Duyang Gao

Highly absorbing multispectral near-infrared polymer nanoparticles from one conjugated backbone for photoacoustic imaging and photothermal therapy

Semiconducting polymers with specific absorption are useful in various applications, including organic optoelectronics, optical imaging, and nanomedicine. However, the optical absorption of a semiconducting polymer with a determined structure is hardly tunable when compared with that of inorganic semiconductors. In this work, we show that the optical absorption of polymer nanoparticles from one conjugated backbone can be effectively tuned through judicious design of the particle morphology and the persistence length of polymers. Highly absorbing near-infrared (NIR) polymers based on diketopyrrolopyrrole-dithiophene (DPP-DT) are synthesized to have different molecular weights (MWs). The DPP-DT polymer with a large molecular weight and high persistence length exhibited remarkably high optical absorption with a peak mass extinction coefficient of 81.7xa0Lxa0g-1xa0cm-1, which is one of the highest value among various photothermal agents reported to date. Particularly, the polymer nanoparticles with different sizes exhibit broadly tunable NIR absorption peaks from 630 to 811xa0nm. The PEGylated small polymer dots (Pdots) show good NIR light-harvesting efficiency and high non-radiative decay rates, resulting in a relatively high photothermal conversion efficiency in excess of 50%. Thus, this Pdot-based platform can serve as promising photothermal agents and photoacoustic probes for cancer theranostics.

A PIID-DTBT based semi-conducting polymer dots with broad and strong optical absorption in the visible-light region: Highly effective contrast agents for multiscale and multi-spectral photoacoustic imaging

As a hybrid imaging technique, photoacoustic imaging (PAI) can provide multiscale morphological information of tissues, and the use of multi-spectral PAI (MSPAI) can recover the spatial distribution of chromophores of interest, such as hemoglobin within tissues. Herein, we developed a contrast agent that can very effectively combine multiscale PAI with MSPAI for a more comprehensive characterization of complex biological tissues. Specifically, we developed novel PIID-DTBT based semi-conducting polymer dots (Pdots) that show broad and strong optical absorption in the visible-light region (500–700 nm). The performances of gold nanoparticles (GNPs) and gold nanorods (GNRs), which have been verified as excellent photoacoustic contrast agents, were compared with that of the Pdots based on the multiscale PAI system. Both ex vivo and in vivo experiments demonstrated that the Pdots have better photoacoustic conversion efficiency at 532 nm than GNPs and showed similar photoacoustic performance with GNRs at 700 nm at the same mass concentration. Photostability and toxicity tests demonstrated that the Pdots are photostable and biocompatible. More importantly, an in vivo MSPAI experiment indicated that the Pdots have better photoacoustic performance than the blood and therefore the signals can be accurately extracted from the background of vascular-rich tissues. Our work demonstrates the great potential of Pdots as highly effective contrast agents for the precise localization of lesions relative to the blood vessels based on multiscale PAI and MSPAI.

Protein‐Modified CuS Nanotriangles: A Potential Multimodal Nanoplatform for In Vivo Tumor Photoacoustic/Magnetic Resonance Dual‐Modal Imaging

Controllable preparation of water-soluble multifunctional nanoprobes is of great significance for cancer early diagnosis. In this study, protein-modified hydrophilic copper sufide (CuS) nanotriangles with tunable absorption in the second near-infrared region are developed in the presence of halide ions. Further, gadolinium ions chelated diethylenetriaminepentaacetic acid is conjugated on it by using the unique characteristics of the protein-protected nanotriangles. Specifically, the as-obtained nanostructures are investigated as contrast agents for enhanced in vivo photoacoustic/magnetic resonance dual-modal tumor imaging. More importantly, in vitro and in vivo toxicity analysis are also performed, which show that the dual-modal nanoprobes are biocompatible for most of the cases. It is demonstrated that the novel as-prepared protein-modified nanotriangles are able to work as a nanoplatform to construct dual-modal nanoprobes, which paves a new avenue for improving the photoacoustic/magnetic resonance imaging contrast in cancer detection. It should be pointed out that other functional blocks may also be linked on it, which makes it a general method to design multifunctional nanoprobes.

Mesoporous Carbon Nanospheres as a Multifunctional Carrier for Cancer Theranostics

Optical nanomaterials with intense absorption in near-infrared (NIR) region hold great promise for biomedical applications such as photothermal therapy (PTT) and photoacoustic imaging (PAI). In this work, we report mesoporous carbon nanospheres (Meso-CNs) with broadband and intense absorption in the UV-Vis-NIR region (300-1400 nm) and explore their potential as a multifunctional platform for photoacoustic imaging and chemo-photothermal therapy. Methods: Meso-CNs were prepared by a “silica-assisted” synthesis strategy and characterized by transmission electron microscope and optical spectroscopy. We investigated the photothermal conversion and photoacoustic imaging of Meso-CNs in comparison with single-walled carbon nanotubes (SWCNTs), graphene and gold nanorods (GNRs). In vitro cellular assays and in vivo chemo-photothermal combination therapy were performed. Results: The absorption coefficients of Meso-CNs are 1.5-2 times higher than those of SWCNTs and graphene and are comparable to those of GNRs in both the first and the second near-infrared optical windows (NIR-I and NIR-II) of tissues. When exposed to an NIR laser, the photothermal and photoacoustic signal generation of Meso-CNs are also stronger than those of SWCNTs, graphene, and GNRs. DOX was loaded into Meso-CNs with a high efficiency (35 wt%) owing to the unique mesoporous structure. Particularly, the drug release from Meso-CNs is sensitive to both pH and NIR light stimulation. In vivo chemo-photothermal combination therapy demonstrates a remarkable inhibition effect on tumor growth under NIR laser treatment. Conclusions: We have developed Meso-CNs for photothermal conversion and photoacoustic imaging. The porous structure also serves as a drug carrier and the drug release can be controlled by pH and external light. The high drug loading capacity, superior photothermal and photoacoustic generation, together with the apparent chemo-photothermal therapeutic effect, make Meso-CNs a promising platform for cancer theranostics.

Photoacoustic-Based Multimodal Nanoprobes: from Constructing to Biological Applications

Multimodal nanoprobes have attracted intensive attentions since they can integrate various imaging modalities to obtain complementary merits of single modality. Meanwhile, recent interest in laser-induced photoacoustic imaging is rapidly growing due to its unique advantages in visualizing tissue structure and function with high spatial resolution and satisfactory imaging depth. In this review, we summarize multimodal nanoprobes involving photoacoustic imaging. In particular, we focus on the method to construct multimodal nanoprobes. We have divided the synthetic methods into two types. First, we call it “one for all” concept, which involves intrinsic properties of the element in a single particle. Second, “all in one” concept, which means integrating different functional blocks in one particle. Then, we simply introduce the applications of the multifunctional nanoprobes for in vivo imaging and imaging-guided tumor therapy. At last, we discuss the advantages and disadvantages of the present methods to construct the multimodal nanoprobes and share our viewpoints in this area.

Highly Stable Conjugated Polymer Dots as Multifunctional Agents for Photoacoustic Imaging-Guided Photothermal Therapy

Theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, most photothermal agents are limited by their instability and low photothermal conversion efficiency. In this study, we report new conjugated polymer dots (Pdots) as multifunctional agents for photoacoustic (PA) imaging-guided PTT. The novel 4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]-2,6-bis(trimethylstannyl)benzo[1,2-b:4,5-b]dithiophene-6,6-dibromo-N,N-(2-ethylhexyl)isoindigo (BDT-IID) Pdots are readily fabricated though nanoreprecipitation and can absorb strongly in the 650-700 nm region. Furthermore, the BDT-IID Pdots possess a stable nanostructure and an extremely low biotoxicity. In particular, its photothermal conversion efficiency can be up to 45%. More importantly, our in vivo results exhibit that the BDT-IID Pdots are able to offer concurrently enhanced PA contrast and sufficient photothermal effect. Consequently, the BDT-IID Pdots can be exploited as a unique theranostic nanoplatform for PA imaging-guided PTT of tumors, holding great promise for their clinical translational development.

Development of a multi-band photoacoustic tomography imaging system based on a capacitive micromachined ultrasonic transducer array

Photoacoustic tomography (PAT) as a hybrid technology combines the high optical contrast and high acoustic resolution in a single imaging modality. However, most of the available PAT systems cannot comprehensively or accurately characterize biological systems at multiple length scales due to the use of narrow bandwidth commercial ultrasonic transducers. In this study, we fabricated a novel multi-band capacitive micromachined ultrasonic transducer (CMUT) array, and first developed a CMUT-based multi-band photoacoustic tomography (MBPAT) imaging system. The MBPAT imaging system was examined by the phantom experiment, and then was successfully applied to image the zebrafish in vivo. The imaging results indicated that CMUT-array-based MBPAT can provide a more comprehensive and accurate characterization of biological tissues, which exhibit the potential of MBPAT/CMUT in various areas of biomedical imaging.

Protein-modified ultra-small gold clusters for dual-modal in vivo fluorescence/photoacoustic imaging

BackgroundnConstruction of nanoprobes for dual-modal fluorescence/photoacoustic imaging (PAI) is of great importance for the detection of disease pathology and the development of innovative therapeutics. Previously ultra-small gold clusters were designed and used as contrast agents for fluorescence imaging (FLI). However, it is not clear whether they can also serve as promising probes for PAI. In this study, protein-modified ultra-small gold clusters are produced and examined quantitatively as enhanced contrast agents for dual-modal in vivo fluorescence and PAI.nnnMethodsnTo construct the dual-modal ultra-small gold clusters, HAuCl4·4H2O aqueous solution was first mixed with the protein solution. NaOH was further introduced to the solution under vigorous stirring. The as-designed dual-modal nanoprobe was formed after stirring for 2 h at 65 °C. And then the solution was purified by gel column for further application. Zebrafish, cultivated in the solution containing gold clusters, was used in this study to demonstrate the dual-modal imaging ability of the nanoprobe by using our home-made optical-resolution photoacoustic microscopy and commercial fluorescence microscopy systems.nnnResultsnThe gold nanoclusters were synthesized with diameters of about 3 nm, which showed the broad absorption with a characteristic peak centered at 520 nm. A strong near-infrared emission ranging from 600 to 750 nm was also observed for the gold clusters. In addition, the cell viability was more than 90% even at a high concentration of the nanoprobes. The zebrafish cultivated with the gold clusters exhibited dramatically enhanced fluorescence and photoacoustic signal intensities.nnnConclusionsnQuantitative analysis results demonstrated that BSA-modified gold clusters were excellent contrast agents for in vivo dual-modal fluorescence/PAI. Due to their ultra-small size and superior biocompatibility, they can be applied to the detection and treatment of various diseases with enhanced sensitivity.

Engineering a protein-based nanoplatform as an antibacterial agent for light activated dual-modal photothermal and photodynamic therapy of infection in both the NIR I and II windows

The rapid rise of drug- and multi-drug resistant pathogenic bacteria constitutes an increasing risk to global public health. Thus, it is essential to develop new agents and/or strategies to overcome the antibiotic resistance crisis. Herein, ultra-small protein-based nanoparticles (NPs) with absorption covering both the near-infrared (NIR) I and II windows were constructed as novel antibacterial agents, which introduced a killing strategy utilizing the synergistic photothermal and photodynamic effects. The agent engineered by the conjugation of Ce6 molecules to ultra-small hydrophilic protein-modified copper sulfide NPs can transfer light energy into thermal energy for photothermal therapy and produce reactive oxygen species for photodynamic therapy. Under the irradiation of both NIR I and II lasers, the agent demonstrated a potent bacteria killing activity on both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) in vitro bacteria with high efficacy and safety. Furthermore, the as-prepared NPs also displayed an efficient in vivo bactericidal activity in a mouse model as monitored by measuring the photoacoustic signals of the blood vessels around the infection site. Consequently, leveraging the synergistic photothermal and photodynamic effects, the as-designed ultra-small NIR NPs may eliminate the emergence of drug resistance due to the mechanical destruction of the bacteria cell, thus representing a promising approach to control the antibiotic resistance crisis.