Nanosized Drug Delivery Systems for Breast Cancer Stem Cell Targeting

Figures & data

Figure 1 Strategies against breast cancer stem cells: (1) targeting BCSC surface markers; (2) inhibition of BCSC-dependent signaling pathways; (3) interfering the BCSC differentiation; (4) targeting metabolisms in BCSCs; (5) targeting the breast tumor microenvironments.

Abbreviations: TAMs, tumor-associated macrophages; CAFs, cancer-associated fibroblasts; MSCs, mesenchymal stem cells.

Table 1 Agents Against BCSCs

Type	Agents	Mechanism of Action	Status	References
Small-molecular inhibitors/drugs	Lovastatin	Inhibit SOX2 promoter transactivation	In vitro	[^Citation88]
	Quercetin	Low the expression of ALDH1A1, CXCR4, MUC1 and EpCAM	In vitro	[^Citation34,^Citation89]
	Curcumin	Suppress SHH and Wnt/β-catenin pathways	In vitro	[^Citation36]
	Tocopherols	Estrogen-dependent and Oct-4 mediated mechanisms	In vitro	[^Citation90]
	Valproic acid	An inhibitor of histone deacetylases	In vitro	[^Citation91]
	GANT61	A Hh inhibitor	In vitro	[^Citation20]
	Actinomycin D	Down-regulation of Sox-2	In vitro	[^Citation92]
	Forskolin	Activation of protein kinase A system (PKA) leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability	In vitro	[^Citation93]
	S2E	Glutathione S-transferase omega 1 inhibitors	In vitro	[^Citation94]
	Niclosamide	Targets NF-κB, Wnt/β-catenin and Notch pathway of BCSCs	In vivo	[^Citation95]
	Simvastatin	Inhibition of mevalonate metabolism	In vivo	[^Citation32]
	Sulforaphane	Downregulate the Wnt/β-catenin pathway	In vivo	[^Citation35]
	Cyclopamine	Inhibitor of the Hh pathway	In vivo	[^Citation96]
	Iadademstat	Inhibitor of the lysine-specific demethylase 1	In vivo	[^Citation97]
	KU758, KU711	C-terminal heat shock protein 90 inhibitors	In vivo	[^Citation98]
	Dasatinib	A Src kinase family inhibitor	In vivo	[^Citation5]
	BKM120	Inhibit the PI3K/Akt signaling pathway in SCs	In vivo	[^Citation99]
	Pyrvinium pamoate	WNT pathway inhibitor	In vivo	[^Citation100]
	Mifepristone	By down-regulating kruppel-like factor 5 expression	In vivo	[^Citation101]
	Chloroquine	Deregulation of janus kinase 2 and DNA methyltransferase 1	In vivo	[^Citation102]
	Kazinol-E	Inhibitor of extracellular regulated protein kinases	In vitro	[^Citation103]
	Salinomycin	Result in the loss of expression of BCSC genes	In vivo	[^Citation37]
	CWP232228	Inhibiting β-catenin-mediated transcription	In vivo	[^Citation7]
	Apigenin	Hippo pathway inhibitor	In vivo	[^Citation76]
	Metformin	Inhibit cellular transformation	In vivo	[^Citation104]
	Thioridazine	Targets dopamine receptor of BCSCs	In vivo	[^Citation105]
	Vitamin D compounds (1α, 25 (OH) 2D3, BXL0124)	Noth signaling pathway inhibitor	In vivo	[^Citation106]
	Doxycycline	Inhibitor of mitochondrial biogenesis	Clinical pilot study	[^Citation107]
Nucleic acid	miRNA-200c	Reduce BCSCs by targeting B cell-specific moloney murine leukemia virus integration site1(BMI1)	In vitro	[^Citation108]
	miR-141	Reduce BCSCs by targeting signal transducer and activator of transcription 5 a (Stat5a)	In vitro	[^Citation109]
	miR-34c	Inhibit BCSCs by targeting Notch4	In vitro	[^Citation110]
	miR-128	Inhibit BCSCs by targeting BMI1 and ATP Binding Cassette Transporter C5 (ABCC5)	In vitro	[^Citation111]
	miR-140	Inhibit BCSCs by targeting ALDH1 and SOX9	In vitro	[^Citation112]
	NF-κB shRNA	Decrease mammosphere and colony formation and lower ALDH^+ CSCs population	In vitro	[^Citation38]
	Let-7	Reduce BCSCs by targeting High mobility group AT-hook 2(HMGA2)	In vivo	[^Citation113]
	miRNA-100	Attenuate expression of the CSCs regulatory genes SMARCA5, SMARCD1, and BMPR2.	In vivo	[^Citation6]
	miR-200b	Inhibit BCSCs by targeting SUZ12, H3K27me3 of E-cadherin and other genes	In vivo	[^Citation114]
	miR-30	Inhibit BCSCs by targeting Ubc9 and ITGB3	In vivo	[^Citation115]
	miR-27a	Inhibit BCSCs by targeting ZBTB10	In vivo	[^Citation116]
	miR-27b	Inhibit BCSCs by targeting ENPP1	In vivo	[^Citation117]
	miR-7	Inhibit BCSCs by targeting KLF4, SETDB1	In vivo	[^Citation118]
	miR-34a	Reduce BCSCs by targeting Notch1	In vivo	[^Citation119]
	integrin α9 gene	Knockout of integrin α9 using CRISPR/Cas9 technology reduced TNBC cell cancer stem cell (CSC)-like property	In vivo	[^Citation120]
	YB-1 gene	Knockout of YB-1gene using CRISPR/Cas9 technology inhibited the proliferation of BCSCs	In vivo	[^Citation121]
Protein	Cholera toxin	Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability	In vitro	[^Citation93]
	Trastuzumab	Inhibit the HER-2 related BCSC-activating pathways	In vivo	[^Citation122]
	PF-06647020	Inhibit Wnt signaling pathway	In vivo	[^Citation123]
	OMP-18R5	Inhibit Wnt signaling pathway	In vivo	[^Citation64]
	Cirmtuzumab	Reduce activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1	In vivo	[^Citation124]
	Anti-CDH11 antibody	Inhibit epithelial-to-mesenchymal transition and repressed cancer stem cell-like phenotype	In vivo	[^Citation18]
	TmSm(T34A)	Down-regulating the expression of Cyclin D1	In vivo	[^Citation125]
	P245	Against the CD44 cell surface receptor	In vivo	[^Citation57]
	RO5429083/RG7356	Modifications of the mitogen-activated protein kinase pathway	In vivo	[^Citation126]
	B6H12.2	Blockade the function of CD47	In vivo	[^Citation127]
	dCD133KDEL	Inhibition of CD133	In vivo	[^Citation59]

Table 2 Delivery of BCSC-Specific Small Molecular Agents

Ligand/Receptor	Therapeutic Agent	Drug Delivery System	Status	References
	Chloroquine	Triphenylphosphonium-functionalized hyperbranched polymer nanocarrier	In vitro	[^Citation138]
	Salinomycin	Gold nanoparticles (AuNPs) coated with poly(ethylene glycol)	In vitro	[^Citation139]
	Doxorubicin	DOX-Hyd@AuNPs nanoparticles	In vivo	[^Citation13]
	CRLX101	Camptothecin-containing nanoparticle-drug conjugate	In vivo	[^Citation140]
	Wedelolactone	PLGA nanoparticle	In vivo	[^Citation40]
	Zileuton™	Pluronic^® F127 polymer micelles	In vivo	[^Citation141]
	Cyclopamine	Liquid–lipid nanoparticles	In vivo	[^Citation96]
	Doxorubicin	Pluronic polymeric micelles	In vivo	[^Citation142]
	All-trans retinoic acid	Stealth liposomes	In vivo	[^Citation143]
Vasoactive intestinal peptide/VIP receptors	Curcumin	DSPE-PEG2000 nanomicelles	In vitro	[^Citation41]
Ferritin/transferritin receptor 1	Mertansine	Biomimetic nanocages of apoferritin	In vitro	[^Citation144]
Chitosan/CD44	Doxorubicin	Pluronic F127 cross-linked and surface-decorated with chitosan nanoparticles	In vivo	[^Citation145]
Glucose/glucose transporter 1	γ-secretase inhibitors	MSN-PEI-Gluc Nanoparticle	In vivo	[^Citation146]
HA/CD44; DCLK1 monoclonal antibody/DCLK1	Doxorubicin	HA and DCLK1monoclonal antibody modified PLGA nanoparticles	In vivo	[^Citation147]
Anti-CD133;TAT peptides/CD33	Tirapazamine	Mesoporous silica nanoparticle (MSN)	In vivo	[^Citation148]
RGD/integrin alpha5 (ITGA5)	Diacidic norcantharidin	Lipid-polymer hybrid (LPH) nanoparticle	In vivo	[^Citation46]
CD44 antibody/CD44	Hsp90 inhibitor	CD44-Fe3O4@SiNPs	In vivo	[^Citation149]
F3 peptide/nucleolin	Doxorubicin	Liposomes functionalized with the nucleolin-binding F3 peptide	In vivo	[^Citation150]
EpCAM aptamer/EpCAM protein	Aspirin	Nanoexosomes	In vivo	[^Citation45]
Herceptin/Her-2	Metformin	Herceptin-Conjugated Liposome	In vivo	[^Citation42]

Table 3 Delivery of BCSC-Specific Nucleic Acid Drugs

Ligand/Receptor	Therapeutic Agent	Drug Delivery System	Status	References
	NF-κB shRNA	Carbamate-mannose modified PEI	In vitro	[^Citation38]
	miR-34a	hTERT promoter-driven VISA nanoparticle	In vivo	[^Citation151]
	AKT2 siRNA	Pluronic^® F127 micelles with polyplexes	In vivo	[^Citation152]
Anti-HER2 nanobody/HER2	Apoptosis-inducing tBid gene	Anti-HER2 nanobody (Nb)-conjugated polyamidoamine (PAMAM) polyplexes	In vitro	[^Citation153]
APTEDB/EDB-FN	EDBsiRNA	Liposomal system (APTEDB‐LS‐siRNAEDB)	In vivo	[^Citation154]
Glucose/glucose transporter 1	Polo-like kinase 1 (PLK1) siRNA	Glucose-installed targeted nanoparticles	In vivo	[^Citation155]

Table 4 Combinational Delivery of Chemotherapeutics and CSC-Specific Agents

Ligand/Receptor	Therapeutic Agent	Drug Delivery System	Status	References
	GANT61+Curcumin	PLGA NPs	In vitro	[^Citation156]
	Camptothecin+GRP78 siRNA/CLUsiRNA	DOTAP liposomes	In vitro	[^Citation157]
	miRNA-200c+Paclitaxel	Solid lipid nanoparticles	In vitro	[^Citation158]
	Salinomycin+Doxorubicin	Cross-linked multilamellar liposomal	In vivo	[^Citation159]
	All-trans-retinoic acid+Doxorubicin	Poly(ethylene glycol)-block-polylactide (PEG-b-PLA)	In vivo	[^Citation31]
	Staurosporine+Epirubicin	PEG-b-poly(aspartate-hydrazide-epirubicin) copolymer	In vivo	[^Citation160]
	siBMI-1+Docetaxel	Ationic-lipid-assisted nanoparticles PEG5Kb-PLGA12K;cationic lipid BHEM-Chol	In vivo	[^Citation17]
	Doxorubicin+SN38	PEG-CH=N-DOX prodrug	In vivo	[^Citation43]
	Curcumin+Doxorubicin	mPEG-PLGA-Pglu nanoparticle	In vivo	[^Citation15]
	Docetaxel+Salinomycin	PLGA/TPGS nanoparticle	In vivo	[^Citation161]
	Doxorubicin+Hymoquinone	Cockle shell-derived aragonite CaCO3 nanoparticles	In vivo	[^Citation162]
	Paclitaxel+Thioridazine +HY19991	Enzyme/pH dual-sensitive nanoparticle with a micelle-liposome double-layer structure	In vivo	[^Citation163]
HA/CD44	Salinomycin+Paclitaxel	PLGA nanoparticle	In vitro	[^Citation164]
HA/CD44	Doxorubicin+ tariquidar	dendritic polyglycerol-conjugated, mesoporous silica-based targeting nanocarriers	In vitro	[^Citation165]
oHA/CD44	Curcumin+Paclitaxel	Double pH-sensitive nano-eggs	In vivo	[^Citation166]
HA/CD44	Doxorubicin+irinotecan	Hyaluronic acid-decorated dual responsive nanoparticles	In vivo	[^Citation167]
CD44 antibody/CD44	Paclitaxel+Salinomycin	Single-walled carbon nanotubes	In vivo	[^Citation44]
HA/CD44	Doxorubicin+ICG	HA-hyaluronan-decorated fullerene-silica	In vivo	[^Citation168]
HA/CD44	Paclitaxel+Curcumin	HA-HAD-PLGA nanoparticles	In vivo	[^Citation169]
Ferritin/Transferritin receptor 1	Epirubicin+DIR	Biomimetic nanocages of apoferritin	In vivo	[^Citation47]
CD44 aptamer TA6/CD44	Doxorubicin+AKT inhibitor peptide	Aptamer-conjugated DNA nanotrain TA6NT-AKTin-DOX	In vivo	[^Citation16]
HA/CD44	Doxorubicin+Cyclopamine	Hyaluronic acid functional amphipathic and redox-responsive polymer particles	In vivo	[^Citation170]

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