Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
Curr Pharm Des. 2011;17(3):293-319. doi: 10.2174/138161211795049642.
The recent elucidation of molecular regulators of apoptosis and their roles in cellular oncogenesis has motivated the development of biomacromolecular anticancer therapeutics that can activate intracellular apoptotic signaling pathways. Pharmaceutical scientists have employed a variety of classes of biologics toward this goal, including antisense oligodeoxynucleotides, small interfering RNA, proteins, antibodies, and peptides. However, stability in the in vivo environment, tumor-specific biodistribution, cell internalization, and localization to the intracellular microenvironment where the targeted molecule is localized pose significant challenges that limit the ability to directly apply intracellular-acting, pro-apoptotic biologics for therapeutic use. Thus, approaches to improve the pharmaceutical properties of therapeutic biomacromolecules are of great significance and have included chemically modifying the bioactive molecule itself or formulation with auxiliary compounds. Recently, promising advances in delivery of pro-apoptotic biomacromolecular agents have been made using tools such as peptide "stapling", cell penetrating peptides, fusogenic peptides, liposomes, nanoparticles, smart polymers, and synergistic combinations of these components. This review will discuss the molecular mediators of cellular apoptosis, the respective mechanisms by which these mediators are dysregulated in cellular oncogenesis, the history and development of both nucleic-acid and amino-acid based drugs, and techniques to achieve intracellular delivery of these biologics. Finally, recent applications where pro-apoptotic functionality has been achieved through delivery of intracellular-acting biomacromolecular drugs will be highlighted.
最近，细胞凋亡分子调控因子及其在细胞癌变中的作用机制已被阐明，这促使人们开发能够激活细胞内凋亡信号通路的生物大分子抗癌治疗药物。制药科学家已经采用了多种生物药物来实现这一目标，包括反义寡核苷酸、小干扰 RNA、蛋白质、抗体和肽。然而，在体内环境中的稳定性、肿瘤特异性的生物分布、细胞内化以及靶向分子所在的细胞内微环境中的定位等问题，都给生物大分子抗癌治疗药物的应用带来了巨大挑战，限制了直接应用细胞内作用的促凋亡生物药物的能力。因此，改善治疗性生物大分子药物的药学特性具有重要意义，包括对生物活性分子本身进行化学修饰或与辅助化合物联合用药。最近，利用肽“订书钉”、穿透肽、融合肽、脂质体、纳米粒子、智能聚合物以及这些成分的协同组合等工具，在促凋亡生物大分子药物的递送上取得了有前景的进展。本文将讨论细胞凋亡的分子介质，以及这些介质在细胞癌变中失调的相应机制，核酸和基于氨基酸的药物的历史和发展，以及实现这些生物药物细胞内递送的技术。最后，将重点介绍通过递送电内作用生物大分子药物来实现促凋亡功能的最新应用。
