Noble metal nanomaterials have been extensively explored in cancer diagnostic and therapeutic applications owing to their unique physical and chemical properties, such as facile synthesis, straightforward surface functionalization, strong photothermal effect, and excellent biocompatibility. Herein, we summarize the recent development of two-dimensional (2D) Pd-based nanomaterials and their applications in cancer diagnosis and therapy. Different synthetic strategies for Pd nanosheets and the related nanostructures, including Pd@Au, Pd@Ag nanoplates and mesocrystalline Pd nanocorolla, are first discussed. Together with their unique properties, the potential bioapplications of these 2D Pd nanomaterials are then demonstrated. With strong absorption in near-infrared (NIR) region, these nanomaterials have great potentials in cancer photothermal therapy (PTT). They also readily act as contrast agents in photoacoustic (PA) imaging or X-ray computed tomography (CT) to achieve image-guided cancer therapy. Moreover, significant efforts have been devoted to studying the combination of PTT and other treatment modalities (e.g., chemotherapy or photodynamic therapy) based on Pd nanomaterials. The remarkable synergistic or collaborative effects to achieve better therapeutic efficacy are discussed as well. Additionally, the biosafety of 2D Pd-based nanomaterials in vitro and in vivo was evaluated. Finally, challenges for the applications of Pd-based nanomaterials in cancer diagnosis and therapy, and future research prospects are highlighted.Download high-res image (72KB)Download full-size image

Currently, the combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a powerful technique for cancer treatment. However, most examples of combined PTT and PDT reported use multi-component nanocomposites under excitation of separate wavelength, resulting in complex treatment process. In this work, a novel theranostic nanoplatform (SiNcOH-DSPE-PEG(NH2) NPs) has been successfully developed by coating silicon 2,3-naphthalocyanine dihydroxide (SiNcOH) with DSPE-PEG and DSPE-PEG-NH2 for photoacoustic (PA) imaging-guided PTT and PDT tumor ablation for the first time. The as-prepared single-agent SiNcOH-DSPE-PEG(NH2) NPs not only have good water solubility and biocompatibility, but also exhibit high photothermal conversion efficiency and singlet oxygen generation capability upon 808 nm NIR laser irradiation. In addition, owing to their high absorption at NIR region, the SiNcOH-DSPE-PEG(NH2) NPs can also be employed as an effective diagnostic nanoagent for photoacoustic (PA) imaging. In vitro and in vivo experimental results clearly indicated that the simultaneously combined PTT and PDT under the guidance of PA imaging with single NIR laser excitation can effectively kill cancer cells or eradicate tumor tissues. Taking facile synthesis and high efficiency in cancer treatment by SiNcOH-DSPE-PEG(NH2) NPs into consideration, our study provides a promising strategy to realize molecular imaging-guided combination therapy.Download high-res image (181KB)Download full-size imageA novel theranostic nanoplatform (SiNcOH-DSPE-PEG(NH2) NPs) has been successfully developed by coating silicon 2,3-naphthalocyanine dihydroxide (SiNcOH) with DSPE-PEG and DSPE-PEG-NH2 for photoacoustic (PA) imaging-guided PTT and PDT tumor ablation.

Two-dimensional (2D) Pd-based nanomaterials with strong near-infrared absorption have recently shown great application prospects in cancer diagnosis and therapy. Most previous studies mainly focused on understanding the in vivo behaviors and treatment effects of these Pd-based nanomaterials after intravenous injection into mice. However, it remains unclear whether other administration routes will affect the in vivo biodistribution, excretion and potential toxicity of Pd-based nanomaterials. In this study, for the first time we systematically explored the in vivo behaviors of different-sized Pd nanosheets (NSs) (approximately 5 nm, 30 nm and 80 nm) following oral feeding and intraperitoneal injection. It was found that Pd NSs with oral administration had a rather low accumulation that decreased with time in all examined organs, and became almost undetectable in these organs at 24 h post-injection. In comparison, the intraperitoneally injected Pd NSs exhibited obvious time-dependent and size-dependent accumulations in the reticuloendothelial (RES) system including the liver and spleen within 24 h post-injection, and then the accumulation amounts decreased with the lapse of time. Moreover in tumor tissue, smaller-sized Pd NSs (5 nm) had a higher uptake than larger-sized Pd NSs (30 nm and 80 nm). Excretion studies uncovered that more than 70% ID of Pd NSs could be rapidly excreted from the body through urine and feces within two days after oral administration, whereas Pd NSs with intraperitoneal injection could be gradually cleared, mainly via urine within 8 days. Further histological examination of organ sections and blood biochemical analysis evidenced that these different-sized Pd NSs do not cause obvious toxicity in the treated mice at the tested period with the given dose. These results not only indicate that the biodistribution and excretion capabilities of Pd NSs are closely related to their administration routes, but also imply that the intraperitoneally injected Pd NSs have greater potential for in vivo biomedical studies compared to oral feeding, because of their relatively higher tissue absorption and gradual excretion from the body. This study will provide valuable information for the clinical translation of 2D Pd-based nanomaterials.

Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core–shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(IV) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au–PEG-Pt) for combined photothermal–chemotherapy. The prepared Pd@Au–PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(IV) prodrug loading. Once injected into biological tissue, the Pt(IV) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(II) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(II) species. More importantly, Pd@Au–PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo–chemotherapy treatment with Pd@Au–PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au–PEG-Pt without irradiation or photothermal treatment using Pd@Au–PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.

In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis.

In this work, a novel bactericidal agent based on two-dimensional Pd@Ag nanosheets (Pd@Ag NSs) that is responsive to near-infrared (NIR) light has been developed. These Pd@Ag NSs were prepared by reducing silver ions on the surface of Pd nanosheets (Pd NSs) seeds by formaldehyde, and displayed excellent NIR absorption and photothermal conversion properties. In addition, the NIR irradiation triggers the release of more Ag+ from the Pd@Ag NSs. Upon exposure to a NIR laser at a low power density (0.5 W cm−2), Pd@Ag NSs kill both Gram-negative (Escherichia coli, E. coli) and Gram-positive (Staphylococcus aureus, S. aureus) bacteria effectively by the synergistic effect of plasmonic heating and Ag+ release, which is much higher than either plasmonic heating or Ag+ alone. Such a novel nanomaterial is promising as an adjuvant therapeutic method for the treatment of patients suffering from severe bacterial infections.

Palladium nanosheets with strong near-infrared absorption have been recently demonstrated as promising photothermal agents for photothermal therapy (PTT) of cancers. However, systematic assessments of their potential risks and impacts to biological systems have not been fully explored yet. In this work, we carefully investigate how surface coatings affect the in vivo behaviors of small Pd nanosheets (Pd NSs). Several biocompatible molecules such as carboxymethyl chitosan (CMC), PEG-NH2, PEG-SH, and dihydrolipoic acid-zwitterion (DHLA-ZW) were used to coat Pd NSs. The blood circulation half-lives, biodistribution, potential toxicity, clearance, and photothermal effect of different surface-coated Pd NSs in mice after intravenous injection were compared. PEG-SH-coated Pd NSs (Pd-HS-PEG) were found to have ultralong blood circulation half-life and show high uptake in the tumor. We then carry out the in vivo photothermal therapeutic studies on the Pd-HS-PEG conjugate and revealed its outstanding efficacy in in vivo photothermal therapy of cancers. Our results highlight the importance of surface coatings to the in vivo behaviors of nanomaterials and can provide guidelines to the future design of Pd NSs bioconjugates for other in vivo applications.Keywords: in vivo behaviors; nanosheet; palladium; photothermal therapy; surface coating;

Plasmonic Pd nanosheets have been emerging as promising materials for applying in near-infrared (NIR) photothermal therapy (PTT) of cancer. However, animal in mice studies indicated that the original synthesized poly(vinylpyrrolidone) (PVP)-protected small Pd nanosheets (Pd-PVP) and some further surface-modified small Pd nanosheets such as Pd-PEG(SH) easily accumulated in reticuloendothelial system (RES) organs (liver, spleen, etc.) and were difficult to be cleared from these organs quickly. In the work, we surprisingly found that glutathione (GSH) could promote the clearance of surface-modified small Pd nanosheets (e.g. Pd-PVP, Pd-PEG(SH) and Pd-GSH) from the RES organs efficiently. The effects of GSH on the biodistribution and clearance of different surface-modified Pd nanosheets were investigated. Our results indicated that these surface-modified Pd nanosheets with or without GSH added caused no morbidity at target primary organs, and GSH can promote the clearance of different surface-modified Pd nanosheets in the order of Pd-PVP≈Pd-PEG(SH)>Pd-GSH. This study suggests that glutathione could be an attractive reagent for promoting nanomaterials eliminated from the reticuloendothelial systems (RES).

In this work, we prepared chlorin e6 (Ce6)-functionalized Pd nanosheets (Pd-PEI-Ce6) for the photodynamic and photothermal combined therapy that use a single laser. To fabricate the Pd-PEI-Ce6 nanocomposite, photosensitizer Ce6 were chemically conjugated to polyethylenimine (PEI) and the formed Ce6-PEI conjugates were then anchored onto Pd nanosheets by electrostatic and coordination interaction. The prepared Pd-PEI-Ce6 nanocomposite were about 4.5 nm in size, exhibited broad, and strong absorption from 450 to 800 nm, good singlet oxygen generation capacity and photothermal conversion efficiency, and excellent biocompability. Significantly greater cell killing was observed when HeLa cells incubated with Pd-PEI-Ce6 were irradiated with the 660 nm laser, attributable to both Pd nanosheets-mediated photothermal ablation and the photodynamic destruction effect of photosensitizer Ce6. The double phototherapy effect was also confirmed in vivo. It was found that the Pd-PEI-Ce6 treated tumor-bearing mice displayed the enhanced therapeutic efficiency compared to that of Pd-PEI, or Ce6-treated mice. Our work highlights the promise of using Pd nanosheets for potential multimode cancer therapies.Keywords: combinational therapy; in vivo; Pd-PEI-Ce6 nanocomposite; photodynamic therapy; photothermal therapy;

In this work, we have demonstrated that mesoporous silica-coated Pd@Ag nanoparticles (Pd@Ag@mSiO2) can be used as an excellent nanoplatform for photodynamic therapy (PDT) drug delivery. Photosensitizer molecules, Chlorin e6 (Ce6), are covalently linked to the mesoporous shell and the prepared Pd@Ag@mSiO2–Ce6 nanoparticles exhibit excellent water solubility, good stability against leaching and high efficiency in photo-generating cytotoxic singlet oxygen. More importantly, the photothermal effect of Pd@Ag nanoplates under the irradiation of a NIR laser can enhance the uptake of Pd@Ag@mSiO2–Ce6 nanoparticles by cells, further increasing the PDT efficiency toward cancer cells. The photothermally enhanced PDT effects were demonstrated both in vitro and in vivo. When the Pd@Ag@mSiO2–Ce6 nanoparticles were injected intratumorally into the S180 tumor-bearing mice, the tumors were completely destroyed without recurrence of tumors upon irradiation with both 808 nm and 660 nm lasers, while the irradiation with 808 nm or 660 nm alone did not. These results indicate that the Pd@Ag@mSiO2 nanoparticles may be a valuable new tool for application in cancer phototherapy.

The preparation, characterization and application of NaYF4:Yb3+, Tm3+–NaYF4:Yb3+, Er3+ core–shell upconversion nanocrystals (UCNPs) with multiple emission peaks (e.g. 539, 654 and 802 nm) have been demonstrated in this work. The monodisperse nanocrystals were prepared via a modified thermal decomposition synthesis. The resulting UCNPs were ∼31 nm in diameter with the lanthanide ions Tm3+ and Er3+ doped in the core and the shell, respectively. Under the laser diode excitation at 980 nm, these core–shell nanocrystals give strong upconversion emissions from the visible to near-infrared (NIR) region. By coating a PEG–phospholipid (PP) layer on the surface of the nanocrystals, the as-prepared UCNPs were favorably endowed with good water solubility for the potential biological applications. Here, a photosensitizer drug of Chlorin e6 (Ce6), which has maximum absorption that overlaps with the red emission of UCNPs, was loaded on these PP-coated UCNPs (UCNP@PP) by physical adsorption. The activity of the Ce6-loaded UCNP@PP (UCNP@PP–Ce6) in photodynamic therapy of cancer cells in vitro has been fully investigated in this work. Our results indicated that these multifunctional UCNP@PP–Ce6 nanoparticles have efficient NIR-to-NIR upconversion luminescence and photodynamic therapy capabilities, which could be potentially employed as a theranostic platform for cancer treatment.

A synthetic method to prepare novel multifunctional core-shell-structured mesoporous silica nanoparticles for simultaneous magnetic resonance (MR) and fluorescence imaging, cell targeting and photosensitization treatment has been developed. Superparamagnetic magnetite nanoparticles and fluorescent dyes are co-encapsulated inside nonporous silica nanoparticles as the core to provide dual-imaging capabilities (MR and optical). The photosensitizer molecules, tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc), are covalently linked to the mesoporous silica shell and exhibit excellent photo-oxidation efficiency. The surface modification of the core-shell silica nanoparticles with folic acid enhances the delivery of photosensitizers to the targeting cancer cells that overexpress the folate receptor, and thereby decreases their toxicity to the surrounding normal tissues. These unique advantages make the prepared multifunctional core-shell silica nanoparticles promising for cancer diagnosis and therapy.

A method for coating magnetite and mimetic enzyme (hemin) with amorphous silica to form a novel mimetic peroxidase (magnetite–hemin/SiO2) has been developed by combining reverse microemulsion and the modified Stöber method. The magnetic silica nanoparticle supported hemin has a long-term stability toward temperature and good reusability. They can be easily separated from the reaction solution by using an external magnetic field and reused directly for next round of reaction. The peroxidase activity of the magnetite–hemin/SiO2 was studied based on its catalytic effect on the reaction of p-hydroxyphenylacetic acid and H2O2. The results indicated that the catalytic activity of the new mimetic enzyme catalyst is higher than that of the free hemin. The possibility of its application was proven by the determination of H2O2, with the detection limits of 7.3 nmol L−1 H2O2.

The preparation and utilization of silica nanoparticles as a carrier of tetra-substituted carboxyl iron phthalocyanine (TCFePc, a novel mimetic peroxidase) is reported in this article. Compared with free TCFePc, the experimental results indicated that the TCFePc entrapped in silica nanoparticles exhibited an improved catalytic activity and good reusability. By using tetra-substituted carboxyl iron phthalocyanine-silica nanoparticles (TCFePc-SiO2 Nps) to catalyze the oxidation reaction of thiamine by hydrogen peroxide, a new fluorimetric method was developed for the quantitative analysis of thiamine in pharmaceutical tablets. The influences of different conditions, such as the medium acidity, the reaction time and temperature, the concentrations of reagents and foreign substances, were all investigated. Under the optimum conditions, the calibration graph for thiamine was linear over the range of 5.0 × 10− 9–1.0 × 10− 6 mol L− 1, with a detection limit of 2.0 × 10− 9 mol L− 1. The proposed method was successfully applied to the direct analysis of thiamine in two kinds of pharmaceutical tablets, and offered the advantages of simple pretreatment, rapid determination, high sensitivity and good reusability. Hence, as a carrier of the mimetic enzyme, the silica nanoparticles are effective for enzymatic reaction processes. This method is supposed to be hopeful for the determination of thiamine in other complex raw materials.

This is the first report on the preparation and utilization of a novel red-region fluorescent dye (tetracarboxy aluminum phthalocyanine) doped silica nanoparticles. In these nanoparticles, the tetracarboxy aluminum phthalocyanine molecules were covalently bound to silica matrix to protect the dye leaking from nanoparticles in bio-applications. The surface of the nanoparticles was modified by amino groups and easily bioconjugated with goat anti-human IgG antibody. By employing these nanoparticles as fluorescent probe, a sensitive fluoroimmunoassay method has been developed for the determination of trace level of human IgG. The calibration graph for human IgG was linear over the range of 0–500 ng mL−1 with a detection limit of 1.6 ng mL−1. Compared with the corresponding system using free AlC4Pc as a probe for determining human IgG, the sensitivity of the proposed system was notably increased. The method was applied to the analysis of human IgG in human sera with satisfactory results.

A sensitive, selective and rapid spectrofluorimetric method is proposed for the determination of hydrogen peroxide using rhodamine B hydrazide as a fluorogenic substrate catalyzed by iron(III)-tetrasulfonatophthalocyanine. It is based on the oxidation of rhodamine B hydrazide, a colorless, non-fluorescent spirolactam hydrazide, by hydrogen peroxide which generates the highly fluorescent product rhodamine B. Under optimum conditions, the responses for hydrogen peroxide were linear from 2.0 × 10−8 to 2.0 × 10−6 mol L−1, with a detection limit of 3.7 × 10−9 mol L−1 in a 3.5 min reaction period. It can easily be incorporated into the determination of biochemical substances that produce hydrogen peroxide under catalytic oxidation in the presence of their oxidase. The possibility has been tested for the determination of glucose in human sera as an example.

In this work, we have demonstrated that mesoporous silica-coated Pd@Ag nanoparticles (Pd@Ag@mSiO2) can be used as an excellent nanoplatform for photodynamic therapy (PDT) drug delivery. Photosensitizer molecules, Chlorin e6 (Ce6), are covalently linked to the mesoporous shell and the prepared Pd@Ag@mSiO2–Ce6 nanoparticles exhibit excellent water solubility, good stability against leaching and high efficiency in photo-generating cytotoxic singlet oxygen. More importantly, the photothermal effect of Pd@Ag nanoplates under the irradiation of a NIR laser can enhance the uptake of Pd@Ag@mSiO2–Ce6 nanoparticles by cells, further increasing the PDT efficiency toward cancer cells. The photothermally enhanced PDT effects were demonstrated both in vitro and in vivo. When the Pd@Ag@mSiO2–Ce6 nanoparticles were injected intratumorally into the S180 tumor-bearing mice, the tumors were completely destroyed without recurrence of tumors upon irradiation with both 808 nm and 660 nm lasers, while the irradiation with 808 nm or 660 nm alone did not. These results indicate that the Pd@Ag@mSiO2 nanoparticles may be a valuable new tool for application in cancer phototherapy.

In this work, a novel bactericidal agent based on two-dimensional Pd@Ag nanosheets (Pd@Ag NSs) that is responsive to near-infrared (NIR) light has been developed. These Pd@Ag NSs were prepared by reducing silver ions on the surface of Pd nanosheets (Pd NSs) seeds by formaldehyde, and displayed excellent NIR absorption and photothermal conversion properties. In addition, the NIR irradiation triggers the release of more Ag+ from the Pd@Ag NSs. Upon exposure to a NIR laser at a low power density (0.5 W cm−2), Pd@Ag NSs kill both Gram-negative (Escherichia coli, E. coli) and Gram-positive (Staphylococcus aureus, S. aureus) bacteria effectively by the synergistic effect of plasmonic heating and Ag+ release, which is much higher than either plasmonic heating or Ag+ alone. Such a novel nanomaterial is promising as an adjuvant therapeutic method for the treatment of patients suffering from severe bacterial infections.

A synthetic method to prepare novel multifunctional core-shell-structured mesoporous silica nanoparticles for simultaneous magnetic resonance (MR) and fluorescence imaging, cell targeting and photosensitization treatment has been developed. Superparamagnetic magnetite nanoparticles and fluorescent dyes are co-encapsulated inside nonporous silica nanoparticles as the core to provide dual-imaging capabilities (MR and optical). The photosensitizer molecules, tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc), are covalently linked to the mesoporous silica shell and exhibit excellent photo-oxidation efficiency. The surface modification of the core-shell silica nanoparticles with folic acid enhances the delivery of photosensitizers to the targeting cancer cells that overexpress the folate receptor, and thereby decreases their toxicity to the surrounding normal tissues. These unique advantages make the prepared multifunctional core-shell silica nanoparticles promising for cancer diagnosis and therapy.