Table 3.

Quench mechanism and platforms for tumor microenvironment-based Signal Turn Off/On.

Quench Mechanism		Trigger	Systems	Advantages
Intramolecular spirocyclic caging		γ-glutamyl transpeptidase	γ-glutamyl hydroxymethyl rhodamine green [206]	Activated within 10 min and detect tumors smaller than 1 mm diaeter.
Intramolecular spirocyclic caging		β-galactosidase	hydroxymethyl rhodol derivatives bearing β-galactoside [207]	Fluorescence activation > 1400-fold and sensitively detect intracellular β-galactosidase activity
Intramolecular photoinduced electron transfer (PeT)		β-galactosidase	2-Me-4OMe TokyoGreen O-β-galactoside [163, 164]	Up to 440-fold fluorescence activation and visualization of intraperitoneal tumors as small as 200 μm
H-dimer induced homoFRET		Antibody-receptor interaction and conformation change	photosensitizer-antibody conjugate [208]	Tumor cell-targeted photoimmunotherapy and fast cell death
Conjugation induced homoFRET		Tumor-associated proteases	Fluorescence probe or photosensitizer conjugated PEG-PLL nanoparticles [168, 209]	12-fold increase in near- infrared fluorescence signal in vivo, able to detect tumors with submillimeter-sized diameters; 6-fold On/Off of SOG with increased tumor inhibition
heteroFRET with fluorescence quencher via direct conjugation	Matrix metalloproteinases		CuS-peptide-BHQ3 [210]	Tumor-activatable photoacoustic imaging with improved detection depth
heteroFRET with fluorescence quencher via direct conjugation	Matrix metalloproteinases		Photosensitizer-peptide-BHQ3 [170]	12-fold fluorescence increase and 18-fold 1O2 production after 3 h cleavage
Restriction of intramolecular rotation (RIR) and prohibition of energy dissipation through nonradiative channels		Cathepsin B	Dual-targeted aggregation-induced emission fluorogens-peptide-target [211, 212]	35-fold higher fluorescence as well as significant SOG in 1 h
Energy/charge transfer and efficient exciton migration		Acidic extracellular tumor microenvironment	Cationic conjugated polyelectrolyte and gold nanoparticle hybrid [213]	8.2-fold enhancement of fluorescence in acid within 1 h
H-type homoaggregates via face-to-face stacking		Acidic pH-triggered fluorophore cleavage	PEGylated dendrimer with hydrazone bonds [214]	6-fold fluorescence increase after 24 h
assembly induced homoFRET		Acidic pH-triggered fluorophore cleavage	Dextran with acid sensitive bond [159]	Low background fluorescence in normal tissues with high tumor/normal tissue ratio
assembly induced homoFRET		Acidic pH-triggered hydrophobicity change and particle disassembly	Ionizable block copolymers of poly(ethylene oxide) and tertiary amine containing poly-methacrylate [172-175]	Ultra pH-sensitivity of 0.25 pH unit, tunable pH transition (from 7.1 to 4.4), fast temporal response (<5 ms) and higher than 100-fold fluorescence On/Off
assembly induced homoFRET		pH-triggered hydrophobicity change and particle disassembly	poly(β-benzyl-L-aspartate) based polymers [167]	0.6 pH sensitivity with multifunctions (MRI and PDT) to overcome tumor heterogeneity and multidrug resistance
assembly induced heteroFRET with fluorescence quencher		pH-triggered hydrophobicity change and particle disassembly	MPEG-PAEs with tertiary amine moiety [158]	Acid-induced fluorescence turn on with several pHt
assembly induced heteroFRET with fluorescence quencher		pH-triggered hydrophobicity change and particle disassembly	Self-assembled oligopeptide nanoparticles [215]	More than 10-fold enhancement of fluorescence in acid within 10 min
Intramolecular photoinduced electron transfer (PeT)		Acidic environment in lysosomes	Selenium-rubyrin-loaded nanoparticles functionalized with folate [166]	Tumor cell-targeting; 10-times SOG On/Off with complete tumor growth inhibition
HomoFRET by absorption		High GSH level intracellular	Redox-sensitive MnO2 nanosheets [169]	High intracellular delivery efficiency and enhanced photodynamic therapy efficacy by reducing glutathione levels in tumor cells