Reversible Cell-Specific Drug Delivery with Aptamer-Functionalized Liposomes
Reversible Cell-Specific Drug Delivery with Aptamer-Functionalized Liposomes
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DOI：
10.1002/anie.200901452
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Lu, Yi
中科院分区：
文献类型：
--
作者：
Cao, Zehui;Tong, Rong;Lu, Yi
Zehui Cao，Rong Tong，Abhijit Mishra，Weichen Xu，Gerard CL Wong，* 程建军，* 和 Yi Lu* 顺式二氯二氨铂 (II)（顺铂）是一种有效的化疗药物，用于治疗多种癌性肿瘤。 [1, 2] 尽管其具有出色的抗肿瘤功效，但其主要缺点 顺铂缺乏肿瘤特异性且副作用严重。 [3]此外，某些肿瘤细胞类型会因接触顺铂药物而产生耐药性。[1]非常需要能够将顺铂特异性递送至肿瘤细胞的策略。已经报道了几种将顺铂特异性递送至肿瘤部位的策略，[4-8]其中最常见的是使用针对不同细胞表面靶标的抗体 (Ab) 识别。[6-8]Abs 与细胞膜受体的结合触发受体介导的内吞作用，从而提高治疗效果。[9]尽管取得了这一成功，但使用抗体作为细胞特异性归巢剂仍面临重大挑战。 Ab 缀合很难控制，并且通常表现出较差的缀合位点特异性和不一致的结合亲和力。 [9]基于抗体的药物递送系统也往往具有免疫原性[10]，因此需要额外的人源化步骤，这使得临床应用更加困难。基于核酸的适体作为细胞特异性试剂提供了抗体的绝佳替代品。它们是通过体外选择过程（称为指数富集配体系统进化 (SELEX)）鉴定的单链寡核苷酸，可选择性地结合靶分子。 [11, 12] SELEX 鉴定的许多适体与抗体具有几乎相同的结合亲和力和特异性。适体更容易制备和扩大规模。它们通常被认为是非免疫原性的，可以被核酸酶逐渐降解并从血液中清除，从而引起最小的系统毒性。适体的功能化以促进位点特异性缀合也很简单。因此，适体是有前途的靶向配体[13-24]，并已用于靶向药物递送系统，其中大多数是嵌段共聚物纳米粒子。[25-29]尽管这些基于纳米技术的新平台看起来很有前途，但纳米粒子用于靶向癌症治疗的临床益处尚未得到证实。脂质体是迄今为止最成功的药物递送系统；[30]美国食品和药物管理局已批准许多基于脂质体的系统用于临床疾病治疗。[31]脂质体已被证明可以增加适体的血浆停留时间。 [32]以前在脂质体药物递送方面的努力主要集中在开发长循环脂质体，通过增强渗透和保留（EPR）效应（一种被动靶向机制）来靶向癌性肿瘤组织[33, 34]。然而，完全基于EPR的癌症靶向仍然存在不良的全身副作用和次优的抗肿瘤疗效：[35, 36]含顺铂脂质体的临床研究仅显示较差至中等的治疗效果。[37, 38]原则上，具有主动肿瘤靶向能力的递送载体可以显着改善这一点。[39]个性化化疗是癌症治疗中尚未解决的挑战。尽管存在粗略的经验剂量指南，但个体患者的反应可能会严重偏离平均行为。这个问题对于化疗药物来说尤其严重，药物过量可能会产生严重后果。目前，一旦给予初始剂量，如果没有“解毒剂”......
Zehui Cao, Rong Tong, Abhijit Mishra, Weichen Xu, Gerard CL Wong,* Jianjun Cheng,* and Yi Lu* cis-Diamminedichloroplatinum (II)(cisplatin) is a potent chemotherapeutic agent for the treatment of a broad range of cancerous tumors.[1, 2] Despite its excellent antitumor efficacy, the major drawbacks of cisplatin include its lack of tumor specificity and severe side effects.[3] In addition, certain tumor-cell types develop resistance to cisplatin from exposure to the drug.[1] Strategies that allow the delivery of cisplatin specifically to tumor cells are highly desirable. Several strategies have been reported for the delivery of cisplatin specifically to tumor sites,[4–8] the most common of which is to use antibody (Ab) recognition against different cell-surface targets.[6–8] The binding of Abs to the cell-membrane receptors triggers receptor-mediated endocytosis, with the result of improved therapeutic efficacy.[9] Despite this success, the use of Abs as cell-specific homing agents poses significant challenges. Ab conjugations are difficult to control and typically show poor site specificity for the conjugation and inconsistent binding affinity.[9] The antibody-based drugdelivery system also tends to be immunogenic,[10] so it requires extra humanization steps, which make it more difficult for clinical application. Nucleic acid based aptamers provide excellent alternatives to antibodies as cell-specific agents. They are singlestranded oligonucleotides identified through an in vitro selection process, termed system evolution of ligands by exponential enrichment (SELEX), to bind the target molecules selectively.[11, 12] Many aptamers identified by SELEX have nearly identical binding affinity and specificity to those of Abs. Aptamers are much easier to prepare and to scale up. They are generally considered nonimmunogenic and can be gradually degraded by nucleases and cleared from the blood to cause minimal system toxicity. Functionalizations of aptamers to facilitate site-specific conjugation are also straightforward. Thus, aptamers are promising targeting ligands [13–24] and have been used in targeted drug-delivery systems, most of which are block-copolymer nanoparticles.[25–29] Although these new nanotechnology-based platforms look promising, the clinical benefit of nanoparticles for targeted cancer therapy is yet to be demonstrated. Liposomes are by far the most successful drug-delivery systems;[30] a number of liposome-based systems have been approved by the US Food and Drug Administration for disease treatment in the clinic.[31] Liposomes have been shown to increase the plasma residence time of aptamers.[32] Previous efforts on liposomal drug delivery have focused on developing long-circulating liposomes that target cancerous tumor tissues through the enhanced permeation and retention (EPR) effect,[33, 34] a passive targeting mechanism. However, cancer targeting entirely based on EPR still has undesirable systemic side effects and suboptimal antitumor efficacy:[35, 36] clinical studies of a cisplatin-containing liposome showed only poor to moderate therapeutic efficacy.[37, 38] Delivery vehicles with active tumor-targeting capability could, in principle, improve this significantly.[39] Personalized chemotherapy is an unmet challenge in cancer treatment. Despite the existence of rough empirical dosage guidelines, the individual patient response can deviate strongly from average behavior. This problem is especially acute for chemotherapy agents, for which drug overdosage can have severe consequences. At present, once an initial dosage is administered, the side effects and drug effectiveness can no longer be modulated if there are no “antidotes” to the …