Simões Sérgio, Moreira João Nuno, Fonseca Cristina, Düzgüneş Nejat, de Lima Maria C Pedroso
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
Adv Drug Deliv Rev. 2004 Apr 23;56(7):947-65. doi: 10.1016/j.addr.2003.10.038.
Strategies used to enhance liposome-mediated drug delivery in vivo include the enhancement of stability and circulation time in the bloodstream, targeting to specific tissues or cells, and facilitation of intracytoplasmic delivery. pH-sensitive liposomes have been developed to mediate the introduction of highly hydrophilic molecules or macromolecules into the cytoplasm. These liposomes destabilize under acidic conditions found in the endocytotic pathway, and usually contain phosphatidylethanolamine (PE) and titratable stabilizing amphiphiles. Formulations without PE have also been developed. Encapsulated compounds are thought to be transported into the cytoplasm through destabilization of or fusion with the endosome membrane. Incorporation of a low mole percentage of poly(ethylene glycol) (PEG)-conjugated lipids into pH-sensitive liposomes confers prolonged circulation times to these liposomes, which are otherwise cleared rapidly. While the incorporation of PEG-lipids reduces the pH-dependent release of encapsulated fluorescent markers in vitro, it does not hinder the cytoplasmic delivery of the markers per cell-associated liposome. This suggests that intracellular delivery is not dictated simply by the destabilization of the liposomes. Antibodies or ligands to cell surface receptors can be coupled to pH-sensitive or sterically stabilized pH-sensitive liposomes for targeting. pH-sensitive liposomes have been used to deliver anticancer drugs, antibiotics, antisense oligonucleotides, ribozymes, plasmids, proteins and peptides to cells in culture or in vivo.
用于增强脂质体介导的体内药物递送的策略包括提高其在血流中的稳定性和循环时间、靶向特定组织或细胞以及促进胞质内递送。已开发出pH敏感脂质体来介导将高度亲水的分子或大分子引入细胞质。这些脂质体在胞吞途径中的酸性条件下会不稳定，通常含有磷脂酰乙醇胺（PE）和可滴定的稳定两亲物。也已开发出不含PE的制剂。据认为，被包裹的化合物通过内体膜的不稳定或与之融合而被转运到细胞质中。将低摩尔百分比的聚乙二醇（PEG）共轭脂质掺入pH敏感脂质体可使这些脂质体的循环时间延长，否则它们会很快被清除。虽然掺入PEG脂质会降低体外包裹的荧光标记物的pH依赖性释放，但它并不妨碍每个与细胞相关的脂质体将标记物递送至细胞质。这表明细胞内递送并非简单地由脂质体的不稳定所决定。可将细胞表面受体的抗体或配体偶联到pH敏感或空间稳定的pH敏感脂质体上以实现靶向。pH敏感脂质体已被用于将抗癌药物、抗生素、反义寡核苷酸、核酶、质粒、蛋白质和肽递送至培养的细胞或体内的细胞。
