Gao Hui-le, Jiang Xin-guo
Yao Xue Xue Bao. 2016 Feb;51(2):272-80.
Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention(EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as p H sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor microvessels to decrease the internal fluid pressure. All these strategies could enhance the accumulation and penetration of nanoparticles into tumor, leading to a homogenous distribution of drugs in tumor. To enhance the internalization by specific cells, active targeting delivery strategies are developed. There were many surface markers, receptors or carriers overexpressed on specific kinds of cells, thus the corresponding ligands were utilized to mediate active targeting to certain cells, including tumor cells, cancer stem cells, tumor neovasculatures, tumor associated macrophages and other tumor stroma cells. Targeting more than one cell type may provide an improved antitumor effect. Although these passive and active targeting strategies all have promising outcome in the treatment of tumor, some shortages are still unaddressed, such as the specificity of responsive is not good enough, and the active targeting may be diminished by the protein corona. Thus more research is required to promote the drug delivery study.
肿瘤是对人类最严重的威胁之一。尽管许多抗肿瘤药物已获批用于临床，但由于肿瘤靶向效率低和在肿瘤中的蓄积量少，治疗效果仍然有限。因此，高效地将抗肿瘤药物递送至肿瘤、提高肿瘤组织中的药物浓度并减少药物在正常组织中的分布至关重要。这一直是药学学术界和产业界最具吸引力的方向之一。人们已经开发了多种策略，尤其是各种纳米颗粒药物递送系统，以解决复杂肿瘤微环境的关键问题，这些策略部分或大部分满足了肿瘤治疗的需求。在本文中，我们仔细回顾了近年来开发的新型靶向递送策略。最有效的方法是基于增强渗透与滞留（EPR）效应的被动靶向递送，大多数商业纳米药物都是基于EPR效应。然而，高渗透性和滞留性需要不同的粒径，因此人们开发了几种可改变尺寸的纳米颗粒，如尺寸可减小的颗粒和组装颗粒，以满足对粒径的争议性要求，并增强肿瘤滞留和渗透能力。表面电荷可逆纳米颗粒也显示出高效率，因为血液循环和正常器官中的阴离子电荷减少了非预期的内化。电荷可在肿瘤微环境中转变为正电荷，促进肿瘤细胞摄取药物。此外，肿瘤微环境响应性药物释放对于降低药物副作用很重要，人们已经开发了许多策略，如pH敏感释放和酶敏感释放。除了响应性纳米颗粒外，塑造肿瘤微环境可以减弱药物递送中的障碍，例如，降低肿瘤胶原蛋白强度并使肿瘤微血管正常化以降低内部流体压力。所有这些策略都可以增强纳米颗粒在肿瘤中的蓄积和渗透，导致药物在肿瘤中均匀分布。为了增强特定细胞的内化作用，人们开发了主动靶向递送策略。在特定类型的细胞上有许多表面标志物、受体或载体过表达，因此相应的配体被用于介导对某些细胞的主动靶向，包括肿瘤细胞、癌症干细胞、肿瘤新生血管、肿瘤相关巨噬细胞和其他肿瘤基质细胞。靶向不止一种细胞类型可能会提供更好的抗肿瘤效果。尽管这些被动和主动靶向策略在肿瘤治疗中都有很有前景的结果，但一些不足仍然未得到解决，例如响应的特异性不够好，并且主动靶向可能会被蛋白冠层削弱。因此，需要更多的研究来推动药物递送研究。
