A pH‐Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P‐Glycoprotein‐Mediated Multidrug Resistance

Abstract

Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT-11) and a NO-releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell-killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.

MALDI‐MS Patterning of Caspase Activities and Its Application in the Assessment of Drug Resistance

“…This may arise from the overexpression of the plasmamembrane P-glycoprotein (Pgp) transporters in MCF/ADR cells,w hich increases the drug efflux and thus prevents the activation of caspase-induced programmed cell death. [28,29] Furthermore,u nlike for the MCF-7 cells,c asp-3 activity was detected in MCF/ADR cells,w hich is consistent with ap revious report. [30] Flow-cytometric assays of the same treated cells using the Annexin V-APC/7-AAD apoptotic kit also validated the caspase-dependent cell apoptosis (Figure 6B).…”

Zwitterionic Polymer Coating of Sulfur Dioxide‐Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy

“…In addition, the expression of the relevant molecular markers of apoptosis, namely Bax, Bcl‐2, and PARP, was examined by western blot analyses (Figure 5F,G). It was noted that MON‐DN@PCBMA and MON‐DN@PCBMA‐DOX could upregulate the expression of pro‐apoptotic proteins, Bax and PARP, and downregulate the expression of the anti‐apoptotic protein, Bcl‐2, which strongly demonstrated that SO 2 could sensitize the MCF‐7/ADR cells for apoptosis. Based on these results, we can conclude that SO 2 ameliorates multidrug resistance in cancer cells through the downregulation of the expression of P‐gp protein and sensitizes the cancer cells to apoptosis.…”

Dual Stimuli‐Responsive Controlled Release Nanocarrier for Multidrug Resistance Cancer Therapy

“…Nitric oxide (NO), a gas molecule that is ubiquitous in living organisms, has important physiological and pathological effects in various cell life activities . In recent years, NO has been reported to reverse the MDR of cancer cells by reducing the expression level of P‐gp, which promptes the development of new NO delivery systems for MDR cancer chemotherapy . However, NO has a short half‐life and high sensitivity to biological substances, which greatly restricts the development of NO‐based therapeutic system in clinical applications .…”