Gold nanocluster-loaded hybrid albumin nanoparticles with fluorescence-based optical visualization and photothermal conversion for tumor detection/ablation.

Gold nanoclusters (AuNCs) are viewed as effective hyperthermal agents for the treatment of tumors. Whereas AuNCs formed by the agglomeration of several to tens of gold atoms (<1-2 nm) possess significant fluorescence, they have a negligible hyperthermal effect, while AuNCs comprised of spherical gold nanoparticles (AuNPs > a few nanometers) have a marked hyperthermic effect but lose their inherent fluorescence and obstruct the intensity of neighboring fluorescent dyes due to Forster resonance energy transfer (FRET). To achieve both hyperthermia and fluorescence-based optical visualization, we generated hybrid albumin nanoparticles containing AuNCs (~88 nm) comprising AuNPs (~4.5 nm). We generated a series of formulated AuNCs and optimized the size, morphology, NIR absorbance (600-900 nm), hyperthermal activity, and fluorescence spectral characters of the resulting hybrid albumin nanoparticles (AuNCs/BSA-NPs) by considering the interparticle distance between the AuNPs and Cy5.5. Among these, AuNCs/BSA-NPs (formula D) had a strong hyperthermic effect and had well-preserved fluorescence intensity (from the attached Cy5.5) due to localized surface plasmon resonance (LSPR) and a reduction in FRET. These AuNCs/BSA-NPs were able to elevate the surface tumor temperature of HCT116-bearing mice to >50 °C following 808 nm laser irradiation (1.5 W/cm2, 10 min), which remarkably suppressed tumor growth (17.8 ±â€¯16.9 mm3vs. PBS and AuNCs/BSA-NPs (formula E): ~1850 and ~1250 mm3, respectively). Also, Cy5.5-modified AuNCs/BSA-NPs (formula D) showed good performance in optical fluorescence imaging of target tumors in HCT116 tumor-bearing mice. Together, our results indicate that the interparticle distance between albumin or Cy5.5 and AuNPs/AuNCs can be optimized to achieve both hyperthermia and fluorescence emission by striking a balance between LSPR and FRET effects. We believe that the AuNC/BSA-NPs formulation presented here can serve as a potential platform for both optically visualizing and treating colon cancers.

Small gold nanorods-loaded hybrid albumin nanoparticles with high photothermal efficacy for tumor ablation.

Photothermal therapy using gold nanorods (AuNRs) has gained great attention for cancer therapy because AuNRs emit heat and induce tumor cell death responding to the near infrared light. However, the anticancer efficiency of AuNRs alone is undermined by its poor in vivo stability and potential toxicity. The prime purpose of this study was to send more AuNRs into tumors to more fully ablate them. For this, we fabricated hybrid albumin nanoparticles encapsulating small AuNRs (AuNRs-Alb-NPs), which take advantage of biocompatible albumin as a carrier, with better tumor targetability and high in vivo photothermal activity. The sizes of length/width of AuNRs were approximately 20.5 nm and 4.6 nm, respectively, showing a 4.5 aspect ratio, and the size of the resulting AuNRs-Alb-NPs was ˜130 nm, all of which are favorable for glomerular filtration and passive tumor targeting via extravasation. We chose the best formulation for AuNRs-Alb-NPs by in vitro cytotoxicity based on photothermal conversion efficiency considering the incorporated number of AuNRs. Visualized by a photothermal camera, the local tumor temperature of mice treated with AuNRs-Alb-NPs increased to 57℃, which was sufficient for the hyperthermal effect with 808 nm laser irradiation. Subsequently, AuNRs-Alb-NPs displayed remarkably better tumor ablation vs. naïve formulation of AuNRs (tumor volume: 73.8 ± 105.8 vs. 1455.3 ± 310.4 mm3 at day 8) in the glioblastoma N2a tumor-bearing mice. Most of all, we demonstrated, using photoacoustic imaging and inductively coupled plasma mass spectrometry, that this much better tumor ablation was due to enhanced tumor targeting with albumin nanoparticles. We believe our AuNRs-Alb-NPs should be considered promising photothermal agents that are safer, have good targetability, and exhibit excellent tumor ablation.

Near infrared light-responsive heat-emitting hemoglobin hydrogels for photothermal cancer therapy.

Photothermal therapy (PTT) is an effective means of treating tumors because tumor cells are sensitive to heat. Gold and carbon nanoparticles are used as efficient PTT materials. However, development of a non-toxic biodegradable PTT agent remains a challenge. Here, we developed a hemoglobin (Hb) hydrogel that exhibited excellent PTT effects in vitro and in vivo. Unlike conventional PTT agents, which are toxic and do not decompose completely in the body, the Hb hydrogel was manufactured using only two components: (i) Hb, a natural substance derived from the human body, and (ii) PEG, an FDA-approved polymer. The gelation time of the Hb hydrogels could be controlled by changing the Hb concentration. Because Hb is present at a high concentration (150 mg/ml) in the body, the Hb hydrogel decomposed and was eliminated in vivo without toxicity. The Hb hydrogel showed an excellent PTT effect in response to 808 nm near-infrared (NIR) laser irradiation and had excellent anticancer effects against A549 lung cancer cells both in vitro and in vivo. Blood hematology and blood biochemical assay results from an animal model treated with Hb hydrogel were similar to those of the control group. Importantly, toxicity was not observed based on H&E staining of major organs (heart, liver, spleen, kidneys and lung). Tumors of A549 cell-xenografted mice treated with Hb hydrogel and 808 nm NIR laser irradiation were significantly smaller than those of the control group (23.1 mm3versus 746.5 mm3, respectively). This is a first report of a biocompatible photothermal hydrogel based on hemoglobin, and our overall results suggest that Hb hydrogels are commercially-promising PTT systems that have excellent anti-cancer effects.

Facile fabrication of highly photothermal-effective albumin-assisted gold nanoclusters for treating breast cancer.

Gold nanoclusters (AuNCs) have been considered to be a promising candidate for hyperthermia-based anticancer therapy. Herein, we introduce albumin-assisted AuNCs composed of small gold nanoparticles (AuNPs, <6 nm) assembled with strands of polyallylamine (PAH), which exhibited strong surface plasmon resonance upon near-infrared (NIR, ∼808 nm) laser irradiation and good in vivo stability. Our albumin-assisted PAH-AuNCs (BSA/PAH-AuNCs) were facilely fabricated as a top-down process by a simple ultrasonication after the preparation of large nano-aggregates of PAH-AuNPs. Albumin played a critical role as a stabilizer and surfactant in making loosely associated large aggregates and thereby producing small gold nanoclusters (∼60 nm) of slightly negative charge upon ultrasonication. The prepared BSA/PAH-AuNCs displayed excellent hyperthermal effects (∼60 °C) in response to ∼808-nm NIR laser irradiation in a 4T1 cell system in vitro and in 4T1 cell tumor xenograft mice in vivo, indicating their remarkable potential to suppress breast cancer growth, without almost no significant toxicity in histology. Consequently, our gold nanoclusters should be considered as a promising photothermal agent that are easy to manufacture and exhibit marked anticancer effects in terms of tumor ablation.