Lee Jihoon, Choi Min-Koo, Song Im-Sook
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
College of Pharmacy, Dankook University, Cheon-an 31116, Republic of Korea.
Pharmaceuticals (Basel). 2023 May 29;16(6):802. doi: 10.3390/ph16060802.
Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, under clinical use or trials to increase its therapeutic efficacy. To improve the bioavailability of DOX in intravenous and oral cancer treatment, studies have proposed a pH- or redox-sensitive and receptor-targeted system for overcoming DOX resistance and increasing therapeutic efficacy without causing DOX-induced toxicity. Multifunctional formulations of DOX with mucoadhesiveness and increased intestinal permeability through tight-junction modulation and P-gp inhibition have also been used as orally bioavailable DOX in the preclinical stage. The increasing trends of developing oral formulations from intravenous formulations, the application of mucoadhesive technology, permeation-enhancing technology, and pharmacokinetic modulation with functional excipients might facilitate the further development of oral DOX.
阿霉素（DOX）是癌症化疗中广泛使用的药物，它通过多种细胞内相互作用诱导细胞死亡，产生活性氧物种和DNA加合物构型，从而诱导细胞凋亡、抑制拓扑异构酶II以及使组蛋白脱落。尽管DOX在实体瘤中具有广泛的治疗效果，但它常常会诱导耐药性和心脏毒性。由于其细胞旁通透性低以及P-糖蛋白（P-gp）介导的外排作用，DOX的肠道吸收有限。我们回顾了各种临床使用或试验中的非肠道DOX制剂，如脂质体、聚合物胶束、聚合物纳米颗粒和聚合物-药物偶联物，以提高其治疗效果。为了提高DOX在静脉内和口服癌症治疗中的生物利用度，研究提出了一种pH或氧化还原敏感且靶向受体的系统，用于克服DOX耐药性并提高治疗效果，同时不引起DOX诱导的毒性。在临床前阶段，具有粘膜粘附性并通过紧密连接调节和P-gp抑制增加肠道通透性的DOX多功能制剂也已被用作口服生物可利用的DOX。从静脉制剂向口服制剂发展的趋势不断增加，粘膜粘附技术、渗透增强技术以及使用功能性辅料进行药代动力学调节的应用可能会促进口服DOX的进一步发展。
