Pettit Marie W, Griffiths Peter, Ferruti Paolo, Richardson Simon C W
School of Science, University of Greenwich, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
Ther Deliv. 2011 Jul;2(7):907-17. doi: 10.4155/tde.11.55.
Polymer-drug and polymer-protein conjugates are emerging as a robust and well-characterized class of therapeutic entity. Although there are no low-molecular-weight soluble polymer conjugates in routine clinical use, there are many examples of routinely used high-molecular-weight drugs conjugated to soluble polymers (e.g., Oncospar). Advances in synthetic polymer chemistry have fostered the development of linear poly(amidoamine)s (PAA)s that impart both biodegradability, 'smart' (pH responsive) biological activity and biocompatibility. In their linear form, such as hyper-branched poly(amidoamine) (PAMAM) dendrimers, linear PAAs can be used to deliver large therapeutic entities such as peptides, proteins and genes to either the cytosol or nucleus. Furthermore, these polymers offer great potential in vivo due to their ability to either target the liver or be directed away from the liver and enter tumor mass via the enhanced permeability and retention (EPR) effect. PAAs also exhibit minimal toxicity (dependent upon backbone chemistry), relative to well-characterized polymers used for gene delivery. The propensity of PAAs to modulate intracellular trafficking resulting in their cytosolic translocation has also recently been quantified in vivo and is the primary focus of this article.
聚合物-药物和聚合物-蛋白质偶联物正成为一类强大且特性明确的治疗实体。虽然目前常规临床使用中没有低分子量的可溶性聚合物偶联物，但有许多将常用高分子量药物与可溶性聚合物偶联的例子（例如，癌得星）。合成聚合物化学的进展推动了线性聚（酰胺胺）（PAA）的发展，这类聚合物兼具生物可降解性、“智能”（pH响应）生物活性和生物相容性。以线性形式存在时，如超支化聚（酰胺胺）（PAMAM）树枝状大分子，线性PAA可用于将诸如肽、蛋白质和基因等大型治疗实体递送至胞质溶胶或细胞核。此外，这些聚合物在体内具有巨大潜力，因为它们能够靶向肝脏或通过增强渗透和滞留（EPR）效应被导向远离肝脏并进入肿瘤组织。相对于用于基因递送的特性明确的聚合物，PAA的毒性也极小（取决于主链化学结构）。PAA调节细胞内运输从而导致其胞质易位的倾向最近也已在体内进行了量化，这也是本文的主要关注点。
