Table 2.

Summary of the Proposed Mechanisms of Anthracycline NPs to Overcome MDR.

Platform	Composition	Mechanism	Status	Ref.
Liposome	CL, PC, CHOL	interact with P-gp modify plasma membrane	in-vitro	[27, 28]
	CL, PC, CHOL	increase drug accumulation intracellular drug redistribution	in-vitro	[26]
	DSPE-PEG, CHOL, DPPC, DPPG	direct inhibit ATPase alter raft lipid composition reduce lipid raft-associated P-gp	in-vitro	[30]
	DSPC, CHOL	PSC 833 (P-gp inhibitor)	in-vivo	[31]
	EPC, CHOL, PEG- DSPE	verapamil (P-gp inhibitor)	in-vitro	[32]
	EPC, CHOL, mPEG-DSPE, MAL-PEG-DSPE	verapamil (P-gp inhibitor) transferrin (targeting)	in-vitro	[33]
	EPC, CHOL, DSPE-PEG, DPPC	MDR1 ASO BCL-2 ASO endocytosis membrane fusion	in-vivo	[34]
	DOTAP	MRP1 siRNA BCL-2 siRNA	in-vitro	[36]
	DSAA, DOTAP, DOPA, CHOL, DSPE-PEG, DSPE-PEG-AA	DSAA (induce ROS, inhibit MDR transporters, enhance drug uptake) VEGF siRNA (increase drug uptake and targeting) c-Myc siRNA (improve therapeutic effect and down- regulate MDR)	in-vivo	[37]
Polymeric NP	PIBCA	PIBCA and its degradation products change or modify cell membrane massive drug diffusion from NPs saturates P-gp NPs do not enter the cells	in-vitro	[39]
	PACA	NP-cell interaction on cell surface form drug-polycyanoacrylic acid ion-pair complex cyclosporine A (P-gp inhibitor)	in-vitro	[40, 45, 46]
	PIHCA	bypass but not direct inhibit P-gp	in-vitro	[42, 43]
	AOT-alginate	methylene blue (inhibit P-gp and generate ROS)	in-vitro	[48, 49]
	PPLA	porphyrin (photosensitizer) TPGS (P-gp inhibitor)	in-vitro	[53]
	stearyl-modified dextran	bypass P-gp	in-vitro	[47]
	PLAG	curcumin (increase drug retention in the nucleus; down-regulate P-gp and BCL-2)	in-vitro	[51]
	PLGA	receptor-mediated endocytosis (HER2)	in-vitro	[52]
Polymeric Micelles	pluronic P85	interact with P-gp change cell membrane structure induce cell membrane permeability	in-vitro	[54]
	PEO-PPO-PEO	endocytosis sensitize cells	in-vitro	[55]
	PLA-TPGS	inhibit P-gp enhance drug cellular uptake promote drug to translocate into the nucleus	in-vitro	[56]
	PLGA-PEG-folate	TPGS (P-gp inhibitor)	in-vitro	[57]
	PEG- polyphosphazene	endocytosis pH-sensitive polymer (disrupt endosomes by proton- sponge effect and/or interact between polymer and endosome membrane)	in-vitro	[62]
	CSO-FA	interact with cell membrane alkyl side chain on chitosan introduces perturbation effect fatty acids form hydrophobic microdomains near shell surface	in-vitro	[63–65]
	polyHis/PEG (or polyHis/PEG- folate), pLLA/PEG- folate	receptor-mediated endocytosis (folate) trigger drug release at low pH (pH-sensitive) interact between polyHis group of the micelle and endosome membrane	in-vivo	[66–69]
	PEO-b-PCL	RGD4C (targeting) TAT (cell-penetration peptide) MDR1 siRNA	in-vivo	[77]
	PEG-PDLLA	drug released to plasma membrane and then internalized into cells PEG-induced fusion to cell membrane	in-vitro	[79]
	PCL-PEO	endocytosis	in-vitro	[80, 81]
	pluronic L61	facilitate drug entry into the nucleus increase drug cellular uptake inhibit drug efflux	in-vitro	[82]
Polymer Conjugate	HPMA	inhibit P-gp and β₂m lysosomally degradable linker (GFLG) endocytosis down-regulate P-gp, MRP, BCL-2, HSP-70, etc.	phase I/II	[83–89]
	dextran	endocytosis bypass P-gp	phase I	[95–97]
	PEG-modified dendrimer	endocytosis rupture endosomes (proton-sponge effect)	in-vitro	[94]
Magnetic NP	Fe₃O₄, ZnO	P-gp inhibitor or competitive P-gp substrate (Fe₃O₄) interact between NPs and cell membrane tetrandrine (P-gp inhibitor) up-regulate BAX, p53, caspase-3 inhibit BCL-2, down-regulate P-gp shRNA (targeting)	in-vivo	[140–147]
Carbon Nanotube	—	controllable and sustained drug release P-gp antibody (targeting)	in-vitro	[161]
CD NP	—	interaction between polymer and P-gp inhibit P-gp	in-vitro	[162]
Peptide/ Protein Conjugate	TAT	bypass but not inhibit P-gp	in-vitro	[100, 101]
	maurocalcine, penetratin, TAT	active mitochondrial independent apoptotic pathways	in-vitro	[102–104]
	Vectocell	internalization	in-vitro	[105, 106]
	penetratin, SynB1	bypass P-gp interact between conjugate and cell membrane	in-vitro	[107]
	transferrin	bypass P-gp (conjugate slowly dissociates after binding to cell membrane) receptor-mediated endocytosis interact between conjugate and DNA	in-vitro	[108, 109]
	IGF-1R mAb	receptor-mediated endocytosis escape P-gp recognition	in-vivo	[115]
	[D-Lys⁶]LHRH	not by receptor-mediated endocytosis down-regulate ErbB/HER receptors disrupt G-protein signaling	in-vivo	[116–118]
	AS-ODN	high drug accumulation inhibit P-gp (AS-ODN)	in-vivo	[119, 120]
	BSA	endocytosis conjugate degrades in lysosomes	in-vivo	[121–123]
	diGly, triGly, GSH, GSSG	rapid drug uptake high drug accumulation	in-vitro	[124]
	poly-D-Lysine, poly-L-Lysine	endocytosis poly-L-Lysine digested by lysosomes	in-vitro	[125]
SLNs	emulsifying wax, Brij 78, TPGS	inhibit P-gp, deplete ATP, increase drug retention	in-vivo	[128, 133]
	monostearin, oleic acid	inhibit P-gp high affinity between lipids or NLC and cell membrane	in-vitro	[135]
	stearic acid, Pluronic F68, HPESO	not inhibit or bypass P-gp not alter cell membrane permeability drug released from outside of cell and then simple passive diffusion phagocytosis GG918 (P-gp inhibitor)	in-vitro	[136–138]
Gold NP	—	change or modify cell membrane properties dysregulate mitochondrial function	in-vitro	[152]
	—	internalization NPs even enter the nucleus	in-vitro	[153]
	—	drug-NP complex formation phagocytosis simple diffusion	in-vitro	[154, 155]
Silica NP	—	endocytosis bypass P-gp	in-vivo	[157]
	—	PEI (proton sponge effect) P-gp siRNA	in-vitro	[158]
	—	inhibit P-gp micropinocytosis	in-vivo	[159]
	—	perinuclear localization BCL-2 siRNA	in-vitro	[160]