The Application of Nanotechnology in the Codelivery of Active Constituents of Plants and Chemotherapeutics for Overcoming Physiological Barriers during Antitumor Treatment

Table 2

The strategies of overcoming the transport barriers of NDDSs to codeliver two different drugs.

Delivery barriers	Physiological basis	Strategies	Feature	Nanocarrier type	Nanocarrier composition	Drug	Ref
(1) Blood circulation	(1) The mononuclear phagocyte system (MPS)	(1) Hydrophilic polymer nanoparticles	PEG-modified	Liposome	DSPE-PEG 2000	Adriamycin + quercetin	[42]
			PEG-modified	Micelles	mPEG-PCL	Doxorubicin + curcumin	[43]
	(2) Electrostatic interaction	(2) RBC cloak nanoparticles	PEG-modified	Nanoparticles	PEG-b-PLL	Doxorubicin + triptolide	[44]
			PEG-MSN	Mesoporous silica nanoparticle (MSN)	PEG-MSN	Paclitaxel + curcumin	[45]
			PEG-modified	Lipid-coated polymeric nanoparticle	PEG2k-DSPE/PLGA	Doxorubicin + curcumin	[46]
			PEG-MNPs	Magnetic nanocomposite	Fe3O4/HAPA/β-CD	Doxorubicin + curcumin	[47]
(2) Drug accumulation and penetrtion	(1) ECM	(1) EPR effect	RGD peptide-targeted	Liposome	DSPE-PEG 2000	Paclitaxel + curcumin	[48]
	(2) Vascular endothelial barrier	(2) Vascular targeting for accumulation	RGD peptide-targeted	Mesoporous silica nanoparticle	PAA-chitosan	Topotecan + quercetin	[49]
			RGD peptide-targeted	Lipid-coated nanoparticles	DSPE-PEG-NHS, PLGA	Sorafenib + quercetin	[50]
	(3) Thick stroma	(3) Antivascular targeting by inhibiting tumor angiogenesis	EPR	Liposome	SPC : Chol : DOPE/EPG	Doxorubicin + biochanin A	[51]
	(4) Proteolytic enzymes in the tumor		EPR	Lipid-polymer hybrid nanoparticles (Lpns)	DOPE/EPG	Cisplatin + curcumin	[33]
			Smaller and compacted scale nanoparticles	Self-assembled nanoparticle	PEG-VES	Sorafenib + curcumin	[52]
(3) Drug internalization into the targeted cells	(1) Electric interaction needed to stride over the cell membrane to enter inside the cells	(1) P-gp inhibitors combining nanoparticles	P-gp inhibitor (curcumin)	Amphiphilic polymeric micelle	PEG(2k)-PLA(5k)	Doxorubicin + curcumin	[53]
			P-gp inhibitor (tetrandrine)	Lipid polymer hybrid nanosystem	MAL-PEG-DSPE, PLGA	Paclitaxel + Tetrandrine	[54]
		(2) Receptor-targeted nanocarriers	Transferrin-targeted, pH-sensitive	Polymer-drug conjugate	Tf-PEG-CUR	Doxorubicin + curcumin	[55]
			FA-targeted	Planetary ball-milled (Pbm) nanoparticles	FA-PCL-PEG	Docetaxel + resveratrol	[56]
			FA-targeted	Lipid nanoparticles	GMS-TPGS-SA-FA	Paclitaxel + curcumin	[57]
			GLUT1-targeted	Polymeric micelles	PEG2000–DSPE	Doxorubicin + curcumin	[58]
			Transferrin-targeted	Polymeric micelles	PEG-PE	Paclitaxel + curcumin	[36]
(4) Drug release	(1) Acidic environment and specific enzymes present in CSCs in the tumor	(1) PH-sensitive nanoparticles	pH-sensitive	Micellar nanoparticles	DSPE-PEG-imine-MTX	Methotrexate + curcumin	[59]
			pH-sensitive	Nanoparticles	PEG-lipid/PAA/CaCO3	Doxorubicin + curcumin	[60]
		(2) Enzyme-sensitive nanparticles	pH-sensitive, CSCs-targeted	Micellar system	PPBV	Paclitaxel + curcumin	[61]
			pH-sensitive	Nanoparticle	TPGS-PAE	Doxorubicin + curcumin	[62]
		(3) Temperature-responsive	pH-sensitive	Copolymer	PCL-St-POX	Terminator + curcumin	[63]
			Pe-targeted, EPR	Peptosome	PePm/PS	Pe + curcumin	[64]
			Thermosensitive copolymer	Nanogels	Heparin-pluronic F127 (Hep-F127)	Cisplatin + curcumin	[65]
			Near-infrared (NIR)-responsive	Gold nanocages	Biotin-PEG-SH	Doxorubicin + quercetin	[66]
(5) Drug response	(1) Based on summarized pathophysiological basis	(1) Directly target and kill CSCs	pH-sensitive, CSCs-targeted	Polymeric nanoparticle	mPEG-PLGA-pglu	Doxorubicin + curcumin	[67]
			pH-sensitive, CSCs-targeted	Core-shell nanoparticle	VES-g-e-PLL/γ-PGA-Dopa	Doxorubicin + curcumin	[68]
		(2) Synergistic combination of two or more drugs	Combination of chemotherapeutic and plants extracts	Nanoliposomes	mPEG2000-DSPE, DOPA	Cisplatin + curcumin	[69]
				Phytosome	Quercetin and phospholipid (lecithin)	Doxorubicin + quercetin	[70]
				Lipid nanoparticles	Glyceryl distearate,triglycerides medium-chain, soybean lecithin/polyoxyl 40 hydrogenated castor oil, glycerin	Doxorubicin + curcumin	[71]
				Polymeric micelles	PCL-b-ABPA-b-POEGMEA	Platinum drugs + curcumin	[72]
				Nanoparticle	mPEG-PCL	Temozolomide + resveratrol	[73]
				Liposomal	Egg sphingomyelin/cholesterol/PEG2000 ceramide	Quercetin + vincristine	[74]
				Polymeric micelles	PGS2000/PEG2000-DSPE	Doxorubicin + curcumin	[75]
				Lipid nanoparticles	PEG-DSPE	Etoposide + curcumin	[76]
				Lipid-polymer hybrid nanoparticles (Lpns)	DSPE-mPEG5000/DSPE-PEG5000 FITC	Paclitaxel + triptolide	[77]
				Liposomes	Egg phosphatidylcholine/DSPE-PEG	Doxorubicin + resveratrol	[78]
				Nanoemulsion (NE)	PEG400-DOCA, HP-beta-CD	Pemetrexed + quercetin	[79]
				Bottlebrush copolymer-Based micelle	PEG-PNB-TC	Paclitaxel + curcumin	[35]
				Lipid-polymeric nanocarriers	PLGA, PEG2000-DSPE	Vincristine + quercetin	[80]
				Niosomes	Tween-60: cholesterol:DPPC : DOTAP : DSPE-PEG2000	Doxorubicin, quercetin + sirna	[81]
				Polymer-lipid nanoparticles	DSPE-PEG2000, POPC,DOPAC	Paclitaxel + curcumin	[82]
		(3) Multifunctional targeted delivery	pH-responsive, CRGDK-targeted, EPR	Nanoparticles	CRGDK-PEG-PCL	Doxorubicin + curcumin	[83]
			Magnetic-guided targeting, T7-mediated targeting	Nanoparticles	PLGA-PEG-T7	Paclitaxel + curcumin	[84]
			Lactoferrin- (Lf-) tethered magnetic-targeted	Magnetic micelle	PVA/PAA	Doxorubicin + curcumin	[37]
			pH-responsive, Folate receptor-targeted	Nanoplates	PEG methacrylate, PEG	Daunorubicin + curcumin	[85]
			EGFR peptide (GE11)-targeted, pH-sensitive, EPR	Prodrug nps	PLGA-PEG-Mal, PLGA-PEG-NH2, PEG-NH2	Docetaxel + curcumin	[86]
			Magnetic targeting, biotin receptors-targeted	Magnetic nanoparticles	Biotin-PEG-PCDA	Paclitaxel + curcumin	[87]
(6) Mutidrug resistance (MDR)	(1) Based on summarized pathophysiological basis	(1) Reverse transporter-mediated MDR (Inhibition of P-p, LRP, MRPs,BCRP)	PEGylation	Prodrug nanopaticle	PEG-curcumin	Docetaxel + curcumin	[88]
			PAMAM dendrimer	Copolymer nanopaticle	PEG-PAMAM	Paclitaxel + Borneol	[89]
			PEGylated	Liposome	DSPE-mPEG2000, PC	Paclitaxel + resveratrol	[90]
		2) Reverse apoptosis gene-mediated MDR	EPR	PLGA-lipid nanoparticles	DSPE-PEG2000, PLGA	Docetaxel + gambogic acid	[32]
			Anisamide- (AA-) targeted	Nanoparticles	PLGA, CHO-hyd-PEG-AA	Doxorubicin + resveratrol	[91]
(7) Immunoregulation	(1) Oxidative and enzymatic environment	(1) Anti-inflammatory effects	CD44-targeted	Nanohydrogel	FA-HA	Rapamycin + quercetin	[92]
			PEGylated	Long-circulating liposomes	DPPC, PEG-2000-DSPE	Docetaxel + curcumin	[93]
(8) Antagonize/reduce toxicity and side effects	(1) Reactive oxygen species (ROS) environment	1) ROS-sensitive nanoparticles	ROS-cavenger: curcumin	Polymeric micelles	mPEG-PCL	Docetaxel + curcumin	[94]

DSPE-PEG: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol); PLGA: poly(lactic-co-glycolic acid); mPEG-PCL: methoxy poly(ethylene glycol)-poly caprolactone; PEG-b-PLL: poly(ethylene glycol)-b-poly(L-lysine); HAPA: hydroxyapatite; β-CD: β-cyclodextrin; PEIIPDI-PEA: branched polyethylenimine-isophorone diisocyanate-poly(L-lactide)-PEI; PAA: polyacrylic acid; DSPE-PEG-NHS: distearoyl-L-a-phosphatidylethanolamine-polyethylene glycol-N-hydroxysuccinimide; SPC: soy phosphatidylcholine, Chol: cholesterol, EPG: egg phosphatidylglycerol, and DOPE: 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine; PEG-VES: polyethylene glycol derivative of vitamin E succinate; MAL: maleimide; Tf: transferrin; FA: folate; GMS-TPGS-SA-FA: glyceryl monostearate-D-alpha tocopherol acid polyethylene glycol succinate-stearic acid and folate; PEG2000–PE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; PPBV: poly(ethylene glycol)-benzoic imine-poly(gamma-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer; TPGS-PAE: d-alpha-tocopheryl polyethylene glycol 1000-block-poly(beta-amino ester); PCL-St-POX: poly caprolactone-starch-poly(2-ethyl 2-oxazoline); PePm: TFIIATVEGVLLFLILVVVVGILIKRRGPLGVRGC, PS: peptosomes; mPEG-PLGA-PGlu: monomethoxy (polyethylene glycol)-b-P (D,L-lactic-coglycolic acid)-b-P (L-glutamic acid); VES-g-e-PLL: RRR-a-tocopheryl succinate-grafted-e-polylysine conjugate; γ-PGA-Dopa: poly-γ-glutamic acid-dopamine; DOPA: 1,2-dioleoyl-sn-glycerol-3-phosphate; PABPA: 3-((tert-Butoxycarbonyl)amino)propyl acrylate; POEGMEA: polymerisation of oligo(ethyleneglycol)methyl ether acrylate; DSPE-PEG5000-FITC: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(polyethylene glycol)-5000]-fluorescein isothiocyanate; DOCA: deoxycholic acid, HP-beta-CD: 2-hydroxypropyl-beta-cyclodextrin; PEG-PNB-TC: polyethylene glycol-polynorbornene-thiocresol; DPPC: 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine phospholipid, DOTAP: 1, 2-dioleoyl-3-trimethylammonium-propane; POPC: 1-palmitoyl-2oleoyl-sn-glycero-3-phosphocholine; CRGDK: Cys-Arg-Gly-Asp-Lys; T7: sequence HAIYPRH.