Berg Kristian, Folini Marco, Prasmickaite Lina, Selbo Pål Kristian, Bonsted Anette, Engesaeter Birgit Ø, Zaffaroni Nadia, Weyergang Anette, Dietze Andreas, Maelandsmo Gunhild M, Wagner Ernst, Norum Ole-Jacob, Høgset Anders
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway.
Curr Pharm Biotechnol. 2007 Dec;8(6):362-72. doi: 10.2174/138920107783018354.
The utilisation of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In many cases the targets of macromolecular therapeutics are intracellular. However, degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. Photochemical internalisation (PCI) is a novel technology for the release of endocytosed macromolecules into the cytosol. The technology is based on the activation by light of photosensitizers located in endocytic vesicles to induce the release of macromolecules from the endocytic vesicles. Thereby, endocytosed molecules can be released to reach their target of action before being degraded in lysosomes. PCI has been shown to stimulate intracellular delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), DNA delivered as gene-encoding plasmids or by means of adenovirus or adeno-associated virus, peptide nucleic acids (PNAs) and chemotherapeutic agents such as bleomycin and in some cases doxorubicin. PCI of PNA may be of particular importance due to the low therapeutic efficacy of PNA in the absence of an efficient delivery technology and the 10-100-fold increased efficacy in combination with PCI. The efficacy and specificity of PCI of macromolecular therapeutics has been improved by combining the macromolecules with targeting moieties, such as the epidermal growth factor. In general, PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that it may have a variety of useful applications for site-specific drug delivery as for example in gene therapy, vaccination and cancer treatment.
大分子在癌症及其他疾病治疗中的应用正变得越来越重要。分子生物学和生物技术的最新进展使得改进细胞毒性药物、DNA复合物及其他大分子的靶向性和设计以用于临床应用成为可能。在许多情况下，大分子疗法的靶点是细胞内的。然而，大分子通过内吞作用被摄取后在内吞小泡中的降解是具有细胞内作用靶点的大分子治疗应用的一个主要细胞内障碍。光化学内化（PCI）是一种将内吞的大分子释放到细胞质中的新技术。该技术基于内吞小泡中光敏剂受光激活以诱导大分子从内吞小泡中释放。由此，内吞的分子可以在溶酶体中降解之前被释放以到达其作用靶点。PCI已被证明能刺激多种不易穿透质膜的大分子及其他分子的细胞内递送，包括I型核糖体失活蛋白（RIPs）、作为基因编码质粒或以腺病毒或腺相关病毒方式递送的DNA、肽核酸（PNA）以及化疗药物如博来霉素，在某些情况下还有阿霉素。由于在缺乏有效递送技术时PNA的治疗效果较低，而与PCI联合使用时疗效可提高10至100倍，因此PNA的PCI可能尤为重要。通过将大分子与靶向部分（如表皮生长因子）结合，提高了大分子疗法PCI的疗效和特异性。一般来说，PCI能诱导大分子有效地光导向递送至细胞质，这表明它在基因治疗、疫苗接种和癌症治疗等位点特异性药物递送方面可能有多种有用的应用。
