Andreana Ilaria, Zoratto Nicole, Di Meo Chiara, Matricardi Pietro, Stella Barbara, Arpicco Silvia
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy.
Expert Opin Drug Deliv. 2025 Sep;22(9):1257-1274. doi: 10.1080/17425247.2025.2515266. Epub 2025 Jun 3.
Hyaluronic acid (HA) has been widely explored in cancer drug delivery due to its biocompatibility, biodegradability and excellent cargo properties. Recently, HA-based formulations have gained renewed interest thanks to the HA involvement in many CD44-overexpressing tumors, offering potential for active targeting, tumor microenvironment modulation, and immune response regulation.
This review explores the role of HA and its receptor in cancer progression and as a strategy for active therapeutic targeting. It also outlines the current status of HA-based formulations in clinical cancer therapy, emphasizing their clinical outcomes. The use of HA-drug conjugates, HA-based and -decorated nanoparticles (NPs), in chemotherapy, gene therapy, and theranostics is reviewed. Additionally, recent advancements in the role of HA in immune system modulation are discussed. All presented systems are herein evaluated for their ability to selectively target CD44-overexpressing cancer cells, with a focus on their in vivo biodistribution and therapeutic efficacy.
Despite significant research, a few HA-based technologies have progressed to clinical trials, with only one showing promising results. Key challenges include high production costs, industrial scale-up feasibility, the need to preserve receptor recognition, and the off-target accumulation of HA in the liver and spleen barriers that must be addressed for successful clinical translation.
由于透明质酸（HA）具有生物相容性、可生物降解性以及出色的载药特性，它在癌症药物递送方面得到了广泛研究。近来，基于HA的制剂重新引起了人们的兴趣，这得益于HA参与了许多CD44过表达肿瘤，为主动靶向、肿瘤微环境调节及免疫反应调控提供了潜力。
本综述探讨了HA及其受体在癌症进展中的作用，以及作为主动治疗靶向策略的作用。它还概述了基于HA的制剂在临床癌症治疗中的现状，强调了它们的临床结果。综述了HA-药物偶联物、基于HA及用HA修饰的纳米颗粒（NPs）在化疗、基因治疗和诊疗中的应用。此外，还讨论了HA在免疫系统调节作用方面的最新进展。本文评估了所有呈现的系统选择性靶向CD44过表达癌细胞的能力，重点关注它们的体内生物分布和治疗效果。
尽管进行了大量研究，但只有少数基于HA的技术进入了临床试验，其中只有一项显示出有前景的结果。关键挑战包括高生产成本、工业放大生产的可行性、保持受体识别的必要性，以及HA在肝脏和脾脏屏障中的脱靶积累，这些都是成功进行临床转化必须解决的问题。
