Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy.

Hanhee Cho,Yujeong Moon,Suah Yang,Jinseong Kim,Man Kyu Shim,Sukyung Song,Cheol-Hee Ahn,Youngro Byun,Kwangmeyung Kim

doi:10.3390/pharmaceutics14010083

Hanhee Cho, Yujeong Moon + Show 7 more

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https://doi.org/10.3390/pharmaceutics14010083

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Abstract

Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine.

Highlights

Chemotherapy is still the first-line treatment option owing to its high sensitivity against wide range of cancers, but it is often accompanied by serious side effects attributed to a lack of cancer selectivity [1]
Maleimide-PEG2 -NHS, human serum albumin (HSA), mouse serum albumin (MSA), bovine serum albumin (BSA), hematoxylin and eosin (H&E) staining kit, and doxorubicin hydrochloride were purchased from Sigma Aldrich (Oakville, ON, USA)
We propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, which can effectively deliver anticancer drugs by in situ albumin-mediated passive targeting with minimal side effects

Summary

Introduction

Chemotherapy is still the first-line treatment option owing to its high sensitivity against wide range of cancers, but it is often accompanied by serious side effects attributed to a lack of cancer selectivity [1]. The risk of side effects by chemotherapy restricts drug dosage, which may limit the tumors from being exposed to sufficiently high drug concentrations, eventually leading to treatment failure [2]. Many endeavors have been made to overcome these issues by improving the cancer selectivity of anticancer drugs to tumors. One of the promising approaches, prodrug, involves bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which greatly improve the cancer selectivity to reduce the off-target toxicity of anticancer drugs [3,4,5]. Many designed prodrugs that selectively release active drugs by overexpressed enzymes in the tumor microenvironment, including caspases, cathepsins, and matrix metalloproteinases (MMPs), have greatly increased the safety of chemotherapy with minimal side effects [7,8,9,10]

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