Intelligent polymeric micelles for multidrug co-delivery and cancer therapy

Figures & data

Table 1. Examples of intelligent polymeric micelles for multidrug co-delivery and cancer therapy.

Intelligent type	Targets/stimulus	Assembly units	Cargoes	Mechanisms	Evaluation	References
Passive
		mPEG-SS-PTX/mPEG-SS-DOX	DOX/PTX	EPR effect	In vitro/In vivo	[119]
Ligands
	Folate	FA-PEG-b-(PCL-g-PEI)-b-PCL	DOX/siRNA	Folate receptor targeting	In vitro/In vivo	[120]
		FA-PCL-PHEMA-Cis-MET	PTX/MET		In vitro	[56]
		FA-CD-PLLD	DOC/MMP-9 siRNA		In vitro/In vivo	[63]
	HA	HA-VES	DOX /Cur	CD44 targeting	In vitro/In vivo	[67]
		HA-g-VES/TPGS2k	DOX/Cur		In vitro/In vivo	[121]
	Tf	Tf- PEG-PE	PCL/Cur	TfR targeting	In vitro/In vivo	[122]
		Tf- PEG-PE	PTX/TRQ		In vitro	[69]
Antibody
	scFv	GLUT1 scFv-PEG-PE	DOX/Cur	GLUT1 targeting	In vitro	[74]
	Herceptin	VE TPGS and TPGS-siRNA	DOX/polo-like kinase 1 siRNA	HER2 targeting	In vitro	[123]
TME
	pH	PHis-PLA-PEG-PLA-PHis	CUR/L61	Protonation of PHis blocks	In vitro/In vivo	[124]
		Dox-DNM	5-Fu/Dox	Proton sponge effect of the polyamidoamine dendron dendron	In vitro/In vivo	[92]
		mPEG-g-PLL-b-Phe	DOX/P-gp siRNA	Schiff's base cleavage	In vitro	[125]
		PEG-b-(PLL-g-PTX/DMA)	DSF/PTX	Tumour-acidity-activated charge conversion	In vitro	[16]
		Dex-SA	DOX/platinum (II)	ionization degree of SA moieties	In vitro/In vivo	[126]
		FA-PCL-PHEMA-Cis-MET	PTX/MET	Cis-aconityl bond cleavage	In vitro	[56]
		STS/Epi/m	DSF/Epi	Hydrazone bond cleavage	In vitro/In vivo	[127]
	Redox	mPEG-SS-C18	PTX/DAS	Disulphide bond cleavage	In vitro	[100]
		mPEG-SS-PTX/mPEG-SS-DOX	PTX/DOX	Disulphide bond cleavage	In vitro/In vivo	[119]
		POEG-b-PSSDas	DOX/DAS	Disulphide bond cleavage	In vitro/In vivo	[128]
		PLG-g-mPEG/CPT	CPT/DOX	Disulphide bond cleavage	In vitro	[97]
		PEG-PLGA-SS-DTX	DTX/VRP	Disulphide bond cleavage	In vitro/In vivo	[129]
	Enzyme	PEG-pp-PEI-PE	PTX/siRNA	MMP2 selective cleavage	In vitro/In vivo	[108]
		TAT-PEG1k-PE	miRNA-34a/DOX	MMP2 selective cleavage	In vitro	[109]
	Temperature	PF127-PEI-FA	NR/DNA	Rigid PPO Chains hydrophobic interaction enhancement	In vitro	[130]
		PF127-PEI	NR/DNA	Rigid PPO chains hydrophobic interaction enhancement	In vitro	[113]
External
	Light	AC-CS-PpIX	DOX/Apa	Photoconversion of PpIX	In vitro/In vivo	[117]
Multi-sensitive
	PH/Redox	PEG-b-pAsp-b-pTyr	DTX/LND	Disulphide crosslinkages/Asp cleavage	In vitro/In vivo	[131]
		PCL-SS-CTS-GA	DOX /CCM	Surface charge was changed/Disulphide bond cleavage	In vitro	[132]
		PEG-PAsp	TNF plasmids/CPT	Disulphide /Cis-aconiticbond cleavage	In vitro/In vivo	[12]
	Enzyme /Redox	PEG-pp-PEI-PE	PTX/siRNA	MMP2/Disulphide bond selective cleavage	In vitro/In vivo	[108]

Apa: apatinib; CD: β-cyclodextrin; Cis: cis-aconityl linkage; CPT: camptothecin; CTS: chitosan; DAS: dasatinib; Dex-SA: succinic acid decorated dextran; DNM: dendritic nanomicelle; DSF: disulfiram; DTX: docetaxel; Epi: epirubicin; GA: glycyrrhetinic acid; HEMA: 2-Hydroxyethylmethacrylate; LND: lonidamine; MET: metformin; mPEG-g-PLL-b-Phe: methoxy-polyethylene glycol-graft-poly(L-lysine)-block-poly(L-phenylalanine); NR: nile red Phis: poly(histidine); PLG: poly(L-glutamic acid; PEG-b-pAsp-b-pTyr: poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine); POEG: poly(oligo(ethylene glycol) methacrylate); PLLD: poly(L-lysine) dendron; STS: staurosporine; TNF: tumor necrosis factor; TPGS_2k: PEG 2000 VES; VRP, veraparmil.

Figure 1. (a) Passive targeting of PMs. PMs selectively were trapped in the tumour tissue through the incomplete vasculature around tumours and appropriate particle size. On the contrary, the free drug diffuses into the tumour tissue by free diffusion and then spreads from the tumour tissue to the other tissue. (b) Active targeting of PMs. PMs selectively bind to various receptors overexpressing the surface of a cancer cell by modified the corresponding ligand on its surface.

Figure 2. Schematic illustrations for intracellular activation and delivery of cisplatin prodrug and siRNA co-loaded pH-responsive micelles. The micelles were degraded inside acidic late endosome/lysosome due to protonation of PDPA segment induction the transition of hydrophobic core from hydrophobic to hydrophilic. Simultaneously, endosome/lysosome rupture releases the Pt(IV)-OC prodrug and siRNA through the “proton sponge effect" and strong haemolytic activity of the micelles.

Zhao D, Wu J, Li C, et al. Precise ratiometric loading of PTX and DOX based on redox-sensitive mixed micelles for cancer therapy. Colloids Surf B Biointerfaces. 2017;155:51–60.

 PubMed Web of Science ®Google Scholar

Wu Y, Zhang Y, Zhang W, et al. Reversing of multidrug resistance breast cancer by co-delivery of P-gp siRNA and doxorubicin via folic acid-modified core-shell nanomicelles. Colloids Surf B Biointerfaces. 2016;138:60–69.

 PubMed Web of Science ®Google Scholar

Xiao Y, Wang S, Zong Q, et al. Co-delivery of metformin and paclitaxel via folate-modified pH-sensitive micelles for enhanced anti-tumor efficacy. AAPS PharmSciTech. 2018;19:2395–2406.

 PubMed Web of Science ®Google Scholar

Liu T, Wu X, Wang Y, et al. Folate-targeted star-shaped cationic copolymer co-delivering docetaxel and MMP-9 siRNA for nasopharyngeal carcinoma therapy. Oncotarget. 2016;7:42017–42030.

 PubMedGoogle Scholar

Ma W, Guo Q, Li Y, et al. Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy. Eur J Pharm Biopharm. 2017;112:209–223.

 PubMed Web of Science ®Google Scholar

Wang J, Li Y, Wang L, et al. Comparison of hyaluronic acid-based micelles and polyethylene glycol-based micelles on reversal of multidrug resistance and enhanced anticancer efficacy in vitro and in vivo. Drug Deliv. 2018;25:330–340.

 PubMed Web of Science ®Google Scholar

Sarisozen C, Abouzeid AH, Torchilin VP. The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors. Eur J Pharm Biopharm. 2014;88:539–550.

 PubMed Web of Science ®Google Scholar

Zou W, Sarisozen C, Torchilin VP. The reversal of multidrug resistance in ovarian carcinoma cells by co-application of tariquidar and paclitaxel in transferrin-targeted polymeric micelles. J Drug Target. 2017;25:225–234.

 PubMed Web of Science ®Google Scholar

Sarisozen C, Dhokai S, Tsikudo EG, et al. Nanomedicine based curcumin and doxorubicin combination treatment of glioblastoma with scFv-targeted micelles: In vitro evaluation on 2D and 3D tumor models. Eur J Pharm Biopharm. 2016;108:54–67.

 PubMed Web of Science ®Google Scholar

Zhao J, Mi Y, Feng SS. Targeted co-delivery of docetaxel and siPlk1 by herceptin-conjugated vitamin E TPGS based immunomicelles. Biomaterials. 2013;34:3411–3421.

 PubMed Web of Science ®Google Scholar

Zhu WJ, Yang SD, Qu CX, et al. Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor. Int J Nanomedicine. 2017;12:3375–3393.

 PubMed Web of Science ®Google Scholar

Han R, Sun Y, Kang C, et al. Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy. J Drug Target. 2017;25:140–148.

 PubMed Web of Science ®Google Scholar

Suo A, Qian J, Zhang Y, et al. Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells. Mater Sci Eng C Mater Biol Appl. 2016;62:564–573.

 PubMed Web of Science ®Google Scholar

Huo Q, Zhu J, Niu Y, et al. pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer. Ijn. 2017;12:8631–8647.

 Web of Science ®Google Scholar

Li M, Tang Z, Lv S, et al. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials. 2014;35:3851–3864.

 PubMed Web of Science ®Google Scholar

Kinoh H, Miura Y, Chida T, et al. Nanomedicines eradicating cancer stem-like cells in vivo by pH-triggered intracellular cooperative action of loaded drugs. ACS Nano. 2016;10:5643–5655.

 PubMed Web of Science ®Google Scholar

Li J, Xu R, Lu X, et al. A simple reduction-sensitive micelles co-delivery of paclitaxel and dasatinib to overcome tumor multidrug resistance. Int J Nanomedicine. 2017;12:8043–8056.

 PubMed Web of Science ®Google Scholar

Sun J, Liu Y, Chen Y, et al. Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy. J Control Release. 2017;258:43–55.

 PubMed Web of Science ®Google Scholar

Li Y, Yang H, Yao J, et al. Glutathione-triggered dual release of doxorubicin and camptothecin for highly efficient synergistic anticancer therapy. Colloids Surf B Biointerfaces. 2018;169:273–279.

 PubMed Web of Science ®Google Scholar

Guo Y, He W, Yang S, et al. Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer. Colloids Surf B Biointerfaces. 2017;1;151:119–127.

 PubMed Web of Science ®Google Scholar

Zhu L, Perche F, Wang T, et al. Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific co-delivery of siRNA and hydrophobic drugs. Biomaterials. 2014;35:4213–4222.

 PubMed Web of Science ®Google Scholar

Salzano G, Costa DF, Sarisozen C, et al. Mixed nanosized polymeric micelles as promoter of doxorubicin and miRNA-34a co-delivery triggered by dual stimuli in tumor tissue. Small. 2016;12:4837–4848.

 PubMed Web of Science ®Google Scholar

Seo SJ, Lee SY, Choi SJ, et al. Tumor-targeting co-delivery of drug and gene from temperature-triggered micelles. Macromol Biosci. 2015;15:1198–1204.

 PubMed Web of Science ®Google Scholar

Lee S-Y, Choi S-J, Seo S-J, et al. Shell cross-linked polyethylenimine-modified micelles for temperature-triggered drug release and gene delivery. RSC Adv. 2014;4:57702–57708.

 Web of Science ®Google Scholar

Wei X, Liu L, Guo X, et al. Light-activated ROS-responsive nanoplatform codelivering apatinib and doxorubicin for enhanced chemo-photodynamic therapy of multidrug-resistant tumors. ACS Appl Mater Interfaces. 2018;10:17672–17684.

 PubMed Web of Science ®Google Scholar

Ruttala HB, Chitrapriya N, Kaliraj K, et al. Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy. Acta Biomater. 2017;63:135–149.

 PubMed Web of Science ®Google Scholar

Yan T, Li D, Li J, et al. Effective co-delivery of doxorubicin and curcumin using a glycyrrhetinic acid-modified chitosan-cystamine-poly(epsilon-caprolactone) copolymer micelle for combination cancer chemotherapy. Colloids Surf B Biointerfaces. 2016;1;145:526–538.

 Web of Science ®Google Scholar

Zhu C, Xiao J, Tang M, et al. Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy. Int J Nanomedicine. 2017;12:3697–3710.

 PubMed Web of Science ®Google Scholar