Research Article: Redox‐Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin‐Promoted Cancer Stemness, Metastasis, and Drug Resistance

Date Published: February 04, 2019

Publisher: John Wiley and Sons Inc.

Author(s): Jia Liu, Bingcheng Chang, Qilin Li, Luming Xu, Xingxin Liu, Guobin Wang, Zheng Wang, Lin Wang.

http://doi.org/10.1002/advs.201801987

Abstract

Chemotherapy is a major therapeutic option for cancer patients. However, its effectiveness is challenged by chemodrugs’ intrinsic pathological interactions with residual cancer cells. While inducing cancer cell death, chemodrugs enhance cancer stemness, invasiveness, and drug resistance of remaining cancer cells through upregulating cyclooxygenase‐2/prostaglandin‐E2 (COX‐2/PGE2) signaling, therefore facilitating cancer repopulation and relapse. Toward tumor eradication, it is necessary to improve chemotherapy by abrogating these chemotherapy‐induced effects. Herein, redox‐responsive, celecoxib‐modified mesoporous silica nanoparticles with poly(β‐cyclodextrin) wrapping (MSCPs) for sealing doxorubicin (DOX) are synthesized. Celecoxib, an FDA‐approved COX‐2 inhibitor, is employed as a structural and functional element to confer MSCPs with redox‐responsiveness and COX‐2/PGE2 inhibitory activity. MSCPs efficiently codeliver DOX and celecoxib into the tumor location, minimizing systemic toxicity. Importantly, through blocking chemotherapy‐activated COX‐2/PGE2 signaling, MSCPs drastically enhance DOX’s antitumor activity by suppressing enhancement of cancer stemness and invasiveness as well as drug resistance induced by DOX‐based chemotherapy in vitro. This is also remarkably achieved in three preclinical tumor models in vivo. DOX‐loaded MSCPs effectively inhibit tumor repopulation by blocking COX‐2/PGE2 signaling, which eliminates DOX‐induced expansion of cancer stem‐like cells, distant metastasis, and acquired drug resistance. Thus, this drug delivery nanosystem is capable of effectively suppressing tumor repopulation and has potential clinical translational value.

Partial Text

Chemotherapy remains a major therapeutic approach for clinic oncotherapy. Although cytotoxic chemotherapeutics brutally kill cancer cells, cancer relapse still nearly inevitably occurs even after removal of tumor mass, which accounts for 90% of cancer death.1 An increasing number of studies suggest that cancer relapse after chemotherapy treatment is partly attributable to chemodrugs’ effects on promoting stemness2 and metastasis[[qv: 2f,h]] of residual cancer cells, and enhancing their drug resistance capability.[[qv: 2b,3]] These effects derived from chemotherapy act as a “backdoor” for cancer cells to re‐thrive.[[qv: 3a,4]] However, such “backdoor” is often neglected in our day‐to‐day oncological clinical practice, largely due to lack of clinically approved agents to effectively block this “backdoor” toward reducing cancer repopulation.

In summary, we offered a new approach to solve the limitation of conventional chemotherapy regimen that reduces tumor bulk while facilitates cancer relapse by enhancing stemness, metastatic capacity, and drug resistance in remaining cancer cells. By designing a smart drug delivery system with an ability of inhibiting COX‐2/PGE2 axis underpinning chemodrugs’ “backdoor” effects, we successfully synthesized celecoxib‐conjugated mesoporous silica nanoparticles as a dual drug delivery system for celecoxib and DOX (MSCPs). MSCPs effectively encapsulated payloads, simultaneously released celecoxib derivative and DOX in response to intracellular redox environment, and effectively transported celecoxib and DOX to tumor local. Combining in vitro and in vivo three preclinical animal cancer models, we provided cell‐biological, biochemical, and genetic and molecular data that not only confirmed that conventional and nanomedicine‐based chemotherapy regimens promote cancer stemness and drug resistance to repopulate tumors, but also more importantly, demonstrate that MSCPs sufficiently abrogate DOX‐mediated enhancement on cancer stemness, metastasis and drug resistance through celecoxib derivative blocking the COX‐2/PGE2 pathway, which thus collectively improved the therapeutic efficacy of DOX‐based chemotherapy. Therefore, we developed a promising dual drug delivery platform for effectively reducing tumor burden while simultaneously reversing chemotherapy‐cultivated cancer stemness, metastasis and drug resistance.

Cell Culture and Animals: Human breast cancer cells (MCF7 and MCF7/ADR cells) were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium (10% fetal bovine serum (FBS), 100 unit mL−1 penicillin and 100 µg mL−1 streptomycin) at 37 °C. Human hepatocellular carcinoma cells (HepG2 and HepG2/ADR cells) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) (10% FBS, 100 unit mL−1 penicillin and 100 µg mL−1 streptomycin) at 37 °C.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201801987

 

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