Polyethyleneimine (PEI) as a Polymer-Based Co-Delivery System for Breast Cancer Therapy

Figures & data

Figure 1 Flow chart of review methods.

Abbreviation: PEI, polyethyleneimine.

Figure 2 Structure of linear PEI (A) and branched PEI (B).

Note: Reproduced from: Polymerdatabase. Available from: https://polymerdatabase.com/PolymerBrands/Polyethyleneimine.html. Accessed March 23, 2022.²¹ © 2015–2022 polymerdatabase.com.

Abbreviation: PEI, polyethyleneimine.

Table 1 PEI as Co-Delivery System for Cancer Therapy

No	PEI Type	Anticancer Drug	Gene-Therapy	Combination	Cancer Type	In vitro	In vivo	Reference
1.	Branched	PTX	-	Ag-PEI-PTX Functionalized AgNPs, PEI, and PTX	Liver cancer	HepG2	-	[^Citation29]
2.	Branched, 10 kDa	PTX	-	(PEI-SA) HA/PTX PEI grafted with SA, modified with HA, and complexed with PTX	Ovarian cancer	SKOV3-TR30 (MDR)	Tumor-bearing nude mice	[^Citation30]
3.	Branched, 25 kDa	EPI and PTX	-	PLGA-PEI-EPI or -PTX PGLA conjugated with PEI, and loaded with EPI and PTX	Lung cancer	A549	-	[^Citation31]
4.	PEI coated with ZnO-SiO2	Ru	-	Ru–CA–PEI–ZnO–SiO2 CSNPs Ru grafted with CA; co-delivery of PEI coated with ZnO-SiO2	Cervical cancer	HeLa	Female athymic nude mice	[^Citation33]
5.	2 kDa	-	pEGFP-N2	Pluronic-PEI-DR5-TAT/pEGFP-N2 DNA DR5-TAT-modified Pluronic-PEI loaded with pEGFP-N2 DNA.	DR5-positive (cervical cancer, liver cancer, prostate cancer)	HeLa, HepG2, and NIH 3T	-	[^Citation34]
6.	Branched, 25 kDa	-	pEGFP, Bcl-2 AS ODN	PEI-CA/pEGFP and Bcl-2 AS ODN PEI-CA complexed with Bcl-2 AS-ODN and pEGFP plasmid	Cervical cancer	HeLa	-	[^Citation35]
7.	Linear, 22, 87, and 217 kDa Branched, 25 kDa	-	pZsGreen1-N1	PEI/pDNA	Bovine fetal fibroblast, kidney cancer, liver cancer	BFF, HEK293, and HepG2	-	[^Citation36]
8.	Branched, 25 kDa	-	MRP1-siRNA	PEI copped-pSiNPs-MRP1-siRNA pSiNPs complex with PEI loaded with MRP1-siRNA	Glioblastoma	U87	CD-1 nude mice	[^Citation37]
9.	Branched, 25 kDa	-	Human DKK-1 and murine PD-L1 cDNA subcloned to pcDNA3.1 plasmid	PLGA/PEI-pPD-L1/pDDK-1 vaccine PLGA/PEI complexed with DKK-1 and PD-L1	Multiple myeloma/Plasma cell cancer	-	Tumor-bearing Female BALB/c mice	[^Citation38]
10.	Branched, 25 kDa	-	Anti-PLK1 (PLK1-homo-581) siRNA	PEG-GO-PEI-FA/anti-PLK1 (PLK1-homo-581) siRNA PEG and PEI complexed with functionalized GO and FA, loaded with anti-PLK1 (PLK1-homo-581) siRNA	Ovarian cancer	SKOV3	-	[^Citation39]
11.	Branched, 25 kDa	DTX	pDNA	TAT-DTX/pDNA LPNs modified TAT, DTX, and pDNA loaded to CPPs modified LPNs	Prostate cancer	PC3	Female BALB/c mice weighing	[^Citation52]
12.	Branched	DTX	p44/42 MAPK siRNA	DTX/BSA-PEILBL/siRNAP PSMAab-conjugated fluorescent BSA-branched PEILBL) loaded with DTX and p44/42 MAPK siRNA	Prostate cancer	PZ-HPV-7, CWR22R, PC3, LNCaP, DU145, HEK293, MGH-U1, and MGH-U1R	Mice	[^Citation53]
13.	Branched, 25 kDa	DOX	pEGFP	HDDN-DOX-HBA-PEI (DHP) complexed with HA and pDNA	Liver cancer	HepG2	-	[^Citation46]
14.	PEI-g-Pleu	DOX	pGL3, Bcl-2-shRNA	PEI-g-Pleu PEI grafted by one step ROP with L-leucine N-carboxy anhydride, and complexed with DNA and shRNA	Melanoma	B16F10	-	[^Citation48]
15.	1.8 kDa	DOX	pEGFP-C1	PEI/DNA-DNPs DNPs condensed with PEI/DNA nano complex	Cervical cancer	HeLa, L929	Male BALB/c nude mice	[^Citation49]
16.	Branched (0.8, 1.3, 25 kDa) Linear (2.5, 8 kDa)	MTX	pcDNA3-FLAG-p53	PEI/p53 encoding pDNA/MTX PEI/pDNA nanoparticles loaded with MTX	Cervical cancer	HeLa	-	[^Citation55]
17.	Branched, 1.8 kDa	DOX	Bcl-2 siRNA	Bcl-2 siRNA/DOX/GH-DPP DSPE-PEG-PEI complexed with GA-HA as liver-targeted nanoparticles (GH-DPP), loaded with Bcl-2 siRNA and DOX	Liver cancer	HepG2	H22-bearing mice	[^Citation51]
18.	Branched, 25 kDa	MTX	Cy5-labeled survivin siRNA	M-MTX/Cy-5 labeled survivin siRNA Functionalized MTX conjugated with LA-modified branched PEI (MTX-bPEI-LA) to form mixed micelles (M-MTX), and loaded with Cy5-labeled survivin siRNA	Cervical cancer	HeLa	Tumor-bearing nude mice	[^Citation56]
19.	Branched	RA	miR-29b	P103-PEI-RA/miR-29b Pluronic P103 linked to PEI, complexed with RA and miR-29b	Lung cancer	A549 and H1299	-	[^Citation58]
20.	1.8 kDa	DOX	siPgp	PAPD nanoparticles Hypoxia-sensitive PAPD loaded with DOX and anti-siPgp	Ovarian cancer	A2780 Adriamycin resistant (ADR), MCF7	-	[^Citation61]
21.	Branched, 25 kDa	PFD	siScr	F-PEI-PFD/siScr F-PEI and PFD emulsions, complexed with siScr	Melanoma	B16F10	C57BL/6 mice	[^Citation65]

Abbreviations: Ag-NPs, silver nanoparticles; AS-ODN, antisense oligodeoxyribonucleotide; Bcl-2, B cell lymphoma-2; BSA, bovine serum albumin; CA, cholic acid; CPPs, cell-penetrating peptides; DKK-1, dickkopf-1; DTX, docetaxel; DOX, doxorubicin; DNPs, doxorubicin nanoparticles; DSPE, 1,2-distearoyl-sn glycerol-3-phosphoethanolamine; EPI, epirubicin; FA, folic acid; F-PEI, fluorinated polyethyleneimine; GA-HA, glycyrrhetinic acid-modified hyaluronic acid; GO, graphene oxide; HA, hyaluronic acid; HBA, hydrazinobenzoic acid; HDDN, hyaluronic-acid DHP/DNA nanoparticles; LA, linoleic acid; LPNs, lipid–PEI hybrid nanoparticles; MAPK, mitogen-activated protein kinase; MRP1, multi-drug resistance-associated protein 1; MTX, methotrexate; PAPD, PEG-azobenzene-PEI-DOPE; pDNA, plasmid DNA; PD-L1, programmed death-ligand-1; PEG, polyethylene glycol; pEGFP, enhanced green fluorescent protein plasmid; PEI, polyethyleneimine; PEI-g-PLeu, PEI-g-poly-L-leucine; PEILBL, PEI layer by layer; PFD, perfluoro decalin; pSiNPs, porous silicon nanoparticles; PLGA, poly-(lactic-co-glycolic) acid; PLK1, polo like kinase 1; PSMAab, prostate-specific membrane antigen-antibody; PTX, paclitaxel; RA, retinoic acid; ROP, ring-opening polymerization; Ru, ruthenium pro-drug; SA, salicylic acid; shRNA, short hairpin RNA; siRNA, small interfering RNA; siPgp, P-gp siRNA; siScr, scrambled siRNA; TAT, RKKRRQRRR peptide.

Table 2 PEI as Co-Delivery System for Breast Cancer Therapy

No	PEI Type	Anticancer Drugs	Gene Therapy	Combination	In vitro	In vivo	Reference
1.	PEtOx-co-PEI	DOX		DOX-loaded PEtOx-co-PEI-b-PCL PEtOx-co-PEI complexed with PCL, and loaded with DOX	MCF-7	-	[^Citation32]
2.	25 kDa	-	siEGFR1, siEGFR2, siEGFR3, siBRD41, siBRD42, siBRD43	GALA-PEG-SS-PEI and CREKA-PEG-SS-PEI GALA- and CREKA-modified with PEG; SS; PEI (PEG-SS-PEI)	MDA-MB-231 and HUVEC	-	[^Citation40]
3.	Branched, 1.2 kDa	-	siRNA, pDNA	pDNA/siRNA/lipopolymer Lipid-grafted PEI loaded with pTRAIL and silencing BCL2L12 and SOD1 siRNA	MCF-7, MDA-MB-231	MDA-MB-231 xenografted mice	[^Citation57]
4.	1.3 kDa	DOX	pArg	DOX-loaded CA-PEI-pArg PMs pH-responsive PMs contain CA-PEI-pArg copolymers, loaded with DOX	MCF-7	-	[^Citation43]
5.	Linear, 5 kDa	GA	pTRAIL	GA/pTRAIL-HA/PP Adding HA to neutralize the excess positive charge	MDA-MB-231 and MCF-7	Tumor-bearing nude BALB/c mice (5-week-old, 18–20 g, female)	[^Citation54]
6.	Branched, 10 kDa	DOX	Bcl-xL shRNA	PLGA-DOX-Alkyl-PEI NPs/shRNA DOX encapsulated by PLGA, complexed with PEI modified with alkyl chain, and loaded with Bcl-xL shRNA.	MCF-7	-	[^Citation45]
7.	Branched, 1 kDa	DOX	p53	PDP/DOX/p53 Grafted lipophilic deoxycholic acid and low molecular weight (1 kDa) branched PEI to pullulan, and complexed with DOX and p53	MCF-7	6–8-week-old female BALB/C nude mice	[^Citation47]
8.	Branched, 25 kDa	DOX	pORF-hTRAIL	PCL-PEI-PEG-T7/DOX/pORF-hTRAIL PEG-PEI-PCL-S-S-PCL-PEI-PEG loaded with pORF-hTRAIL and DOX	MCF-7	6-week-old BALB/c female nude mice	[^Citation50]
9.	Branched, 1.8 kDa	EMB	pTRAIL	EMB/TRAIL-HA/PBAE-PEI EMB and pTRAIL delivered with amphiphilic polymers PEI- PBAE. Tumor targeting mediated by HA	MDA-MB-231	-	[^Citation59]
10.	Branched, 1.8 kDa	GemC18	NF-κB siRNA	GemC18-containing PMs/anti NF-κB siRNA PCL-PEI-PEG functionals PMs, loaded with 4-(N)-stearoyl GemC18 and NF-κB siRNA	AsPC-1 and MCF7	Balb/c mice bearing 4T1 xenograft breast tumor	[^Citation60]
11.	JetPEI	DOX	miR-142-3p	Jet PEI/CD44-specific-siRNA/DOX Jet PEI complexed with CD44-specific-siRNA and DOX	MDA-MB-468	-	[^Citation62]

Abbreviations: Bcl-Xl, B-cell lymphoma-extra-large; BCL2L12, Bcl2-like12; CA, cholic acid; DOX, doxorubicin; EMB, embelin; GemC18, gemcitabine pro-drug; HA, hyaluronic acid; hTRAIL, human tumor necrosis factor-related apoptosis-inducing ligand; NF-κB, nuclear factor-κB; pArg, poly-L-arginine; PBAE, poly[(1,6-hexanediol)-diacrylate-β-5-hydroxyamylamine; PCL, poly(E-caprolactone); pDNA, plasmid DNA; PEG, polyethylene glycol; PEI, polyethyleneimine; PetOx-co-PEI, poly(2-ethyl-2-oxazoline)-co-poly(ethyleneimine); PLGA, poly-(lactic-co-glycolic) acid; PMs, polymeric micelles; pORF, plasmid open reading frame; pTRAIL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasmid; siRNA, small interfering RNA; SOD1, superoxide dismutase 1; SS, disulfide.

Figure 3 Scheme of nanoparticles containing PEI as drug and RNAi delivery.

Abbreviations: miRNA, micro-RNA; PEI, polyethyleneimine; RNAi, RNA interference; siRNA, small interfering RNA.

Figure 4 Mechanism of action of PEI for drug and nucleic acid internalization via endocytosis.

Abbreviations: AD, anticancer drugs; mRNA, messenger RNA; PEI, polyethyleneimine; RNAi, RNA interference; siRNA, small interfering RNA.

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