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Progress in Chemistry 2021, Vol. 33 Issue (10): 1900-1916 DOI: 10.7536/PC200956 Previous Articles   

• Review •

Application of Nanocarriers in Co-Loading siRNA and Chemotherapeutic Drugs to Reverse Multidrug Resistance of Tumor

Qiangqiang Yang1, Chuan Li1, Shuxian Yu1, Shuhua Fan1, Yuexia Wang2, Min Hong1()   

  1. 1 School of Chemistry and Chemical Engineering, Liaocheng University,Liaocheng 252059, China
    2 Key Laboratory of Fine Chemicals in Universities of Shandong, School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology(Shandong Academy of Sciences),Jinan 250353, China
  • Received: Revised: Online: Published:
  • Contact: Min Hong
  • Supported by:
    National Natural Science Foundation of China(91543206); Natural Science Foundation of Shandong Province(ZR2015BM024); Tai-Shan Scholar Research Fund of Shandong Province and Research Foundation of Liaocheng University(318012026)
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In recent years, gene interference technology based on small interfering RNA(siRNA) has shown great potential in reversing multidrug resistance of chemotherapy by regulating various proteins related to multidrug resistance of tumor at the gene level. In view of this, the researchers have done a lot of work in the area of RNA interference and chemotherapy drugs. But the free siRNA is not easy to be absorbed by cells without carrier, and it will be degraded by endogenous ribonuclease in plasma and tissues. Therefore, it is necessary to load siRNA on the carrier in order to effectively apply it to tumor treatment. In view of the safety, high efficiency and targeting of nanocarriers, a large number of nanocomposite systems have been developed which can simultaneously load siRNA and chemotherapy drugs. In this paper, the application of nanomaterials in co-loading siRNA and reversing multidrug resistance of chemotherapy drugs are reviewed. In addition, in order to have a better understanding of the related work, some targets which are often used in the study to reverse multidrug resistance are also briefly described.

Contents

1 Introduction

2 Main targets of siRNA regulation

2.1 ATP-binding cassette transporters

2.2 Apoptosis related proteins

2.3 Other targets

3 Nanocarriers for co-delivery of siRNA and chemotherapeutic drugs

3.1 Mesoporous silica nanoparticles

3.2 Metal-organic frameworks

3.3 Polymeric micelles

3.4 Liposome/Niosome

3.5 Dendrimer

3.6 Layer-by-layer nanoparticles

3.7 Hyaluronic acid nanosystem

3.8 Summary

4 Expansion

5 Conclusion and outlook

Key words: RNA interference technology, gene regulation, reversal of multidrug resistance, nanocarrier
Fig.1 Schematic illustration of the Synthesis of DOX-MSN-COOH@ZIF-8/Bcl-2 siRNA NPs[61]. Copyright 2018, American Chemical Society
Fig. 2 Synthesis process and response mechanism for functional metal-organic framework-based nanodrug(DOX@AMOFs@DRHC/CPPs)[73]. Copyright 2017, American Chemical Society
Fig. 3 Preparation of TPGS-siPlk1/TPGS micelles(micSDH) combined with targeted drug Herceptin and DTX[76]
Fig. 4 Schematic diagram of the preparation and drug-loading of triblock copolymer micelle mPEG45-b-PCL80-b-PPEEA[80]. Copyright 2011, American Chemical Society
Fig. 5 Schematic view of our design to co-deliver the Pt(Ⅳ) prodrug DSCP and XPF-targeted siRNA using self-assembled lipid nanoparticles. Cisplatin prodrug DSCP is released and activated to damage DNA. At the same time, siRNA is carried into cells and specifically down-regulates both mRNA and protein levels of endonuclease XPF to prevent the repair of Pt-DNA damage to potentiate the platinum drug[83].Copyright 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Fig. 6 Schematic illustration of the co-delivery system using biodegradable PSomes to deliver Bcl-xL siRNA and DOX.(i) Bcl-xL siRNA is directly encapsulated into PSomes(SPSomes).(ii) DOX is then loaded into the shell of SPSomes through hydrophobic interaction to form CPSomes[93]. Copyright 2013, WILEY-VCH Verlag GmbH & Co
Fig. 7 Schematic diagram of layer-by-layer nanoparticle[97]. Copyright 2013, American Chemical Society
Fig. 8 Schematic illustration of (1)preparation of siRNA/DOX/GH-DPP nanoparticles(2)liver-targeted drug delivery via blood cycle(3)cellular uptake(4)pH-triggered release of Bcl-2 siRNA and DOX[101]. Copyright 2019
Table 1 Summary of co-loaded siRNA and chemotherapeutic drug nanosystems
Materials for
surface modification		 Drug siRNA Substances with targeting effect Release conditions References Advantages of carrier Deficiency of carrier
MSN PEI-PEG DOX P-gp、Bcl-2、c-Myc、PXR - Acidic 56 Biological stability;
Low toxicity;
Biodegradable;Modifiability;High
porosity; Uniform
and adjustable
aperture; Better load capacity		 Risk of hemolysis; Complicated preparation
ZIF-8 DOX Bcl-2 - Lysosome 57
PEG DOX T-type Ca2+
channel		 - Acidic 58
S-S bond、PAE DOX P-gp - Reductive(GSH) 59
PEI DOX P-gp - Reductive(GSH) 62
CA PTX
DTX		 AKT
ERBB2		 - Acidic 63
LDHs Se P-gp
β-tubulin Ⅲ		 - Biodegradation 65
Ca/P/Liposome DTX GRP78 RGD Biodegradation 36
MOF UiO DPP P-gp、Bcl-2
Survivin		 - Phosphate 68 Biodegradable; High porosity; Large
specific surface area; Better load capacity; self-assembly		 Poor biocompatibility; poor drug release propertie
MIL-101 Se、Ru P-gp - Biodegradation 69
AMOFS DOX HIF-1α CPPS Azoreduction 70
Polym
ericmi
celles		 LDL NSC-SS-UA PTX BCRP LDL Reductive (GSH)、Acidic 71 High stability in
vivo; Controlled drug release; Functional design		 Poor storage
stability; Toxicity;
Prepared by
chemical reaction
TPGS DTX PLK1 Herceptin Reductive (GSH)、Acidic 72
HA-ss-(OA-g-bPEI) PTX AURKA HA Reductive(GSH) 73
C18-N
DSPE-PEG2000		 DOX PLK1 - Acidic 74
DPA+PEI PTX Akt - Acidic 75
mPEG45-b-PCL80-b-PPEEA PTX PLK1 - Biodegradation 76
Liposome/
Niosome		 DOTAP、CHOL
DSPE-mPEG DPPC		 PTX GAPDH - Biodegradation 78 Easy assembly; High
entrapment efficiency; Narrow
size distribution;
Controlled drug
release		 Poor storage
stability; High-cost
DOTAP、CHOLDSPE-
mPEG DOPE		 DSCP XPF - Acidic 79
PRTM、DOPE
DDCTMA		 PTX survivin - Biodegradation 80
PRTM、DOTAP
CHOL		 Gem Mcl-1 - Biodegradation 81
mPEG-PLGA
EPL、PEG		 Gem HIF-1a - Biodegradation 82
LHSSG2C14 SPC、CHOL PTX Survivin - Reductive(GSH) 83
PRTM、DOPE
CHOL		 DOX Fab - Biodegradation 84
EDOPC PTX Mcl-1 - Biodegradation 86
LDL、DOPE
CHOLDSPE-PEG		 PTX Bcl-2 - Biodegradation 87
Span80、DOTAP DOX Bcl-2 BCRP - Biodegradation 88
mPEG-b-PLA DOX Bcl-xl - Biodegradation 89
Dendrimer Fol-PEG-GUG-β-CDE DOX PLK1 FA Acidic 92 Structural uniformity; Easily
attached		 Toxicity; Complicated preparation
LbL AuNP IM STAT3 - Biodegradation 94 Modular design;
Modifiability; Controlled drug
release;		 Poor bearing
capacity; Less
available materials
PLA、HA DOX MRP1 HA Biodegradation 95
HA CaP、DPA/ZnHA-CA DOX P-gp HA Acidic 96 Biocompatibility; Targetability; Modifiability; High
degradability;		 Poor bearing
capacity; Uncontrolled drug
release
DSPE-PEG-PEIGA-HA DOX Bcl-2 GA-HA Acidic 97
Table 2 List of abbreviation
Abbreviation full name Abbreviation full name
MDR multi-drug resistence
(多药耐药)		 DSCP disuccinatocisplatin
(琥珀酸顺铂)
P-gp P-glycoprotein
(P-糖蛋白)		 IM imatinib mesylate
(甲磺酸伊马替尼)
MRP1 multidrug resistance-associated protein 1
(多药耐药相关蛋白1)		 GST glutathione S-transferase
(谷胱甘肽巯基转移酶)
BCRP breast cancer resistance protein
(乳腺癌耐药蛋白)		 MGMT O6-methyguanine-DNA methytransferase
(O6-甲基鸟嘌呤-DNA-甲基转移酶)
Bcl-2 B-cell lymphoma-2
(B淋巴细胞瘤-2基因)		 RRM2 ribonucleotide reductase M2
(核糖核苷酸还原酶M2)
Mcl-1 myeloid cell leukemia 1
(一种凋亡调控基因)		 GAPDH glyceraldehyde-3-phosphate Dehydrogenase
(甘油醛-3-磷酸脱氢酶)
PLK1 Polo-like Kinase 1
(Polo样蛋白质激酶1)		 HIF-1 hypoxia-inducible factor-1
(缺氧诱导因子1)
EPR
效应		 enhanced permeability and retention effect
(高渗透长滞留效应)		 c-Myc 一种可使细胞无限增殖的基因
RES
系统		 reticuloendothelial system
(网状内皮系统)		 MSN mesoporous Silica Nanoparticles
(介孔二氧化硅)
CPPs cell penetrating peptide
(细胞穿透肽)		 MON mesoporous Organosilica Nanoparticles
(介孔有机二氧化硅)
LDL low-density Lipoprotein
(低密度脂蛋白)		 MOF metal-Organic Frameworks
(金属有机框架)
PXR pregnane X receptor
(孕烷X受体)		 DPA dipicolylamine
(二甲基吡啶胺)
PAE poly (β-amino esters)
(聚β-氨基酯)		 PRTM protamine
(鱼精蛋白)
DPPC 1,2-Dihexadecanoyl-rac-glycer0-3-phosp
(二棕榈酰磷脂酰胆碱)		 EPL ε-polylysine
(ε-聚赖氨酸)
DOTAP N-[1-(2,3-dioleyloxy)proply]-N,N,
N-trimethylammonium chloridep
(1,2-二油酰-3-三甲基丙烷基氯化铵)		 DOPE dioleoyl Phosphoethanolamine
(二油酰基磷脂酰乙醇胺)
XPF xeroderma pigmentosum complementation group F
(F组着色性干皮病偶联因子重组蛋白)		 DSPE 1,2-distearoyl-sn-glycero-3-phosphoethanolamine
(二硬脂酰基磷脂酰乙醇胺)
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