Lysosome‐Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

Abstract

Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS-dependent prodrugs. In particular, known prodrug 4-(N-ferrocenyl-N-benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome-specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC =3.5-7.2 μm) and in vivo (40 mg kg , NK/Ly murine model) but remained weakly toxic towards non-malignant cells (IC =15-30 μm).

Self‐Amplified Photodynamic Therapy through the 1O2‐Mediated Internalization of Photosensitizers from a Ppa‐Bearing Block Copolymer

“…[2] Recently,s timuli-responsive drug delivery systems have drawn increasing attention, since they can effectively expose the hydrophobic drugs to tumor sites. [9] Considering the specific endogenous microenvironment of tumors,s uch as lower interstitial pH, [10] higher glutathione concentration [11] and ROSl evels [12] or elevated level of certain enzymes, [13] many internal stimuli-responsive polymeric prodrugs have been developed as nanocarriers. [14] Although these polymeric prodrugs can avert drug leakage during circulation in vivo,the release of drugs in tumor is uncontrollable due to the heterogeneity of tumor cells.…”

Recent Advances in Subcellular Targeted Cancer Therapy Based on Functional Materials

“…In view of this, a lysosome‐specific oxidation‐activable prodrug was developed in a recent study. Specifically, a known prodrug 1, 4‐( N ‐ferrocenyl‐ N ‐benzylaminocarbonyloxymethyl)‐phenylboronic acid pinacol ester was converted into its analogs (prodrugs 2 (nonfluorogenic) and 5 (fluorogenic)) with the modification of an alkylated piperidine fragment, which could be protonated in acidic lysosomes for organelle‐specific localization ( Figure a) . Compared with the parent compound, the lysosome‐specific analogs showed remarkably enhanced accumulation in lysosomes and caused severe lysosomal disruption (Figure b), resulting in high toxicity against a variety of cancer cell lines rather than nonmalignant cells.…”

“…b) DU‐145 cells treated with LysoTracker Red (LTR) and prodrug 5. c) Animal growth curves after different treatments. a–c) Adapted with permission . Copyright 2017, Wiley‐VCH.…”

Imidazole and Benzimidazole Modified Half-Sandwich IridiumIIIN-Heterocyclic Carbene Complexes: Synthesis, Anticancer Application, and Organelle Targeting

“…As shown in Figure 7, A549 cells subjected to AO alone showed significant red fluorescence in their lysosomes, but the intensity of the red fluorescence decreased quickly after the cells were exposed to complex 3B with concentrations of 1.0 × IC 50 and 2.0 × IC 50 for 6 h, which was the result of lysosomal damage, which was mainly attributed to the introduction of nitrogen-containing ligands into the complexes. The ligands increased the total alkalinity of the molecules, which easily accumulated and damaged the integrity of the acidic lysosomes (Daum et al, 2017). Additionally, the intracellular iridium contents of 3B in the cytosol, nucleus, nuclear chromatin and cytoskeleton fractions isolated from A549 cells were determined by inductively coupled plasma mass spectrometry (ICP-MS) after 24 h exposure.…”