Olumide Ogunlade

Gold–silica quantum rattles for multimodal imaging and therapy

Significance Therapeutic and diagnostic nanoparticles combine multiple functionalities to improve efficacy of treatment but often require assembling complex systems at the expense of overall performance. Here we present a simple strategy to synthesize a hybrid, rattle-like, gold–silica nanoparticle that very efficiently combines therapy and imaging in an animal model. The nanoparticle design is uniquely centered on enabling the use of gold quantum dots (<2 nm) in biological systems. The resulting nanoparticles are highly biocompatible and display emergent photonic and magnetic properties matching and in some instances outperforming state-of-the-art nanotechnology-based medical agents for each of the functionalities investigated, promising a tighter integration between imaging and therapy. Gold quantum dots exhibit distinctive optical and magnetic behaviors compared with larger gold nanoparticles. However, their unfavorable interaction with living systems and lack of stability in aqueous solvents has so far prevented their adoption in biology and medicine. Here, a simple synthetic pathway integrates gold quantum dots within a mesoporous silica shell, alongside larger gold nanoparticles within the shell’s central cavity. This “quantum rattle” structure is stable in aqueous solutions, does not elicit cell toxicity, preserves the attractive near-infrared photonics and paramagnetism of gold quantum dots, and enhances the drug-carrier performance of the silica shell. In vivo, the quantum rattles reduced tumor burden in a single course of photothermal therapy while coupling three complementary imaging modalities: near-infrared fluorescence, photoacoustic, and magnetic resonance imaging. The incorporation of gold within the quantum rattles significantly enhanced the drug-carrier performance of the silica shell. This innovative material design based on the mutually beneficial interaction of gold and silica introduces the use of gold quantum dots for imaging and therapeutic applications.

Accelerated high-resolution photoacoustic tomography via compressed sensing.

Current 3D photoacoustic tomography (PAT) systems offer either high image quality or high frame rates but are not able to deliver high spatial and temporal resolution simultaneously, which limits their ability to image dynamic processes in living tissue (4D PAT). A particular example is the planar Fabry-Pérot (FP) photoacoustic scanner, which yields high-resolution 3D images but takes several minutes to sequentially map the incident photoacoustic field on the 2D sensor plane, point-by-point. However, as the spatio-temporal complexity of many absorbing tissue structures is rather low, the data recorded in such a conventional, regularly sampled fashion is often highly redundant. We demonstrate that combining model-based, variational image reconstruction methods using spatial sparsity constraints with the development of novel PAT acquisition systems capable of sub-sampling the acoustic wave field can dramatically increase the acquisition speed while maintaining a good spatial resolution: first, we describe and model two general spatial sub-sampling schemes. Then, we discuss how to implement them using the FP interferometer and demonstrate the potential of these novel compressed sensing PAT devices through simulated data from a realistic numerical phantom and through measured data from a dynamic experimental phantom as well as from in vivo experiments. Our results show that images with good spatial resolution and contrast can be obtained from highly sub-sampled PAT data if variational image reconstruction techniques that describe the tissues structures with suitable sparsity-constraints are used. In particular, we examine the use of total variation (TV) regularization enhanced by Bregman iterations. These novel reconstruction strategies offer new opportunities to dramatically increase the acquisition speed of photoacoustic scanners that employ point-by-point sequential scanning as well as reducing the channel count of parallelized schemes that use detector arrays.

Exogenous contrast agents for thermoacoustic imaging: an investigation into the underlying sources of contrast.

PURPOSE Thermoacoustic imaging at microwave excitation frequencies is limited by the low differential contrast exhibited by high water content tissues. To overcome this, exogenous thermoacoustic contrast agents based on gadolinium compounds, iron oxide, and single wall carbon nanotubes have previously been suggested and investigated. However, these previous studies did not fully characterize the electric, magnetic, and thermodynamic properties of these agents thus precluding identification of the underlying sources of contrast. To address this, measurements of the complex permittivity, complex permeability, DC conductivity, and Grüneisen parameter have been made. These measurements allowed the origins of the contrast provided by each substance to be identified. METHODS The electric and magnetic properties of the contrast agents were characterized at 3 GHz using two rectangular waveguide cavities. The DC conductivity was measured separately using a conductivity meter. Thermoacoustic signals were then acquired and compared to those generated in water. Finally, 3D electromagnetic simulations were used to decouple the different contributions to the absorbed power density. RESULTS It was found that the gadolinium compounds provided appreciable electric contrast but not originating from the gadolinium itself. The contrast was either due to dissociation of the gadolinium salt which increased ionic conductivity or its nondissociated polar fraction which increased dielectric polarization loss or a combination of both. In addition, very high concentrations were required to achieve appreciable contrast, to the extent that the Grüneisen parameter increased significantly and became a source of contrast. Iron oxide particles were found to produce low but measurable dielectric contrast due to dielectric polarization loss, but this is attributed to the coating of the particles not the iron oxide. Single wall carbon nanotubes did not provide measurable contrast of any type. CONCLUSIONS It is concluded that gadolinium based contrast agents, iron oxide particles, and single walled carbon nanotubes have little intrinsic merit as thermoacoustic contrast agents. Simple electrolytes such as saline which yield high contrast based on ionic conductivity provide much higher dielectric contrast per unit solute concentration and are likely to be significantly more effective as contrast agents.

Photoacoustic imaging using an 8-beam Fabry-Perot scanner

The planar Fabry Perot (FP) photoacoustic scanner has been shown to provide exquisite high resolution 3D images of soft tissue structures in vivo to depths up to approximately 10mm. However a significant limitation of current embodiments of the concept is low image acquisition speed. To increase acquisition speed, a novel multi-beam scanner architecture has been developed. This enables a line of equally spaced 8 interrogation beams to be scanned simultaneously across the FP sensor and the photoacoustic signals detected in parallel. In addition, an excitation laser operating at 200Hz was used. The combination of parallelising the detection and the high pulse repetition frequency (PRF) of the excitation laser has enabled dramatic reductions in image acquisition time to be achieved. A 3D image can now be acquired in 10 seconds and 2D images at video rates are now possible.

Photoacoustic tomography using orthogonal Fabry-Pérot sensors.

Abstract. Fabry–Pérot sensors have been used to produce in-vivo photoacoustic images of exquisite quality. However, for ease of construction and interrogation, they are produced in a planar form. Planar arrays suffer from a limited detection aperture, which leads to artifacts in the reconstruction of the initial pressure distribution. Here, an L-shaped detection geometry is described that allows a greater field of view by placing a second planar array orthogonal to the first. This captures data from the deeper lying regions of interest and mitigates the limited view, thus reducing artifacts in the reconstructed initial pressure distribution.

Tunable Semiconducting Polymer Nanoparticles with INDT-Based Conjugated Polymers for Photoacoustic Molecular Imaging

Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo.

Electric and magnetic properties of contrast agents for thermoacoustic imaging

The endogenous contrast in thermoacoustic imaging is due to the water and ionic content in tissue. This results in poor tissue speci city between high water content tissues. As a result, exogenous contrast agents have been employed to improve tissue speci city and also increase the SNR. An investigation into the sources of contrast produced by several exogenous contrast agents is described. These include three gadolinium based MRI contrast agents, iron oxide particles, single wall carbon nanotubes, saline and sucrose solutions. Both the dielectric and magnetic properties of contrast agents at 3GHz have been measured using microwave resonant cavities. The DC conductivity of the contrast agents were also measured. It is shown that the measured increase in dielectric contrast, relative to water, is due to dipole rotational loss of polar non electrolytes, ionic loss of electrolytes or a combination of both. It is shown that for the same dielectric contrast, electrolytes make better thermoacoustic contrast agents than non-electrolytes, for thermoacoustic imaging.

Orthogonal Fabry-Pérot sensors for photoacoustic tomography

Fabry-Pérot (FP) sensors have been used to produce in-vivo photoacoustic images of exquisite quality. However, for simplicity of construction FP sensors are produced in a planar form. Planar sensors suffer from a limited detection aperture, due to their planarity. We present a novel sensor geometry that allowed a greater field of view by placing a second sensor orthogonal to the first. This captured data from the deeper lying regions of interest and mitigated the limited view.

Quantitative thermoacoustic image reconstruction of conductivity profiles

A numerical inversion scheme for recovering a map of the absolute conductivity from the absorbed power density map that is conventionally reconstructed in thermacoustic imaging is described. This offers the prospect of obtaining an image that is more closely related to the underlying tissue structure and physiology. The inversion scheme employs a full 3D full wave model of electromagnetic propagation in tissue which is iteratively fitted to the measured absorbed power density map using a simple recursive method. The reconstruction is demonstrated numerically using three examples of absorbers of varying geometries, tissue realistic complex permittivity values and noise. In these examples, the reconstruction is shown to rapidly converge to within good estimates of the true conductivity in less than 20 iterations.

Photoacoustic tomography of vascular therapy in a preclinical mouse model of colorectal carcinoma

Vascular therapy in oncology exploits the differences between normal blood vessels and abnormal tumour neoangiogenesis to selectively target cancer. For optimal treatment efficacy, and translation of novel compounds, the response of the tumour vasculature needs to be assessed. Photoacoustic tomography (PAT) is capable of this as it provides highly spatially resolved 3D images of vascular networks in biological tissue to cm depths. In preclinical models of cancer this is sufficient to encompass entire subcutaneous tumours, and can therefore be used to evaluate pharmacological intervention directed at the vasculature. In this study the vascular disrupting agent OXi4503 was used to treat subcutaneous tumour mouse models of two human colorectal carcinoma tumour types (SW1222, LS174T) at a range of concentrations (40mg/kg, 10mg/kg, 1mg/kg and sham dose control). The characteristic destruction of tumour vasculature caused by OXi4503 was observed by PAT and confirmed ex vivo via histology. Differences observed between the two tumour types assessed demonstrate the importance of tumour microenvironment and pathophysiology on response to therapy. Differential response to different doses of OXi4503 was observed, with outward tumour growth only seen once entire tumour viability had been re-established; this demonstrates the potential of PAT to act as a biomarker of response for the translation of novel anti-vascular compounds and also within the clinic. This study shows clearly that PAT can accurately assess the time course of drug action and relapse of pharmacodynamic effect in preclinical models of cancer and the important translational prospects for vascular targeted tumour therapies.