A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

Abstract

The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate‐ester‐caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2‐activatable GEM (A‐GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A‐GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A‐GEM treatment compared with that following GEM treatment.

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

“…For comparison, the most common ROS-responsive chemistry utilizes Chan-lam type coupling with an arylboron. [24][25][26][27] The activating oxidant is hydrogen peroxide and has shown selectivity in different cancer cell models. While boron-based prodrugs are sensitive to H 2 O 2 concentrations their half-lives is in minutes.…”

“…[21][22] For example, we designed compounds that release antioxidants to protect skin cells in UV-induced high ROS environments. [24][25][26][27] The activating oxidant is hydrogen peroxide and has shown selectivity in different cancer cell models. This design prevents activation in healthy cells that have ROS and likely confers stability to the liver environment.…”

Recent Advances in Hydrogen Peroxide Responsive Organoborons for Biological and Biomedical Applications

“…For example, GEM causes nausea, vomiting, fever, reversible elevation of liver transaminases, peripheral edema, myelosuppression, etc. Obika group designed a boronate‐ester caged prodrug 90 of GEM that showed an anticancer effect equivalent to that of GEM while exhibited lower myelosuppression than GEM [150] . Compound 90 contains a boronate‐ester‐based carbamate protecting group for masking the 4‐NH 2 group of cytosine, which can be activated by the high level of H 2 O 2 found in cancer cells to release GEM.…”

Advances in Reactive Oxygen Species Responsive Anti-cancer Prodrugs

“…在 2017～2018 年, 该课题组 [39][40][41] [42][43][44][45][46][47][48][49][50][51][52][53] . 早在 2014 年, Hong 等 [46] [54][55][56][57][58][59][60][61] .…”

“…早在 2014 年, Hong 等 [46] [54][55][56][57][58][59][60][61] . 2018 年, Jiang 等 [58] 将 CHL 与亲水性聚乙二醇 (polyethylene glycol, PEG)和 4-(羟甲基)苯基硼酸结合 图 3 芳基硼酸/酯基 ROS 响应型前药的化学结构 [46][47][48][49][50][51][52][53] Figure 3 Chemical structure of arylboronic acid/ester ROS-responsive prodrugs [46][47][48][49][50][51][52][53] SN38: 7-ethyl-10-hydroxycamptothecin, 5'-DFUR: 5'-deoxy-5-fluorouridine, GEM: gemcitabine, GA: gambogic acid, AMT [58] . Figure 4 (a) Chemical structure of the ROS-responsive CHL prodrug and its self-assembly into prodrug micelles, (b) schematic illustration of intracellular H 2 O 2 -triggered drug release and quinone methide (QM) generation [58] .…”