Table 1.

A summary of various stimuli responsive sorafenib nanodelivery systems.

Stimuli responsive	Structure	Mechanism of drug release	Observations	Ref.
pH	Micelles constructed using HES-TG100–115 and PEG-CDM polymers	Low pH conditions caused the depolymerization of micelles due to the sensitivities of amide bond and CDM bond	In vivo studies showed a higher level of antitumor efficacy and better tolerance against mice with Hep-3B cells	[143]
pH	Liquid crystalline nanoparticles assembled from layer-by-layer polymers	A phase inversion of LCN occurred in acid conditions	Nanoparticles had significantly higher cytotoxicity to HepG2 cells than free drug	[19]
pH	Liposomes functionalized with CMCS	The CMCS which bearing -COOH and -NH2 could become positively charged at acidic environment.	In vivo studies showed enhanced antitumor efficacy of liposomes as compared to free sorafenib.	[50]
GSH	Micelle constructed by linking PAA with VES via a disulfde bond linker.	Cleavage of the disulfide bonds occurred in a reductive environment.	Cytotoxicity assay using BGC-823 cells showed higher cytotoxicity as compared to free sorafenib	[58]
GSH	MSN doped with manganese-oxidation bonds.	Manganese-oxidation bonds of nanoparticles could break in the presence of high GSH concentration.	In vitro studies, this nanoparticles had a significant tumor suppression effect for HepG2 cells.	[59]
MMPs	Nanoystem self-assembled from PPDC	The peptide segments would be digested by the overexpressed MMP-2.	In vivo studies in HT-29 tumor-bearing mice demonstrated enhanced therapeutic effect.	[64]
Light	Nanosystems composed of gold nanorod cores and polycationic mesoporous silica shells.	Under NIR light irradiation, the gold nanorod cores could trigger the drug release by opening the polycation cloak.	In vivo studies using hepatoma-bearing mice showed its significant synergistic antitumor effects after NIR irradiation.	[70]
Light	HSA nanoparticles functionalized with gold nanorods.	The denaturation of HSA crosslinking secondary occurred after light irradiation.	Under light irradiation, nanoparticles could induce significant hyperthermia and further enhance cytotoxicity to kill RCC 786-O cells.	[75]
Temperature	Polymeric system constructed from block copolymers of PLGA-PEG-PLGA.	The copolymers are in a sol-state at low critical solution temperature but will turn into the gel-state when at high temperature.	In vivo studies showed site-specific and long-term antitumor efficacy by using this thermosensitive drug-loading system	[39]
Ultrasound	Phase transition perfluorocarbon liquid nanodroplets.	The release behavior of nanodroplets are correlated with its inertial cavitation process	Under ultrasound irradiation, the nanodroplet significantly inhibited the migration and invasion of tumors in vitro/vivo	[78]
Magnetic field	PEG-functionalized ultrasmall melanin nanoparticles.	The slow in vivo degradation rate of melanin nanoparticles ensured its long-lasting integration.	In vivo studies showed the nanoparticles exhibited significant higher tumor inhibition as compared to free sorafenib.	[91]
pH, Magnetic field	Nanocomposite composed of iron oxide nanoparticles and pH-sensitive synthetic peptides.	At acidic environment, synthetic peptides will destabilize due to the ionization of imidazole groups.	This nanocomposite showed significant tumor growth inhibition in rodent HCC models.	[79]
GSH, Light	Nanoparticles self-assembled from chitosan oligosaccharide -connected black hole quencher -IR780-Hex nanophotosensitizer	The ether bond between black hole quencher and IR780 was a response to GSH	This nanoparticle showed an excellent tumor accumulation ability and effectively inhibited tumor growth in breast tumor mice models	[84]