Redox-Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin-Promoted Cancer Stemness, Metastasis, and Drug Resistance.

Jia Liu,Qilin Li,Bingcheng Chang,Xingxin Liu,Guobin Wang,Lin Wang,Zheng Wang,Luming Xu

doi: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.

Highlights

Chemotherapy remains a major thera peutic approach for clinic oncotherapy
As a specific COX-2 inhibitor approved by FDA, celecoxib reportedly reverses prostaglandin E2 (PGE2)-mediated cancer stem cells (CSC) expansion[2b,3b,13] and metastasis,[6c,7] and dampens P-gp-dependent drug resistance induced by chemotherapy,[2b,3b,10a,11b,14] thereby presumably suppressing cancer repopulation
The redox-sensitive MSNs-based drug delivery system with COX-2 inhibition activity was fabricated in four steps (Figure 1A): 1) through hydrolysis of TEOS as our previously reported,[19] MSNs (MCM-41 type) were functionalized with thiol (-SH) groups to generate MSNs-SH; 2) MSNs-SH were reacted with S-(2-aminoethylthio)-2-thiopyridine hydro chloride (SATH) to obtain amine modified MSNs with disulfide linkages (MSNs-SS-NH2); 3) amine groups of MSNs-SS-NH2 were covalently conjugated with celecoxib succinamidic acid (Figure S1, Supporting Information) to prepare MSNs-SS-CEL; (4) after DOX was loaded into MSNsSS-CEL, the nanoparticles’ celecoxib moieties were capped by cyclodextrin units of PCD through host-guest interactions, yielding PCD-capped, DOX-loaded MSNs-SSCEL nanoparticles (DOX@MSNs-SS-CEL@PCD), which were termed as DOX@MSCPs for simplicity (Figure 1A)

Summary

Introduction

Chemotherapy remains a major thera peutic approach for clinic oncotherapy. cytotoxic chemotherapeutics bru tally kill cancer cells, cancer relapse still nearly inevitably occurs even after removal of tumor mass, which accounts for 90% of cancer death.[1]. As a specific COX-2 inhibitor approved by FDA, celecoxib reportedly reverses PGE2-mediated CSCs expansion[2b,3b,13] and metastasis,[6c,7] and dampens P-gp-dependent drug resistance induced by chemotherapy,[2b,3b,10a,11b,14] thereby presumably suppressing cancer repopulation. This notion is supported by several observations that celecoxib helped reduce cancer inci dence and pre-cancerous lesion occurrence in high-risk popula tions (for instance, colon and skin cancer).[15] given celecoxib’s poor solubility and low bioavailability as well as lim ited tumor infiltration capability,[16] celecoxib has to be orally administered in a high dose, which can lead to severe cardio vascular events[15c,17] that resulted in termination of two govern ment-sponsored clinical trials.[18]. MSCPs containing celecoxib moieties are a promising drug delivery nanosystem toward tumor eradication

Synthesis and Characterization of MSCPs

Conclusion

Experimental Section

Conflict of Interest