Rezler Evonne M, Khan David R, Lauer-Fields Janelle, Cudic Mare, Baronas-Lowell Diane, Fields Gregg B
Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431, USA.
J Am Chem Soc. 2007 Apr 25;129(16):4961-72. doi: 10.1021/ja066929m. Epub 2007 Mar 31.
Nanotechnology-based drug delivery systems (nanoDDSs) have seen recent popularity due to their favorable physical, chemical, and biological properties, and great efforts have been made to target nanoDDSs to specific cellular receptors. CD44/chondroitin sulfate proteoglycan (CSPG) is among the receptors overexpressed in metastatic melanoma, and the sequence to which it binds within the type IV collagen triple-helix has been identified. A triple-helical "peptide-amphiphile" (alpha1(IV)1263-1277 PA), which binds CD44/CSPG, has been constructed and incorporated into liposomes of differing lipid compositions. Liposomes containing distearoyl phosphatidylcholine (DSPC) as the major bilayer component, in combination with distearoyl phosphatidylglycerol (DSPG) and cholesterol, were more stable than analogous liposomes containing dipalmitoyl phosphatidylcholine (DPPC) instead of DSPC. When dilauroyl phosphatidylcholine (DLPC):DSPG:cholesterol liposomes were prepared, monotectic behavior was observed. The presence of the alpha1(IV)1263-1277 PA conferred greater stability to the DPPC liposomal systems and did not affect the stability of the DSPC liposomes. A positive correlation was observed for cellular fluorophore delivery by the alpha1(IV)1263-1277 PA liposomes and CD44/CSPG receptor content in metastatic melanoma and fibroblast cell lines. Conversely, nontargeted liposomes delivered minimal fluorophore to these cells regardless of the CD44/CSPG receptor content. When metastatic melanoma cells and fibroblasts were treated with exogeneous alpha1(IV)1263-1277, prior to incubation with alpha1(IV)1263-1277 PA liposomes, to potentially disrupt receptor/liposome interactions, a dose-dependent decrease in the amount of fluorophore delivered was observed. Overall, our results suggest that PA-targeted liposomes can be constructed and rationally fine-tuned for drug delivery applications based on lipid composition. The selectivity of alpha1(IV)1263-1277 PA liposomes for CD44/CSPG-containing cells represents a targeted-nanoDDS with potential for further development and application.
基于纳米技术的药物递送系统（nanoDDSs）因其良好的物理、化学和生物学特性，近年来受到广泛关注，人们为使nanoDDSs靶向特定细胞受体付出了巨大努力。CD44/硫酸软骨素蛋白聚糖（CSPG）是转移性黑色素瘤中过表达的受体之一，其在IV型胶原三螺旋内的结合序列已被确定。一种与CD44/CSPG结合的三螺旋“肽两亲分子”（α1(IV)1263 - 1277 PA）已被构建，并被整合到不同脂质组成的脂质体中。以二硬脂酰磷脂酰胆碱（DSPC）作为主要双层成分，与二硬脂酰磷脂酰甘油（DSPG）和胆固醇结合的脂质体，比含有二棕榈酰磷脂酰胆碱（DPPC）而非DSPC的类似脂质体更稳定。当制备二月桂酰磷脂酰胆碱（DLPC）:DSPG:胆固醇脂质体时，观察到了偏晶行为。α1(IV)1263 - 1277 PA的存在赋予了DPPC脂质体系统更高的稳定性，且不影响DSPC脂质体的稳定性。观察到α1(IV)1263 - 1277 PA脂质体在转移性黑色素瘤和成纤维细胞系中进行细胞荧光团递送与CD44/CSPG受体含量之间存在正相关。相反，无论CD44/CSPG受体含量如何，非靶向脂质体向这些细胞递送的荧光团极少。当在与α1(IV)1263 - 1277 PA脂质体孵育之前，用外源性α1(IV)1263 - 1277处理转移性黑色素瘤细胞和成纤维细胞，以潜在地破坏受体/脂质体相互作用时，观察到递送的荧光团量呈剂量依赖性下降。总体而言，我们的结果表明，可以基于脂质组成构建并合理微调PA靶向脂质体用于药物递送应用。α1(IV)1263 - 1277 PA脂质体对含CD44/CSPG细胞的选择性代表了一种具有进一步开发和应用潜力的靶向nanoDDS。
