Introduction
Preparation of layered BP
Fig.1 Schematic illustration of the atomic structure of 2D BP. (a) Top view. (b) 3D view. Reproduced from Ref. [17]. (c) Schematic illustration of the 2D layered-BP preparation methods. (d) Schematic illustration of mechanical exfoliation. (e) Schematic illustration of liquid-phase exfoliation. (f) Schematic illustration of the CVD method |
Preparation of BP bulk crystal
Mechanical exfoliation of BP
Liquid exfoliation of BP
Tab.1 Summary of the popular synthesis methods |
synthesis method | description | advantages | disadvantages | |
---|---|---|---|---|
top-down | mechanical exfoliation | making BP layers flake off and thin from BP bulk crystal by repeatedly bonding/separating with the help of adhesive tapes or plasma etching | • high quality BPNSs | • not suitable for large-scale production of BPNSs • hard to control the thickness and size of BPNSs |
liquid exfoliation | BP bulk crystal is immersed into solvents and the ions weaken and break the interlayer attractions between BP layers under sonication | • large-scale production • diverse BP nanostructures (e.g., BPQDs and BPNSs) • controllable size and thickness of final product • low cost | • hard to produce large area phosphorene • lower purity | |
bottom-up | chemical vapor deposition (CVD) | forming BP thin films by doping phosphorus atoms in the vacuum | • suitable for large area BPNSs production | • high cost • produce by-products |
Direct growth of layered-BP thin films
Tab.2 Biomedical applications of layered black phosphorus-based platforms in disease diagnosis and treatment |
material | application | disease | highlight of the research | Ref. |
---|---|---|---|---|
TiL4@BPQDs | photoacoustic imaging (PAI) | MCF-7 tumor | It demonstrates that BP-based PA agents are stable and can be used for efficient bioimaging of cancer; the performance is superior to that of gold nanoparticles (AuNPs). | [30] |
BP-DEX/PEI-FA | PAI and photothermal therapy (PTT) | BP-DEX/PEI-FA | The biocompatible and water-soluble BP nanoparticles exhibit high photothermal conversion efficacy for PAI and photothermal therapy of cancer. | [79] |
BP@lipid-PEG | PAI/NIR-II optical imaging | It first reports that the BPNSs modified with cholesterol display strong NIR-II fluorescence and can be capsulated with the PEGylated lipid into BP@lipid-PEG nanoparticles for NIR-II optical imaging. | [80] | |
BPNS@TA-Mn | PAI/MRI/PTT | HeLa tumor | It applies PAI/MRI dual-mode imaging for guided PTT. | [81] |
MUCNPs@BPNs-Ce6 | MRI/PAI/ultrasound /fluorescence/ PTT/ photodynamic (PDT) | HeLa tumor | The multi-functional layered-BP platform can simultaneously implement four imaging modalities and two treatment schemes; the agent has strong absorption of NIR light for deep tissue applications. | [82] |
NB@BPs | PTT | MCF7 breast tumor | A Nile Blue (NB) diazonium tetrafluoroborate salt is covalently doped with BPs, enhancing the stability. | [83] |
NIR-II-CD/BP | PTT | 4T1 tumor | NIR-II-CD/BP show remarkably enhanced photothermal conversion efficacy and antitumor efficiency in NIR-II region, the most suitable optical window for clinical use. | [84] |
MTP-BP-al-PEG | PTT | 4T1 tumor | Targeting to higher potential membrane and mitochondria of cancer cells greatly boost the PTT efficiency. | [85] |
BPQDs/GA/PLLA-PEG-PLLA | PAI/PTT | T47D tumor | Gambogic acid inhibits heat shock protein expression conducing a better PTT effect. | [86] |
PEGylated BPQDs | PDT | S180 tumor | It demonstrates the good stability, no cytotoxicity and PDT potential of BP. | [87] |
Cy5-dHeme-BPNS-FA | PDT | HeLa tumors | The excessive intracellular H2O2 were catalyzed with passivated BP-based nanoplatform to generate O2 that is essential for PDT, leading to significant enhancement of PDT efficacy for tumor treatment. | [88] |
BP-DOX | PDT/PTT/chemotherapy | 4T1 tumor | The drug loading rate of layered-BP is increased by up to 9.5 folds. | [89] |
BP@hydrogel | chemotherapy | MDA-MB-231 tumors | By loading DOX in the layered-BP modified with hydrogel, laser exposure can be regulated to release drugs to treat cancer. | [90] |
BP-DOX@PDA-PEG-FA | PTT/chemotherapy | Hela tumor | BP-DOX@PDA-PEG-FA combined with laser irradiation yields dramatic synergistic antitumor effects, inducing no acute side effects. | [91] |
BP-R-D@PDA-PEG-Apt | genetherapy/ chemotherapy/PTT | MCF-7 tumor | BP can be used in targeted chemo, PTT, and gene against multidrug-resistant cancer. | [92] |
BSPTD | chemotherapy/PTT/ fluorescence | 4T1 tumor | It can specifically target the tumor site, and inhibit metastasis during the targeting chemo-photothermal therapy, benefiting from the secondary drug delivery facilitated by photothermal degradation. | [93] |
RV/CAT-BP@MFL | fluorescence/PTT/ PDT/chemotherapy | MCF-7 tumor | It displays folate receptor-targeted delivery, tumor hypoxia relief, and synergistic suppression of tumorous cell propagation. | [94] |
BPNVs-CpG | PDT/immunotherapy/PAI | 4T1-tumor | It enhances deeper tumor penetration synergized immunotherapy induced by CpG, yielding an excellent cancer therapy effect. | [95] |
R-MnO2-FBP | MRI/fluorescence/PDT | HeLa tumor | It demonstrates a dual-mode of fluorescence imaging and MR imaging for guided PDT. | [96] |
NE hydrogel | osteanagenesis | calvarial defect | It demonstrates BP nanosheets-based nanoengineered hydrogels can increase biological mineralization and promote bone osteogenic cell differentiation and bone regeneration. | [97] |
BPNs/chitosan/PRP | osteanagenesis/PTT/PDT | rheumatoid arthritis | Platelet-rich plasma-chitosan was combined with BP which induced calcium-extracted biomineralization and phototherapy, getting a better curative effect of rheumatoid arthritis. | [98] |
BP@PDA-incorporated GelMA scaffold | MSC differentiation | It can significantly promote the differentiation of mesenchymal stem cells (MSC) into neural-like cells under the synergistic electrical stimulation. | [99] | |
BP nanosheets | Cu2+ regulation | neurodegenerative disorder | BP nanosheets are promising neuroprotective nanodrug for NDs because they process preeminent photothermal effect, increasing its blood–brain barrier permeability and subsequently act as a chelator to regulate Cu2+ concentration. | [100] |
PEG-LK7@BP | Cu2+ regulation /chemotherapy | Alzheimer’s disease | BP can efficiently bind with the peptide inhibitor LK7 to inhibit amyloid formation. | [101] |
BP nanosheets | antioxidative therapy | acute kidney injury | BP nanosheets are easily to be oxidized into phosphorus oxides which can act as promising antioxidative agents for consuming excess cytotoxic reactive oxygen species. | [102] |
Functionalized layered-BP nanoparticles and their applications
Fig.2 (a) Preparation of the PEGylated BP theranostic delivery platform. 1: PEG–NH2 (surface modification), 2: DOX (therapeutic agents), 3: Cy7–NH2 (NIR imaging agents), 4: FA–PEG–NH2 (targeting agents), 5: FITC–PEG–NH2 (fluorescent imaging agents). (b) Screening and summary of the endocytosis pathways and the biological activities of PEGylated BPNSs in cancer cells. Reproduced from Ref. [32] |
Multifunctional layered-BP nanoparticles for diagnostic imaging
Fig.3 (a) and (b) Targeted imaging of tumors with BP-DEX/PEI-FA nanoparticles. (a) In vivo PA images of the 4T1 tumor-bearing mice before and after tail vein injection of BP-DEX/PEI and BP-DEX/PEI-FA nanoparticles (2 mg/mL) at different time points. (b) PA signal intensities of the tumors from the 4T1 tumor-bearing mice collected at different time points after tail vein injection of BP-DEX/PEI and BP-DEX/PEI-FA nanoparticles. (c) In vivo NIR-II fluorescence images of a mouse collected at different time intervals using a 1400-nm optical filter after intravenous injection of BP@lipid-PEG nanosphere aqueous solutions. (d) Enlargement of the image acquired at 30 s post-injection with different optical filters (1400 and 1250 nm, respectively). Scale bar = 5 mm. Reproduced from Refs. [80,107] |
Multifunctional layered-BP nanoparticles for PTT
Fig.5 (a) Schematic illustration of the fabrication of NB@BPs. (b)–(f) Material stability examinations. Time-dependent variations in the (b) absorption ratios at the respective peak wavelength (A/A0) and (c) increase in the temperature of the bare BPs and NB@BPs in water under 808 nm and 1.0 W/cm2 laser irradiations for 10 min. (d) Time-dependent variations of the fluorescence intensity of NB@BPs in water. Optical images of micro-sized (e) bare BPs and (f) NB@BPs exposed under ambient conditions for different dispersion time lengths. Reproduced from Ref. [83] |
Fig.6 (a) Schematic illustration of in vitro deep-tissue PTT. (b) and (c) Temperature change of the NIR-II-CD/BP solution irradiated by an 808- or 1064-nm laser in the presence of varied thicknesses of additional tissue. (d) Fitted temperature change exponential decay of NIR-II-CD/BP hybrids upon 808- and 1064-nm laser irradiations. Reproduced from Ref. [84] |
Fig.7 (a) HSP90 expressions in tumors collected from mice 2 days after applying various treatments, as determined by immunofluorescence staining. (b) Western blot data of T47D tumor lysates collected from mice 2 days after applying various treatments. (c) Relative expression of HSP90 normalized against β-actin (control). **P < 0.01, ***P < 0.001. Reproduced from Ref. [86] |
Multifunctional layered-BP nanoparticles for PDT
Fig.8 (a) Schematic illustration of singlet-oxygen production by BPNSs under laser irradiation. (b) Photographs of PEGylated BPQDs dispersed in various media. (RPMI refers to RPMI 1640 media) (c) Cell viability of HeLa and L02 cells after incubation with BPQDs at different concentrations at 37°C for 24 h. (d) In vivo imaging monitoring of the PDT effect on tumor-bearing mice in both the left and right flanks after the injection of Cy5-dHeme-BPNS-FA or Cy5-BPNS-FA. After 24 h post-injection, the tumor in the right flank was irradiated with laser, whereas the tumor in the left was kept away from light as the control. (e) Relative change of the averaged tumor volume after treatment with PBS, Cy5-dHeme-BPNS-FA, and Cy5-BPNS-FA with and without laser irradiation. Statistical analysis was performed using Student’s t-test (**P < 0.01 and ***P < 0.001). Reproduced from Refs. [87,88,113] |
Multifunctional layered-BP nanoparticles for drug delivery
Fig.9 (a) Schematic illustration of the working principle of BP@hydrogel. BP@hydrogel releases the encapsulated chemotherapeutics under NIR-light irradiation to break the DNA chains, thereby inducing apoptosis. (b) Viability of HeLa cells cultured with DOX-loaded nanoformulations in comparison with that of free DOX at the same DOX dose after 24 h (∗∗P < 0.01). (c) Anti-tumor efficacy of saline, DOX, BP-DOX@PDA-PEG, BP-DOX@PDA-PEG-FA, and BP-DOX@PDA-PEG-FA + NIR on the nude mice bearing HeLa cell xenografts. Tumor weight of each group was obtained from the sacrificed mice at the end of the study (∗∗P < 0.01). Reproduced from Refs. [90,91] |
Functional layered-BP nanoparticles for multifunctional co-delivery
Fig.10 (a) Schematic illustration of the procedure used to fabricate nanostructures and the combined chemo/gene/photothermal targeted therapy of tumor cells. (b) Inhibition of tumor growth after different treatments. (c) Morphology of tumors removed from the sacrificed mice in all groups at the end of the study (**P < 0.01, ***P < 0.001). Reproduced from Ref. [92] |
Fig.12 (a) and (b) In vivo time-dependent imaging. (a) Time-dependent in vivo fluorescence images by dual-channel of RhB and Cy5.5. (b) MR images of a mouse bearing a subcutaneous HeLa tumor after being injected with R-MnO2-FBP. Scale bar: 5.0 mm. (c)–(e) In vivo assessment of the PDT therapeutic efficacy as monitored by (c) fluorescence and (d) MRI on the tumor-bearing mice at 24, 28, and 36 h, separately, after injection of R-MnO2-FBP. The tumors were irradiated by a 660-nm laser at 150 mW/cm2 for 10 min. Scale bar: 5.0 mm. (e) Relative change of the averaged tumor volume after different treatments. Mean ± SD, n = 5 (**P < 0.01). Reproduced from Ref. [96] |