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PH and redox dual-responsive nanoparticles based on disulfide-containing poly(?-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer.

ABSTRACT: BACKGROUND:Multidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. Celecoxib (CXB), a selective COX-2 inhibitor, can dramatically enhance the cytotoxicity of doxorubicin (DOX) in breast cancer cells overexpressing P-gp. Thus it can be seen that the combination of DOX and CXB maybe obtain synergistic effects against breast cancer by overcoming drug resistance. RESULTS:In this study, we designed a pH and redox dual-responsive nanocarrier system to combine synergistic effects of DOX and CXB against drug resistant breast cancer. This nanocarrier system denoted as HPPDC nanoparticles showed good in vitro stability and significantly accelerated drug releases under the acidic and redox conditions. In drug-resistant human breast cancer MCF-7/ADR cells, HPPDC nanoparticles significantly enhanced the cellular uptake of DOX through the endocytosis mediated by CD44/HA specific binding and the down-regulated P-gp expression induced by COX-2 inhibition, and thus notably increased the cytotoxicity and apoptosis-inducing activity of DOX. In MCF-7/ADR tumor-bearing nude mice, HPPDC nanoparticles showed excellent tumor-targeting ability, remarkably enhanced tumor chemosensitivity and reduced COX-2 and P-gp expressions in tumor tissues. CONCLUSION:All results demonstrated that HPPDC nanoparticles can efficiently overcome drug resistance in breast cancer both in vitro and in vivo by combining chemotherapy and COX-2 inhibitor. In a summary, HPPDC nanoparticles show a great potential for combination treatment of drug resistant breast cancer.

SUBMITTER: Zhang S

PROVIDER: S-EPMC6798417 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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pH and redox dual-responsive nanoparticles based on disulfide-containing poly(β-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer.

Zhang Sipei S Guo Nan N Wan Guoyun G Zhang Tao T Li Chunyu C Wang Yongfei Y Wang Yinsong Y Liu Yuanyuan Y

Journal of nanobiotechnology 20191017 1

<h4>Background</h4>Multidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. Celecoxib (CXB), a selective COX-2 inhibitor, can dramatically enhance the cytotoxicity of doxorubicin (DOX) in breast cancer cells overexpressing P-gp. Thus it can be seen that the combin ...[more]

PMID: 31623608

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Project description:Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(?-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66?mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. STATEMENT OF SIGNIFICANCE:In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Dataset Information

PH and redox dual-responsive nanoparticles based on disulfide-containing poly(?-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer.

Publications

pH and redox dual-responsive nanoparticles based on disulfide-containing poly(β-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer.

Similar Datasets

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