Black Phosphorus and its Biomedical Applications

Abstract

Black phosphorus (BP), also known as phosphorene, has attracted recent scientific attention since its first successful exfoliation in 2014 owing to its unique structure and properties. In particular, its exceptional attributes, such as the excellent optical and mechanical properties, electrical conductivity and electron-transfer capacity, contribute to its increasing demand as an alternative to graphene-based materials in biomedical applications. Although the outlook of this material seems promising, its practical applications are still highly challenging. In this review article, we discuss the unique properties of BP, which make it a potential platform for biomedical applications compared to other 2D materials, including graphene, molybdenum disulphide (MoS₂), tungsten diselenide (WSe₂) and hexagonal boron nitride (h-BN). We then introduce various synthesis methods of BP and review its latest progress in biomedical applications, such as biosensing, drug delivery, photoacoustic imaging and cancer therapies (i.e., photothermal and photodynamic therapies). Lastly, the existing challenges and future perspective of BP in biomedical applications are briefly discussed.

Keywords: biosensing; black phosphorus; drug delivery; photoacoustic imaging; photothermal and photodynamic therapies..

Figure 1

Black phosphorus (BP) as a promising material for biomedical applications. In particular, BP nanosheets and BP quantum dots (BPQD) have been widely used in biosensing, as field effect transistor sensors, colorimetric sensors, fluorescent sensors and electrochemical sensors, cancer imaging, drug delivery and cancer therapy. Reproduced with permission from references: , copyright 2017 Elsevier; , copyright 2016 ACS publications; , copyright 2017 Royal Science Chemistry; , copyright 2017 John Wiley & Sons.

Figure 2

Synthesis of black phosphorus (BP). (A) Mechanical cleavage method and (B) liquid exfoliation method were used to synthesize ultrathin BP nanosheets . (C) (i) Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) were used as solvents to synthesize BP nanosheets. (ii) Scanning electron microscopy (SEM) image of BP nanosheets . (iii) Transmission electron microscopy (TEM) images of BP quantum dots (BPQDs) synthesized by liquid exfoliation. (iv) Top: enlarged BPQDs image; bottom: high resolution TEM images of BPQDs . (D) (i) Scanning transmission electron microscopy (STEM) image and (ii) energy-dispersive X-ray spectroscopy (EDX) elemental map of BP synthesized by the mechanical cleavage method. (iii) STEM and (iv) EDX elemental map of BP synthesized by the liquid exfoliation method . Reproduced with permission from references: , copyright 2014 Royal Science Chemistry; , copyright 2015 John Wiley & Sons.

Figure 3

Black phosphorus (BP) as a material of field effect transistors for sensitive detection of target analytes. (A) BP nanosheets were exfoliated and transferred onto the device for the detection of immunoglobulin G (IgG) (B) Scanning electron microscopy image of the mechanically exfoliated BP nanosheets on gold electrodes. (C) Sensor responses to different concentrations of IgG. (D) Specific binding of IgG onto the device shows a higher sensitivity than those without anti-IgG probe and with non-specific protein (i.e., avidin). Reproduced with permission from reference , copyright 2017 Elsevier.

Figure 4

Black phosphorus (BP) as a material for electrochemical detection of target analytes. (A) Aptamer-functionalized BP for electrochemical detection of myoglobin (Mb). (i) Liquid phase exfoliation of BP nanosheets. (ii) Electrochemical response of bare, poly-L-lysine (PLL)-BP and PLL-BP-aptamer modified electrodes with a scan rate of 100 mV/s at potentials ranging from -1 V to +1 V. (iii) Electrochemical response to different concentrations of Mb on PLL-BP aptamer modified sensors . (B) BPNP for electrochemical detection of IgG. (i) BPNP was used as a tag for electrochemical detection based upon nano impact methods. (ii) Chronoamperograms of the competitive immunoassay shows that increasing concentration of IgG reduces the spike count due to competitive binding between IgG-BP and IgG. (iii) The small spike count in the control samples (in the absence of IgG and presence of non-specific protein, hemoglobin (in green)) indicates the good specificity of the assay . Reproduced with permission from references , , copyright 2016 ACS Publications.

Figure 5

Black phosphorus (BP) as a material for fluorescent detection of target analytes. (A) The fluorescent detection of nucleic acids using BPNPs as fluorophores. (B) The fluorescence emission spectra of BPNPs at 200-230 nm excitation wavelength. The maximum photoluminescence was observed at 200 nm, showing the fluorescent nature of the BPNPs. (C) BPNPs calibration curve at different concentrations of the targeted complementary DNA. (D) The fluorescence response of BPNPs towards the complementary (cDNA), three-base mismatched (mDNA-3) and non-complementary DNA (ncDNA). Reproduced with permission from reference , copyright 2017 Royal Science Chemistry.

Figure 6

Black phosphorus (BP) as a material for colorimetric detection of target analytes. (A) BP was used as an electron reservoir coupling with gold nanoparticles to enhance catalytic activity towards 4-nitrophenol reduction for the detection of carcinoembryonic antigen (CEA). Mixing of hexachloroauric acid and BP demonstrated a high catalytic activity of 4-nitrophenol (4-NP) reduction, resulting in the color change from yellow 4-NP to the colorless 4-aminophenol. (B) Plot of C_t/C₀ against reaction time in the presence of different concentrations of CEA in human serum. (C) The calibration plot shows a good linear relationship between (C₀ - C_t)/C₀ and the logarithm values of the concentration of CEA in serum . Reproduced with permission from reference , copyright 2017 John Wiley & Sons.

Figure 7

Black phosphorus (BP) as a material for cancer imaging. (A) Titanium ligand (TiL4)-coordinated BPQDs for photoacoustic imaging (PA) of cancer. (i) Transmission electron microscopy and (ii) atomic force microscopy images of TiL4-BPQDs. (iii) Time-dependent PA images and quantitative image analysis of MCF-7 cells in mice after intravenous injection of TiL4-BPQDs. (B) Polyethylene glycol treated (PEGylated) BPNP for PA of cancer. (i) Fourier transform infrared (FT-IR) spectrum of PEGylated BPNP. (ii) In vivo PA of PEGylated BPNP solution, liver, kidney and tumour after intravenous injection of PEGylated BPNP at different time points . Reproduced with permission from references: , copyright 2016 Elsevier; , copyright 2017 John Wiley & Sons.

Figure 8

Black phosphorus (BP) as a material for cancer therapy. (A) Upconversion nanoparticle (UCNP)-BP for cancer therapy under 808 nm near infrared (NIR) light irradiation. (i) Synthesis of UCNP-BP. (ii) HeLa cells with UCNP-BP under irradiation at different wavelengths. (iii) Images of tumour in mice on day 14. (iv) The tumor volume of mice over time . (B) Biodegradable BP for photothermal cancer therapy. (i) The process of degradation of the poly (lactic-co-glycolic acid) (PLGA) loaded with BP quantum dots (BPQDs) in the physiological environment. (ii) Infrared thermographic maps. (iii) Upon laser irradiation, the temperature increased in MCF7 breast tumour-bearing mice after injection with PBS, PLGA, BPQDs-PLGA nanospheres (NSs) and BPQDs. (iv) Growth curves of breast tumor (MCF7) in different groups of treated mice under laser irradiation . Reproduced with permission from references: , copyright 2016 Royal Science Chemistry; , copyright 2016 Nature Publishing Group.

Figure 9

Black phosphorus as a material for drug delivery. (A) BP-based theranostic delivery platform. (B) DOX loaded BP nanosheets enhanced the therapeutic effect by reducing the percentage of viable HeLa cells. (C-D) Strong fluorescence signals were observed in the tumor tissues of both BP-PEG/Cy7 and BP-PEG-FA/Cy7 nanosheets at 24 h post-injection of drugs. (G1: BP-PEG/Cy7 nanosheet group; G2: BP-PEG-FA/Cy7 nanosheet group; H: Heart; LI: Liver; S: Spleen; LU; Lung; K: Kidney; T: Tumor). Reproduced with permission from reference , copyright 2017 John Wiley & Sons.