Anticancer Prodrugs Targeting the Tumor Microenvironment and Their Clinical Advances

DOI

10.2991/978-94-6463-910-0_14How to use a DOI?

Keywords

TME-targeting; Anticancer; Prodrugs

Abstract

Targeting the tumor microenvironment (TME) has become a critical strategy in the development of anticancer prodrugs. This article reviews advances in the research of anticancer prodrugs utilizing TME-targeting strategies, including Aldoxorubicin, NC-6300, OBI-3424, and Legubicin. Aldoxorubicin employs a pH-sensitive hydrazone bond to conjugate doxorubicin to albumin, designed to release the active drug in the acidic TME. In a Phase III clinical trial for soft tissue sarcoma, it significantly prolonged progression-free survival (PFS) compared to standard chemotherapy; however, it increased hematological toxicity and gastrointestinal adverse events, without significantly reducing cardiotoxicity. NC-6300 enhances systemic stability through its micellar carrier; its maximum tolerated dose (MTD) far exceeds that of conventional epirubicin, and it demonstrates significantly improved cardiac safety at high cumulative doses, yet its objective response rate (ORR) is remarkably low (only 5%). OBI-3424 and Legubicin target TME-overexpressed enzymes AKR1C3 and Legumain, respectively, for activation. OBI-3424 showed significant efficacy in preclinical models of T-cell leukemia with high AKR1C3 expression; in clinical studies for solid tumors, it exhibited manageable safety but low ORR (2.6%), with efficacy highly dependent on tumor AKR1C3 expression levels. Legubicin utilizes a Legumain-cleavable peptide linker to release doxorubicin; preclinical studies indicated it significantly increases drug exposure at tumor sites while drastically reducing cardiac and renal toxicity, leading to an improved MTD. Prodrug strategies targeting the TME can enhance safety or enable targeted killing. However, the key challenge lies in balancing prodrug stability with targeted release capability. Optimizing this balance represents a crucial future direction for TME-targeted therapeutics.

Copyright

© 2025 The Author(s)

Open Access

Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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TY  - CONF
AU  - Runze Li
PY  - 2025
DA  - 2025/12/15
TI  - Anticancer Prodrugs Targeting the Tumor Microenvironment and Their Clinical Advances
BT  - Proceedings of the 2025 2nd International Symposium on Agricultural Engineering and Biology (ISAEB 2025)
PB  - Atlantis Press
SP  - 132
EP  - 141
SN  - 2468-5747
UR  - https://doi.org/10.2991/978-94-6463-910-0_14
DO  - 10.2991/978-94-6463-910-0_14
ID  - Li2025
ER  -