH from 7.4 to 6.5 followed by significant (50%) internalization. In subcutaneous BT474 xenografts in nude mice, targeted pH tunable vesicles decrease tumor volumes by 159% relative to nontargeted vesicles, and they also exhibit better tumor control by 11% relative to targeted vesicles without an unmasking property. These results suggest the potential of pH tunable vesicles to ultimately control tumor growth at relatively lower administered doses.
我们研究了一种将靶向选择性与靶向细胞的高摄取率以及细胞对递送至的化学疗法的高生物暴露相结合的血管化癌症药物输送策略的可行性和疗效。设计了由 pH 响应膜组成的靶向脂质体，以可逆地形成相分离的脂质域，从而调整囊泡的表观功能和渗透性。在循环过程中，囊泡掩盖功能性配体并稳定地保留其内容物。在肿瘤间质中渗出后，配体标记的脂质会被暴露并在脂质域内分离，从而触发对癌细胞的靶向作用，随后发生内化。在酸性内涵体中，囊泡通过相分离的脂质域周围的渗漏边界爆裂释放包封的治疗剂。pH 可调脂质体包含多柔比星并标记有抗 HER2 肽。在体外，抗 HER2 pH 可调脂质体以 pH 依赖性方式释放多柔比星，并且在 pH 从 7.4 降低至 6.5 时，与 HER2 过表达的 BT474 乳腺癌细胞的结合增加 233%，随后显著（50%）内化。在裸鼠的皮下 BT474 异种移植瘤中，与非靶向脂质体相比，靶向 pH 可调脂质体使肿瘤体积减小 159%，与没有去掩蔽特性的靶向脂质体相比，肿瘤控制也更好，减少了 11%。这些结果表明 pH 可调脂质体有可能在相对较低的给药剂量下最终控制肿瘤生长。
