Table 4.

The selected examples of studied fluorinated and PFC nanosystems explaining their preparation technique, fluorine component, characterisation techniques used for studying various aspects of the nanosystems, pros and cons based on the synthesis/preparation and the practicality, and applications. * The abbreviations are expanded at the ‘Abbreviation’ session.

Type	Name	Preparation Technique	Fluorine Component	Characterisation *	Pros and Cons	Application	Ref
POLYMERIC	Fluorous colloidal NPs	Copolymer by ATRP. NPs formation by self-assembly to micelle	Trifluoroethyl methacrylate	DLS (260 nm), TEM, FMRI, FC, CM, UV-Vis, CyA–on macrophage cells, animal studies–female athymic NCR nude mice for breast cancer	Simple preparation of copolymer	Immune cell tracking and systemic disease monitoring	[187]
					No surfactant
					Little off target accumulation
					Tumour-homing
	Poly(OEGA-co-TFEA)-b-poly(St-co-VBA)	Polymerisation by RAFT and NPs by PISA	2,2,2-trifluoroethyl acrylate	FMRI and NMR, DLS, TEM, CM	Little or no cytotoxicity–Chinese Hamster Ovarian cells	In vivo cell tracking	[190]
					Multiple NPs morphologies by controlling reaction time and polymer chain length in one preparation (spherical, worm, vesicle)
	ROS-responsive fluorinated polymers	Polymer by ATRP and NPs by self-assembly	2,2,2-trifluoroethyl methacrylate	H and F NMR, FMRI, DLS (62, 32 and 18 nm), UV-Vis	Enhanced sensitivity for acidic microenvironment and the presence of ROS	ROS/pH dual-responsive 19F MRI agent	[191]
					The concentration of H2O2 studied (~1 M) were higher than biological levels (50–100 μM)
					6-step synthesis that requires purification
					“OFF–ON” regulation of NPs to acidic environment
	Amino activable nanoprobe- p(mPEGMA)-co-poly(AMA-DNBS-F) (PEDF nanoprobe)	Copolymers by RAFT polymerisation and nanoprobe by nanoprecipitation	Trifluoromethyl-containing segments	H and F NMR, DLS (33 nm), FMRI, TEM, FTIR, CLSM, in vivo imaging in tumours–xenograft tumour models in mice	2 step preparations for monomers	In vivo bio-thiols imaging	[192]
					Highly sensitive to bio-thiols
					Water soluble
	Fluorinated block copolymers NPs	RAFT for the block polymers and NPs by self-assembly in aqueous solution	2,2,2-trifluoroethylamide L-arginine methacrylamide	H, F- NMR, DLS (25 to 60 nm), TEM	Fluorinated functionalities in the hydrophilic shell	MRI Imaging	[300]
					Increased T2
	19F MRI-detectable drug delivery system	Layer-by-layer technique deposition of polyelectrolyte shells on nanoemulsion drops	Polyelectrolyte Nafion–fluorinated anionic polymer	DLS (170 nm), LDV, NTA, C-SEM, QCM, FMRI	Sufficient SNR ratio	Passive tumour targeting and drug delivery	[193]
					Highly cationic particle (+68 ± 5 mV)
	Self-assembled 19F nanoprobes	Self-assembly of amphiphilic redox-responsive 19F-containing polymers and NIR-absorbing ICG molecules	3,5-Bis(trifluoromethyl) benzoic acid part in the polymer	TEM, DLS (40 nm), UV–Vis, FNMR and MRI, TEM	Water-soluble	Accurate sensing and imaging of tumours	[66]
					In vivo and in vitro studies–HepG2 tumour-bearing cells and mice
					High SNR ratio
					Good biocompatibility
					5 steps for preparation with purification requirement and moderate yield
					Novel system which has potential to be extended for imaging other tumour targets
	Multi-functional fluorocarbon NPs	Single and double emulsion	PFD, PFH, perfluorooctane, PFOB, PFCE	DLS (200 nm–200 µm), SEM, CM, FC, FI, FMRI, Cell viability–primary human dendritic cells, histology	Customizable NPs, minimal toxicity	In vivo imaging and targeting applications	[194]
					Size smaller than 200 nm is not formed by this NP formation
	PLGA PFPE	Emulsification (Sonicator)–1:1 molar ratio of autoclaved PFPE and sterile filtered Pluronic	PFPE	DLS (103 nm), FNMR and MRI, FM, cellular viability–diabetogenic mice T cells	Specificity for the labelled cells	Non-invasive monitoring the trafficking of cellular therapeutics	[195]
					Reliable estimates of the apparent number of cells from image data
	PFCE encapsulated PLGA	Single emulsion	PFCE	DLS, FNMR and MRI, SANS, animal studies–male Wistar rats, mouse, mice, cell studie–primary murine/human dendritic cells	Biocompatible NPs	US and 19F MRI	[197]
					Better acquisition time	Murine cardiac 19F MRI/MRS	[199]
					Obtains complimentary information when in combination with other imaging agents	In vivo PAI, 19F MRI and fluorescent imaging (FI)	[198]
					NPs loaded with chemotherapeutic drugs could give it a theranostic effect, Resomer RG 502 H, lactide: glycolide molar ratio 48:52 to 52:48 is the mostly used PLGA. The other ratios of lactide: glycolide and also their end group might give interesting results. The encapsulation efficiency of PFC could be studied each time to better understand the sensitivity	FMRI and CT (with gold NPs)	[200]
						SPECT/PET and 19F MRI	[204]
	Chitosan coated PLGA -PFOB NPs	Single emulsion by homogenisation followed by sonication using 1.5% sodium cholate	PFOB	DLS (170 nm), CLSM, FC, FNMR and FMRI, TEM	Background-free signal compared to Gd (III) and super paramagnetic iron oxides NPs	Labelling and tracking therapeutic cells in vivo	[206]
					As chitosan coating is just a physical adsorption, the stability of it has to be verified in biological environment
					Size of NPs is increased (200–400 nm) after the chitosan coating
	PEGylated PLGA NPs (PLGA NP (NIR700 + PFC)-PEG-800 CW	O/W emulsion and solvent evaporation-extraction method	PFCE	DLS (240–250 nm), TEM, FMRI, TEM, FM, histology, cell culture–murine breast carcinoma cell line	Quantitative 3D information from deeper tissues	In vivo imaging	[212]
					Rapid qualitative optical monitoring
	PLGA–PEG folate-receptor-targeted NPs	Single emulsion-evaporation (1.5% sodium cholate surfactant)	PFOB	DLS (150 nm), FC, CLSM, F MRI, NIRS, CyA-KB cells	Encapsulate imaging agent and drug	Theranostic NP	[207]
					Insufficient SNR in vivo for FMRI
					The loading capacity of the NPs is low for doxorubicin and ICG (0.04% and 0.127%)
	Doxorubicin-conjugated PFPE NPs	Polymers by RAFT polymerization	PFPE	DLS (8.1, 9.3 and 8.3), FNMR, MD	Improved cellular uptake	Improved therapeutic efficacy	[222]
					Deep tumour penetration
					Studies done using 3D tumour spheroids
	F3-PLGA and F9-PLGA	Nanoprecipitation–surfactant free	Fluorinated PLGA (2,2,2-trifluoroethanolamine, nonafluoro-t-butoxyethylamine)	DLS (~54 nm and 58 nm), TEM, F NMR, FM, CyA–immortalized human glomerular endothelial cells and podocytes	No surfactant used	Theranostic NPs	[217]
					Encapsulate hydrophobic drugs
					The reaction yield of the fluorinated polymer is not understood
HYPERBRANCHED	Multifunctional hyperbranched polymers containing 19F	RAFT polymerization for polymer, NPs by self-assembly in water	2,2,2-trifluoroethylacrylate	DLS (∼13 nm), GPC, TEM, FNMR and MRI, CT	Direct dissolution in water	Quantitative 19F MRI CA	[232]
					Biodegradable
					3 step preparation and the final product is not pure (3 mixture products)
					FNMR with multiple peaks
					T2 shortened
	PFPE based hyperbranched NPs conjugated with targeting aptamers	RAFT polymerization–for NPs, click chemistry for aptamers attaching	PFPE	F-DOSY (<10 nm), FM, FC, CrM, MD, FNMR and MRI	Superior MR imaging sensitivity and fluorine content -breast cancer cells	Quantitative 19F MRI CA	[233]
					Low-cost fluorescence imaging
					Unsuitable for long term studies due to faster clearance from the body
					Accumulation of polymer in the liver was observed after 48 h and the 19F signal could be still detected in the liver
	Fluorinated hyperbranched polyether copolymers	ROMBP and copolymerization for polymers and self-assembly of the colloids	2-[(2,2,2-trifluoroethoxy) methyl]oxirane/epifluorohydrin	DLS (160–200 nm), H NMR and F MRI, FM, HPLC, cytotoxicity studies - immortalized human glomerular endothelial cells and immortalized human podocytes	Repair damaged kidney glomerular cells in vitro	New generation 19F MRI nanotheranostics	[234]
					Negligible cytotoxicity
					Narrow size distribution
					Relatively long T1
					Higher amount of F gives less SNR
DENDRIMERS	Fluorinated Gd(III)-DOTA complexes	Convergent synthesis for polymer and self-assembly for NPs	Fluorinated amino acid group	F NMR, DOSY, H and F MRI, KB cells for in vitro cytotoxicity study, animal imaging—Sprague Dawley female rats	Substantial improvement in relaxation rate and SNR ratio	CA for high field imaging	[239]
					Easily cleared through the kidneys
					The fluorine in the surface layer of dendrimers is toxic which can be diminished by burying the fluorine further into the dendrimer interior
	Second-generation dendron	Sonogashira coupling, alkyne deprotection and CuAAC	PFTB group attached to the dendron	FNMR	Higher number of equivalent fluorine than commercially available 19F MRI probes	Probes for 19F MRI	[240]
					Too unpolar to be water-soluble
					Just one characterisation technique used
	Pseudo-symmetrical fluorines dendrimers	Polymer prep–bromination and Williamson ether synthesis, NPs by self-assembly	Bis(4-fluorophenyl) trifluoromethyl carbinol group	FNMR and MRI	Large amount of fluorine with a single NMR peak	19F MRI-guided drug therapy	[241]
					Optimize 19F relaxation time
					High sensitivity
					Reliable quantification
					Comparatively low yield (8%) for 11 synthesis steps
	Self-assembled fluorinated amphiphiles	Convergent way–Sonogashira coupling and Williamson ether synthesis for polymer, NPs by self-assembly	Fluorinated benzyl group	FNMR, DLS (6.3 nm), TEM	Quantifying drugs, detecting drug microenvironments and weak interactions	19F NMR/MRI guided drug therapy.	[242]
					Several synthetic step for the preparation with most of them requiring separation
NANOHYDROGELS	Chitosan	Ionic gelation using hyaluronic acid and tripolyphosphate	4,4,4-trifluorobutyric acid	DLS (274 nm), ELS (+30 mV), FNMR (−66 ppm), HNMR, TGA, DOSY, IR	Good biocompatibility toward murine macrophages cell line	Chitosan drug delivery systems for MRI lymphography	[247]
					Degree of substitution is comparatively low (0.3% and 20%) and varies between different substitutes, and determination is laborious
	Diblock polymers	Self-assembly by heating in aqueous solution	Poly[N(2,2 difluoroethyl)acrylamide]	SLS (100 and 67 nm), TEM, C-TEM, FNMR	Good sensitivity	19F MR imaging–angiogenesis imaging or the labelling of pancreatic islets	[248]
					Non-cytotoxic for several cell lines
					Long synthesis steps for preparation of polymers
	Fluorinated amphiphilic polymers	Self-assembly of polymers–direct dissolution of amphiphilic polymers in PBS buffer	-CF3 groups attached to the chains of polymer	DLS (6- 14 nm), FNMR, FMRI–phantom and animal imaging, CM, CyA-HeLa cells	Enhancement in T2 relaxation times by increasing the segment mobility	Multimodal imaging and therapeutic applications.	[249]
	Superhydrophilic 19F MRI CA	Hydrogel matrix attached to zwitterionic, fluorinated and alkynyl molecule by click chemistry	The fluorine atoms on trifluoromethyl groups	HMRS, FTIR, GPC, CD, Rheometer, SEM, FMRI, degradation study–female BALB/c mice, CyA-Dendritic cells, NIH 3T3 cells	Gelation properties of hydrogels unaffected by labelling CA	Real-time FMRI to precisely locate and quantify the degradation rate of hydrogel scaffolds in vivo	[250]
					3D-stereoscopic and 2D-anatomical information
LIPIDS	Antigen-loaded PFC particles	High-frequency mixing of the liquid PFC with a cationic lipid mixture-particles coat with PEG	PFH or PFCE	CM, TEM, F NMR, Cytotoxicity in transplanted pancreatic islets and beta cell-like cells and T-cell proliferation assay	Improving pancreatic islets transplantation technique	Theranostic PFC NPs	[255,256]
					Good cell viability and no change in cells’ phenotypical properties
					High resolution localization of transplanted cells
					The use of PFCE is better than PFH because the latter have 3 peaks in FNMR which reduces its sensitivity
	Thermally responsive lipid nano-emulsion	Nano-emulsion	Modified α-tocopherol	FNMR, DLS (50 nm), ZP	Proved that T2 changes more than T1 due to variation in temperature for FNMR	Potential tumour diagnosis	[258]
					The temperature studied is extreme (37 and 42 °C) compared to real tumour
	Multifunctional paramagnetic PFC NP	Microfluidization	PFCE	DLS (132 nm), AFM, UV–vis, FM, cellular toxicity on bronchial epithelium, FC, clinical pathology, FMRI	Enhanced intratumoural penetration	PFC NP delivery from intravenous applications to intratracheal use (for lung cancer)	[259]
					NPs stored under very special condition
					The lipid surfactant used have a laborious preparation
					The studied NPs contain Gd3+ as Gd-lipid chelates
MICELLE	Fluorinated thermoresponsive assembled protein (F-TRAP)	Self-assembly micelle	Fluorinated amino acids within a protein (5,5,5-DL-trifluoroleucines)	DLS (30 nm), FA, SLS, CD, MALDI-TOF-MS, TEM, turbidometry, FNMR, FMRI, Animal studies-mouse xenograft model of human breast cancer	No change in T1	Thermoresponsive 19F MRI/MRS-traceable theranostic agents	[260]
					Doxorubicin encapsulation and thermoresponsive release
					Zero echo time 19F MRI was used to get the direct imaging of protein as after micelle formation, there is a reduction in T2
					The release of drug is at 45 °C (usually tumour temperature range is 37 °C to 39 °C)
INORGANIC	Gold NPs protected by fluorinated ligands (F- MPC)	Homogeneous phase synthesis	Fluorinated tetraethylene glycol part of the ligand	DLS (10 nm), TEM, HAADF-STEM, FNMR, UV-Vis, ESR, CLSM, cell interaction with HeLa cells	Elimination of the use of surfactants	Nanovector	[266]
					Size may help to reach small vasculature vessels
					Soluble in many organic solvents
					The preparation of fluorinated ligands contains 6 steps, most of them requiring purification
	Functionalized gold NPs	Homogeneous phase synthesis	Fluorinated tetraethylene glycol part of the ligand	DLS, HNMR, TEM (1.5–2 nm), UV-Vis, FNMR and MRI	Water-soluble	Dual 1H/19F MRI	[267]
					Good quality MRI images
					Same as ref [266] + Gd(III) is embedded deep in the layer of Au NPs that causes reduction in T1 relaxation times of bulk water proton
	Gold NP functionalised with fluorine atoms	Reduction of HAuCl4 in the presence of NaBH4	PFTB	ICP-MS, F-NMR/MRI, UV-Vis, TEM, Cell viability and apoptosis assays -MDA-MB-231, C33-A and MDA-MB-435S cell lines, MTS CyA	Colloidal stability in water and other solvents	19F MR imaging	[268]
					Single chemical shift
					Long storage
					High fluorine loading
					Long preparation and purification procedure for the fluorine ligands
					The position of fluorine in the NPs is not established
	Hollow mesoporous silica NPs (HMSN-PFCE)	Modified protocol from [301]	PFCE	DLS, SEM (290 nm), TEM, MRI, NMR, PAGE	Prolonged circulation time	Dual MRI (1H and 19F)	[270]
					Helps in understanding the effect of loading agent on the biodistribution of NPs
					Better biodistribution of NPs
					The study is majorly applicable to systems whose cargo is on the outer surface
	Fluorinated mesoporous silica NPs (FMSNs and polyFMSNs)	Repeated impregnation-calcination process	Fluorosilane or polyfluorosiloxane	TGA, TEM (140 nm), DLS, FNMR and MRI, XPS, relaxometric properties	Colloidal stability	Dual MRI (1H and 19F)	[273]
					Increase in 19F relaxivities
					Meticulous NPs preparation
					Contains Gd3+
					The detection of probe might be impeded by the strong reduction of T2 after NPs formation
	PEG modified silica NP	Dehydration polymerizing reaction–PFCE including micelle as a platform	PFCE	TEM, DLS (50 nm), 1H/19F MRI	High sensitivity	Tumour imaging	[274]
					Water stability
					Information on long term stability, encapsulation efficiency of PFCE is deficient
	Silica multifunctional core–shell NPs (FLAMEs)	PFCE-phospholipid nanoemulsion by sol-gel process using a novel surfactant, PAP	PFCE	DMS (76 nm), F NMR and MRI, TEM, biocompatibility by MTT assay-colon-26 cells, Passive targeting, and accumulation- mice bearing a tumour	High sensitivity	Detection of gene expression and in vivo tumour imaging	[277]
					Modifiability of the surface, biocompatibility
					In vivo stability
					The FLAME NPs needs to be PEGylated as naked NPs is trapped immediately by the RES
					The information on long term stability of NPs is lacking
	Mesoporous FLAME (mFLAME)	PFCE emulsion by Sol–gel process	PFCE	DLS (165 nm), TEM, FNMR and MRI, CLSM, FC, MTT CyA-KB cells, FM	Ample cellular uptake and drug release in folate receptor-overexpressing tumour cells	Theranostic cancer treatment	[278]
					Drug release abilities at lower pH. (pH 5)
					Efficient tumour cell internalization
	Gd3+ complexes on FLAME NPs surface (FLAME-SS-Gd3+)	Gd3+ complexes were attached to the FLAME surface by disulfide linkers	PFCE	DLS (53.4 nm), FNMR and MRI, ICP-AES	Smart nanoprobe–based on PRE effect	Novel 19F MRI probes that visualize reducing environments	[279]
					In vivo imaging
					High SNR ratio
	PFC based 19F MRI nanoprobes (PFC@SiO2, FLAME)	PFC emulsion by sol–gel process	PFCE, PFOB, FC-43, PFN, PFDCO, TPFBME	DLS, TEM (40–120 nm), FI-RAW264.7 cells, H MRI and FMRI, hepatic uptake in mouse	T2 values -relatively longer than polymer-based or inorganic 19F MRI nanoprobes	Multicolour MRI probes	[281]
					In vivo triple-colour 19F MRI
					The shelf-life information is lacking for the NPs
	Fluorinated paramagnetic CAs	Multistep synthesis–cycloaddition reaction	Nonafluorinated carboxylic acid	FNMR, relaxivity measurements, MD	Relaxation times depending on the lanthanide ion	19F MRI	[35]
					Low solubility in aqueous media
	Hexagonal-phase NaGdF4:Yb3+/Tm3+ NPs	Hydrothermal method	NH4F/NaF	XRD, SEM, EDX, UV, photoluminescence spectra, EPR	Conducive to the UV light	IR tomography and MRI	[261]
					Good water solubility
					Lanthanide-based upconversion NPs
	Inorganic nanocrystals-PEG-coated CaF2 nanocrystals	Solvothermal approach	CaF2	H and C and F-NMR, DLS (<10 nm), TEM, XRD, EDX, FTIR, TGA, mouse model of inflammation	Maximal 19F density	Imaging tracers for in vivo 19F MRI	[263]
					Average out homonuclear dipolar interactions
					Direct and real-time in vivo 19F MRI
					Chemically surface modifiable
					Long T2
	Halloysite nanotubes- benzeneboronic acids (HNTs-6FBB)	One-pot synthesis	3,5-bis(trifluoromethyl) benzeneboronic acid	FNMR (−60 ppm), XRD, FTIR, XPS, TEM, EA (0.31% F)	Relatively long T2	Selective response toward H2O2	[285]
					Water dispersibility
					Detection of H2O2 is based on a very minute shift in FNMR (0.2 ppm)
					Low cell cytotoxicity
MIXED/HYBRID	Fe(III) tris-β-diketonate with PFPE (‘FETRIS’)	Microfluidization –metal-binding β-diketones conjugated to PFPE using pluronic surfactant	PFPE and PFPE derivatives, PFOB	DLS (140 nm to 200 nm), FNMR and FMRI, cell labelling-rodent glioma cell line	Ability to tune T1 by Fe concentration	In vivo detection of cell therapies and inflammatory cells	[288]
					Low cytotoxicity
					Small rates of metal leakage in the presence of EDTA in vitro and after cell labelling
	Cu1.75S–19F@OFP–SiO2	One-pot encapsulation method-PFCE anchored to Cu1.75S NPs and trapped within the silica shell	PFCE	DLS (20.8 nm), TEM, FMRI, PTT	Ultrahigh F signal	Ablation and sensitive multimodal imaging	[290]
					Biocompatible
					Capable of both in vivo imaging (F-MRI) and photothermal ablation
					Presence of excess of metals in a single probe!
					The degradation of this complex should be evaluated since without the SiO2 coating it is cytotoxic
	Fluorinated POSS-star polymers	Synthesis of star polymers by RAFT polymerization and polymer formation in water	2,2,2-Trifluoroethyl acrylate in the ligands attached to POSS	DLS (8–10 nm), FNMR and FMRI	High imaging intensity	Theranostic agents for cancer diagnosis and treatment	[291]
					No surfactants
					The yield for the formation of star polymers is low and extreme conditions for preparation
	Hybrid of fluorinated graphene oxide and iron oxide (IFGO)	Graphene oxide-Hummer’s method. Hybrid–co-precipitation	Fluorinated graphene	DLS (8–10 nm), FMRI, XRD, XPS, SEM and HRTEM, FTIR, MTT CyA-benign breast epithelial cell line, Raman, UV-Vis, hysteresis	Additional imaging modality–magnetic targeted drug delivery	Superior CAs for MRI and fluorescent imaging	[292]
					Increased magnetic saturation-better contrast
	Cu7S4−Au heterodimer Cu7S4−Au@PSI−19F/PEG nanocomposites	Wet-chemical method for Cu7S4-Au nano seeds followed by click chemistry	2,2,2-trifluoro-N-2-propyn-1-yl-acetamide	DLS, HRTEM (27 nm), XRD, EDX, HAADF-STEM, XPS, STEM, F NMR and MRI, CT, cell viability-4T1 cell lines, PTT–liver of female mice	Deep penetration	Multimodal imaging guided photothermal therapy	[293]
					High spatial resolution
					Enhances the photothermal efficacy
					Long preparation for the nanocomposite
	Mn-LDH@PFPE NPs	Composite system by conjugating a PFPE onto the surface of manganese-incorporated layered double hydroxide	PFPE	NMR and MRI, DLS (10 nm), TEM, GPC, CM, MTT assay–MDA-MB- 468 breast cancer cells, histopathologic examination	High specificity to breast cancer cells	Potential “smart” 19F MRI agent for detection of cancer diseases	[297]
	Fe3+@F,N-CD (fluorine and nitrogen co-doped carbon dot)	Simple microwave-assisted thermal decomposition method–from glucose and levofloxacin	Levofloxacin	DLS (16 nm), TEM, GPC, FTIR, XPS, FM, ESR, cytotoxic studies–HeLa cells, In vivo experiments -4T1 tumour bearing BALB/c mice, FMRI, CLSM	High T1 relaxivity	T1-weighted MRI CA	[298]
					Strong photoluminescence
					Low synthetic cost
					Low toxicity
					Cannot be used for long term imaging in the body as they are excreted in a very short time from the body