Biocatalysis and Organic Chemistry, Department of Biotechnology, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands.
Bioorg Med Chem. 2011 Feb 1;19(3):1123-30. doi: 10.1016/j.bmc.2010.06.036. Epub 2010 Jun 18.
Liposomes, capable of temperature-triggered content release at the site of interest, can be of great importance for imaging and therapy of tumors. The delivery of imaging agents or therapeutics can be improved by application of liposomes with a gel-to-liquid phase-transition temperature suitable for mild hyperthermia (41-43°C), and by prolonging their circulation time by incorporation of lipids containing polyethyleneglycol moieties. Still, the rapid wash out of the delivered material from the tumor tissue is a major obstacle for both imaging and therapy. In this study, we developed an optimized temperature sensitive liposomal system to be used with mild hyperthermia: highly stable at physiological temperature and with a sharp transition of the bilayer at 41.5°C, with subsequent rapid release of entrapped compounds such as calcein or tumor cell-targeting contrast agents. Intravital microscopy on calcein/rhodamine containing liposomes was applied to demonstrate the applicability of this system in vivo. The calcein loaded liposomes were injected iv into nude mice with a human BLM melanoma tumor implanted in a dorsal skin-fold window chamber. Arrival of the liposomes at the tumor site and content release after temperature increase were monitored. The results demonstrated not only accumulation of the liposomes at the tumor site, but also a massive release of calcein after increase of the temperature to 41°C. The versatility of the thermosensitive liposomes was further demonstrated by encapsulation of a tumor cell-targeting DOTA-phenylboronate conjugate and its release at elevated temperatures. The DOTA ligand in this system is able to chelate a variety of metals suitable for both diagnostic and therapeutic applications, whereas the phenylboronate function is able to target specifically to tumor cells through a covalent binding with sialic acid moieties over-expressed on their surface upon heat-triggered release from the liposomal carrier.
脂质体能够在感兴趣的部位实现温度触发的内容释放，对于肿瘤的成像和治疗非常重要。通过应用具有适合温和热疗（41-43°C）的凝胶到液相相变温度的脂质体，并通过掺入含有聚乙二醇部分的脂质来延长其循环时间，可以改善成像剂或治疗剂的递送。然而，从肿瘤组织中快速冲洗输送的材料仍然是成像和治疗的主要障碍。在这项研究中，我们开发了一种优化的温度敏感脂质体系统，用于温和热疗：在生理温度下高度稳定，在 41.5°C 时双层急剧转变，随后快速释放包封的化合物，如钙黄绿素或肿瘤细胞靶向造影剂。应用含有钙黄绿素/罗丹明的脂质体的活体显微镜来证明该系统在体内的适用性。将负载钙黄绿素的脂质体静脉注射到植入背部皮肤窗室的人类 BLM 黑色素瘤肿瘤的裸鼠中。监测脂质体到达肿瘤部位和温度升高后内容物释放的情况。结果不仅证明了脂质体在肿瘤部位的积累，还证明了温度升高至 41°C 后钙黄绿素的大量释放。热敏脂质体的多功能性进一步通过封装肿瘤细胞靶向 DOTA-苯硼酸缀合物及其在升高温度下的释放来证明。该系统中的 DOTA 配体能够螯合多种适合诊断和治疗应用的金属，而苯硼酸功能能够通过与表面表达的唾液酸残基共价结合，特异性靶向肿瘤细胞，在从脂质体载体热触发释放后。
