Recent advances in drug delivery systems for targeting cancer stem cells

Abstract

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.

Keywords: ABC, ATP binding cassette; AFN, apoferritin; ALDH, aldehyde dehydrogenase; BM-MSCs-derived Exos, bone marrow mesenchymal stem cells-derived exosomes; Biomarker; CAFs, cancer-associated fibroblasts; CL-siSOX2, cationic lipoplex of SOX2 small interfering RNA; CMP, carbonate-mannose modified PEI; CQ, chloroquine; CSCs, cancer stem cells; Cancer stem cells; Cancer treatment; Cellular level; DCLK1, doublecortin-like kinase 1; DDSs, drug delivery systems; DLE, drug loading efficiency; DOX, doxorubicin; DQA-PEG2000-DSPE, dequlinium and carboxyl polyethylene glycol-distearoylphosphatidylethanolamine; Dex, dexamethasone; Drug delivery systems; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EPND, nanodiamond-Epirubicin drug complex; EpCAM, epithelial cell adhesion molecule; GEMP, gemcitabine monophosphate; GLUT1, glucose ligand to the glucose transporter 1; Glu, glucose; HCC, hepatocellular carcinoma; HH, Hedgehog; HIF1α, hypoxia-inducible factor 1-alpha; HNSCC, head and neck squamous cell carcinoma; IONP, iron oxide nanoparticle; LAC, lung adenocarcinoma; LNCs, lipid nanocapsules; MAPK, mitogen-activated protein kinase; MB, methylene blue; MDR, multidrug resistance; MNP, micellar nanoparticle; MSNs, mesoporous silica nanoparticles; Molecular level; NF-κB, nuclear factor-kappa B; Nav, navitoclax; Niche; PBAEs, poly(β-aminoester); PDT, photodynamic therapy; PEG-PCD, poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol); PEG-PLA, poly(ethylene glycol)-b-poly(d,l-lactide); PEG-b-PLA, poly(ethylene glycol)-block-poly(d,l-lactide); PLGA, poly(ethylene glycol)-poly(d,l-lactide-co-glycolide); PTX, paclitaxel; PU-PEI, polyurethane-short branch-polyethylenimine; SLNs, solid lipid nanoparticles; SSCs, somatic stem cells; Sali-ABA, 4-(aminomethyl) benzaldehyde-modified Sali; TNBC, triple negative breast cancer; TPZ, tirapazamine; Targeting strategies; cRGD, cyclic Arg-Gly-Asp; iTEP, immune-tolerant, elastin-like polypeptide; mAbs, monoclonal antibodies; mPEG-b-PCC-g-GEM-g-DC-g-CAT, poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cationic ligands); ncRNA, non-coding RNAs; uPAR, urokinase plasminogen activator receptor.

Graphical abstract

Figure 1

Schematic illustration of multiple unique characteristics of cancer stem cells (CSCs) (A) CSCs possess the ability of self-renewal and differentiation, and express high levels of drug efflux pumps and boosting special biomarkers (B) CSCs reside in complex niche. Reprinted with the permission from Ref. 6. Copyright © 2018 The Authors. Published by Elsevier Ltd.

Figure 2

Emerging cancer stem cells (CSCs)-targeted drug delivery systems for efficient cancer therapy following the main line of CSC occurrence and development process.

Figure 3

Schematic illustration of cancer stem cell (CSC) biomarkers-mediated delivery systems (A) Schematic illustration of HA-SLNs/PTX delivering PTX to CSCs through HA-mediated mechanism (B) Schematic illustration of Glu-NPs for the targeted delivery of siPLK1 through selective recognition of the glucose ligand to GLUT1. Reprinted with the permission from Ref. 25. Copyright © 2019 Elsevier B.V. (C) Schematic illustration of CD133Ab-NPs to effectively deliver SN38 through receptor-mediated endocytosis. Reprinted with the permission from Ref. 26. Copyright © 2016 American Chemical Society.

Figure 4

Schematic illustration of mertansine-apoferritin (M-AFN) preferentially taken up by cancer stem cells (CSCs)-enriched tumorspheres. Reprinted with the permission from Ref. 27. Copyright © 2018 Elsevier B.V.

Figure 5

Schematic illustration of mitochondria-targeted delivery. Reprinted with the permission from Ref. 28. Copyright © 2010 American Chemical Society.

Figure 6

Schematic illustration of R646 nano-miRs targeting multiplexed cancer stem cells-regulating miRNAs. Reprinted with the permission from Ref. 29. Copyright © 2018 American Chemical Society.

Figure 7

Schematic illustration of co-delivery system for simultaneously eliminating cancer stem cells (CSCs) and non-CSCs (A) HGNPs for co-delivering miR-21i and DOX. Reprinted with the permission from Ref. 30. Copyright © 2016 Elsevier B.V. (B) PPBV micelles for co-delivering paclitaxel and curcumin. Reprinted with the permission from Ref. 31. Copyright © 2017 Elsevier Ltd.