Overcoming Multidrug Resistance through the Synergistic Effects of Hierarchical pH-Sensitive, ROS-Generating Nanoreactors

Abstract

Recently, multidrug resistance (MDR) has become a major clinical chemotherapeutic burden that robustly diminishes the intracellular drug levels through various mechanisms. To overcome the doxorubicin (Dox) resistance in tumor cells, we designed a hierarchical nanohybrid system possessing copper-substituted mesoporous silica nanoparticles (Cu-MSNs). Further, Dox was conjugated to copper metal in the Cu-MSNs framework through a pH-sensitive coordination link, which is acutely sensitive to the tumor acidic environment (pH 5.0–6.0). In the end, the nanocarrier was coated with D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), a P-gp inhibitor-entrenched compact liposome net for obstructing the drug efflux pump. Copper ions in the framework synergize the antitumor activity of Dox by enhancing the intracellular reactive oxygen species (ROS) levels through a Fenton-like reaction-mediated conversion of hydrogen peroxide. Furthermore, intracellularly generated ROS triggered the apoptosis by reducing the cellular as well as mitochondrial membrane integrity in MDR cells, which was confirmed by the mitochondrial membrane potential (MMP) measurement. The advancement of the design and critical improvement of cytotoxic properties through free radical attack demonstrate that the proposed hierarchical design can devastate the MDR for efficient cancer treatment.

Engineered pH‐responsive hydrazone‐carboxylate complexes‐encapsulated 2D matrices for cathepsin‐mediated apoptosis in cancer

“…To determine the delivery efficacy of the LDH nanocontainers and their lysosomal escape, we performed the cellular internalization efficiency of these nanohybrids (LDH‐hydrazone‐Dox) and compared it with the uptake of free Dox using CLSM observations. Due to the auto‐fluorescence efficacy of Dox, it is highly convenient to track the nanocontainers effectively without using any other fluorescent moities . For cell uptake using CLSM, the cells were seeded in a 6‐well plate and cultured overnight for proper cell attachment.…”

“…However, among all, precursors with NO 3 − species are most appropriate for ion‐exchange process due to their easy displacement from the interlayers . These 2D matrices possessing an overall positively charged surface not only facilitate the accommodation of negatively charged drug species in their interlayer gallery but also augment the cell internalization efficiency of such compounds through establishing the interactions with the biological membrane . More often, the LDHs facilitate the encapsulation of anionic drugs that with carboxylic functional groups, which could be difficult to encapsulate Dox in their gallery space.…”

“…Motivated by the facts behind the current advancements in engineering various intelligent nano‐delivery systems, conjugation of drugs with the stimuli‐responsive molecular switches has become one of the most efficient approaches in delivering a drug cargo in spatiotemporal controlled way, while experiencing the chemical or physical changes in regard to the biological stimuli . Among the various external stimuli, pH of the surrounding microenvironment is the most efficient biological stimuli in delivering chemotherapeutic agents . Moreover, it is highly convenient to fabricate such controlled delivery systems as the tumors hold lower pH of ~4.5–6.0 compared to that of the neighboring physiological fluids (pH 7.4) .…”

“…Moreover, it is highly convenient to fabricate such controlled delivery systems as the tumors hold lower pH of ~4.5–6.0 compared to that of the neighboring physiological fluids (pH 7.4) . Often times, the internalized nanocarriers in the tumor cells are engulfed by the endosomes or lysosomes, that are with mildly acidic microenvironment, which significantly results in the intracellular delivery of the therapeutic cargo . Furthermore, the utilization of LDH for enclosing these complexes is advantageous as the surface hydroxyl groups of these 2D LDH matrices were protonated and result in the weakening of the interactions within the layers leading to their breakdown, which also facilitate the release of the complexes in the acidic environment …”

Poly‐allylamine hydrochloride and fucoidan‐based self‐assembled polyelectrolyte complex nanoparticles for cancer therapeutics

“…The amount of released MTX was analyzed periodically using UV–vis spectroscopy as mentioned earlier. All the tests, including measurements, were carried out in triplicate …”