Doxorubicin-Tethered Responsive Gold Nanoparticles Facilitate Intracellular Drug Delivery for Overcoming Multidrug Resistance in Cancer Cells

Abstract

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. Through the development of a drug delivery system that tethers doxorubicin onto the surface of gold nanoparticles with a poly(ethylene glycol) spacer via an acid-labile linkage (DOX-Hyd@AuNPs), we have demonstrated that multidrug resistance in cancer cells can be significantly overcome by a combination of highly efficient cellular entry and a responsive intracellular release of doxorubicin from the gold nanoparticles in acidic organelles. DOX-Hyd@AuNPs achieved enhanced drug accumulation and retention in multidrug resistant MCF-7/ADR cancer cells when it was compared with free doxorubicin. It released doxorubicin in response to the pH of acidic organelles following endocytosis, opposite to the noneffective drug release from doxorubicin-tethered gold nanoparticles via the carbamate linkage (DOX-Cbm@AuNPs), which was shown by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between the doxorubicinyl groups and the gold nanoparticles. DOX-Hyd@AuNPs therefore significantly enhanced the cytotoxicity of doxorubicin and induced elevated apoptosis of MCF-7/ADR cancer cells. With a combined therapeutic potential and ability to probe drug release, DOX-Hyd@AuNPs represent a model with dual roles in overcoming MDR in cancer cells and probing the intracellular release of drug from its delivery system.

Roadmap for Computer-Aided Modeling of Theranostics and Related Nanosystems

“…2, we built and calculated several other NPs in two ways: by enlarging the number of core Au atoms and, changing the functionalizing coverage as well. Even more, we have included doxorubicin into the NP [6] as a known way of facilitating drug delivery.…”

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

“…For another example, the platinum (IV) prodrugs conjugated GNRs can evade the deactivation of overexpressed detoxification proteins including metallothionein and GSH in A549R cells, and for restoration of the drug sensitivity in cisplatin‐resistant cancer cells. Besides, the efficacy of anticancer agents delivered by gold nanoparticles can overcome MDR, which has been confirmed on several different types of MDR cancer cell lines 100, 101. In addition, the targeting ligands, polymers, and nuclei acids can be fixed onto the surface of gold nanoparticles to achieve higher accumulation in tumor tissues for enhancing the therapeutic efficacy.…”

Supramolecular nanoscale assemblies for cancer diagnosis and therapy

“…This study highlights the potential of using AuNPs for overcoming MDR in cancer chemotherapy. Another example is DOX-conjugated AuNPs for treatment of breast cancer [187]. These results showed an increase in cancer cell death compared to the free DOX and an outgrown drug efflux from the cells.…”