Photodynamic Therapy-Induced Microvascular Changes in a Nonmelanoma Skin Cancer Model Assessed by Photoacoustic Microscopy and Diffuse Correlation Spectroscopy
TL;DR: The PDT-induced vasculature destruction in a mouse model of skin cancer is observed using photoacoustic microscopy and diffuse correlation spectroscopy, indicating a significant blood flow decrease after PDT.
Abstract: One of the main mechanisms of action for photodynamic therapy (PDT) is the destruction of tumor vasculature. We observed the PDT-induced vasculature destruction in a mouse model of skin cancer using two techniques: Photoacoustic microscopy (PAM) and diffuse correlation spectroscopy (DCS). PAM showed high-resolution images of the abnormal microvasculature near the establishing tumor area at pre-PDT, as well as the subsequent destruction of those vessels post-PDT. DCS indicated a significant blood flow decrease after PDT, confirming the vascular destruction. Noninvasive assessment of vascular changes may be indicative of therapy response.
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TL;DR: The role of ultrasound (US) and photoacoustic imaging in improving PDT‐mediated outcomes in cancer—from tracking photosensitizer uptake and vascular destruction, to measuring oxygenation dynamics and the overall evaluation of tumor responses is elucidated.
Abstract: Photodynamic therapy (PDT) is a phototoxic treatment with high spatial and temporal control and has shown tremendous promise in the management of cancer due to its high efficacy and minimal side effects. PDT efficacy is dictated by a complex relationship between dosimetry parameters such as the concentration of the photosensitizer at the tumor site, its spatial localization (intracellular or extracellular), light dose and distribution, oxygen distribution and concentration, and the heterogeneity of the inter- and intratumoral microenvironment. Studying and characterizing these parameters, along with monitoring tumor heterogeneity pre- and post-PDT, provides essential data for predicting therapeutic response and the design of subsequent therapies. In this review, we elucidate the role of ultrasound (US) and photoacoustic imaging in improving PDT-mediated outcomes in cancer-from tracking photosensitizer uptake and vascular destruction, to measuring oxygenation dynamics and the overall evaluation of tumor responses. We also present recent advances in multifunctional theranostic nanomaterials that can improve either US or photoacoustic imaging contrast, as well as deliver photosensitizers specifically to tumors. Given the wide availability, low-cost, portability and nonionizing nature of US and photoacoustic imaging, together with their capabilities of providing multiparametric morphological and functional information, these technologies are thusly inimitable when deployed in conjunction with PDT.
39 citations
Cites background from "Photodynamic Therapy-Induced Microv..."
...beautifully illustrates the utility of monitoring vascular destruction due to PDT (66,67)....
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...Adapted with permission from (66) and (71)....
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TL;DR: It is demonstrated that a kind of relatively small sized and partially hollow GSNCs can enhance the intrinsic photoacoustic imaging performances for blood vessels around tumor sites, and may assist PAM-based tumor diagnosis and induce a tumor targeted PTT effect.
Abstract: Gold-silver nanocages (GSNCs) are widely used in cancer imaging and therapy due to excellent biocompatibility, internal hollow structures, and tunable optical properties. However, their possible responses toward the tumor microenvironment are still not well understood. In this study, it is demonstrated that a kind of relatively small sized (35 nm) and partially hollow GSNCs (absorbance centered at 532 nm) can enhance the intrinsic photoacoustic imaging performances for blood vessels around tumor sites. More importantly, the high concentration of glutathione around the tumor cells' microenvironment may induce the aggregation, disintegration, and agglomeration of these GSNCs sequentially, allowing significant shifts in the absorbance spectrum of GSNCs to the near-infrared (NIR) region. This enhanced absorbance in the NIR region entails the significant photothermal therapy (PTT) effect. In vivo experiments, including photoacoustic microscopy (PAM) for cancer diagnosis and PTT in tumor model mice, also show coincident consequences. Taken together, the slightly hollow GSNCs may assist PAM-based tumor diagnosis and induce a tumor targeted PTT effect. This work paves a new avenue for the development of an alternative tumor diagnostic and therapeutic strategy.
27 citations
TL;DR: In this paper, the authors investigated the feasibility of label-free quantitative photoacoustic microscopy (PAM) for monitoring the vasculature changes under the effect of photodynamic therapy (PDT) in mouse ear melanoma tumors.
Abstract: Vascular damage is one of the therapeutic mechanisms of photodynamic therapy (PDT). In particular, short-term PDT treatments can effectively destroy malignant lesions while minimizing damage to nonmalignant tissue. In this study, we investigate the feasibility of label-free quantitative photoacoustic microscopy (PAM) for monitoring the vasculature changes under the effect of PDT in mouse ear melanoma tumors. In particular, quantitative vasculature evaluation was conducted based on Hessian filter segmentation. Three-dimensional morphological PAM and depth-resolved images before and after PDT treatment were acquired. In addition, five quantitative vasculature parameters, including the PA signal, vessel diameter, vessel density, perfused vessel density, and vessel complexity, were analyzed to evaluate the influence of PDT on four different areas: Two melanoma tumors, and control and normal vessel areas. The quantitative and qualitative results successfully demonstrated the potential of the proposed PAM-based quantitative approach to evaluate the effectiveness of the PDT method.
16 citations
TL;DR: Results show that the optical method may be used for the early prediction of ulcer progression by measuring dermal and subcutaneous red cell motion and optical absorption and scattering properties in spinal cord injury subjects with only nonbleachable redness in the sacrococcygeal area.
Abstract: Pressure injuries (PIs) originate beneath the surface of the skin at the interface between bone and soft tissue. We used diffuse correlation spectroscopy (DCS) and diffuse near-infrared spectroscopy (DNIRS) to predict the development of PIs by measuring dermal and subcutaneous red cell motion and optical absorption and scattering properties in 11 spinal cord injury subjects with only nonbleachable redness in the sacrococcygeal area in a rehabilitation hospital and 20 healthy volunteers. A custom optical probe was developed to obtain continuous DCS and DNIRS data from sacrococcygeal tissue while the subjects were placed in supine and lateral positions to apply pressure from body weight and to release pressure, respectively. Rehabilitation patients were measured up to four times over a two-week period. Three rehabilitation patients developed open PIs (POs) within four weeks and eight patients did not (PNOs). Temporal correlation functions in the area of redness were significantly different ( p < 0.01 ) during both baseline and applied pressure stages for POs and PNOs. The results show that our optical method may be used for the early prediction of ulcer progression.
8 citations
References
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TL;DR: This paper will attempt to deal with the complex subject of PDT tumor destruction by giving a sequential account of the effects occurring during PDT tissue treatment on a cellular and tissue level.
Abstract: Those readers already familiar with the field of photodynamic therapy (PDT)t will consider this title somewhat presumptuous since it implies that the answer to the posed question is known. Indeed, answers to many questions regarding PDT have been found over the past decade, but a comprehensive understanding of all mechanisms involved in PDT tumor destruction has not yet emerged. This paper will attempt to deal with this complex subject by giving a sequential account of the effects occurring during PDT tissue treatment on a cellular and tissue level. Photodynamic therapy is based on the dye-sensitized photooxidation of biological matter in the target tissue (Foote, 1990). This requires the presence of a dye (sensitizer) in the tissue to be treated. Although such sensitizers can be naturally occurring constituents of cells and tissues, in the case of PDT they are introduced into the organism as the first step of treatment. In the second step, the tissuelocalized sensitizer is exposed to light of wavelength appropriate for absorption by the sensitizer. Through various photophysical pathways, also involving molecular oxygen, oxygenated products harmful to cell function arise and eventual tissue destruction results. In keeping with the chronological nature of this review, the subject matter will be divided into the
2,308 citations
TL;DR: The underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.
Abstract: Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2–3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.
1,793 citations
TL;DR: This study is a thorough nationwide estimate of the incidence of nonmelanoma skin cancer and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States.
Abstract: Importance Understanding skin cancer incidence is critical for planning prevention and treatment strategies and allocating medical resources. However, owing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC) has been difficult. Objective To estimate the incidence of NMSC (keratinocyte carcinomas) in the US population in 2012 and the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the 2012 Medicare fee-for-service population. Design, Setting, and Participants This study analyzes US government administrative data including the Centers for Medicare & Medicaid Services Physicians Claims databases to calculate totals of skin cancer procedures performed for Medicare beneficiaries from 2006 through 2012 and related parameters. The population-based National Ambulatory Medical Care Survey database was used to estimate NMSC-related office visits for 2012. We combined these analyses to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population. Main Outcomes and Measures Incidence of NMSC in the US population in 2012 and BCC and SCC in the 2012 Medicare fee-for-service population. Results The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 13% from 2 048 517 in 2006 to 2 321 058 in 2012. The age-adjusted skin cancer procedure rate per 100 000 beneficiaries increased from 6075 in 2006 to 7320 in 2012. The number of procedures in Medicare beneficiaries specific for NMSC increased by 14% from 1 918 340 in 2006 to 2 191 100 in 2012. The number of persons with at least 1 procedure for NMSC increased by 14% (from 1 177 618 to 1 336 800) from 2006 through 2012. In the 2012 Medicare fee-for-service population, the age-adjusted procedure rate for BCC and SCC were 3280 and 3278 per 100 000 beneficiaries, respectively. The ratio of BCC to SCC treated in Medicare beneficiaries was 1.0. We estimate the total number of NMSCs in the US population in 2012 at 5 434 193 and the total number of persons in the United States treated for NMSC at 3 315 554. Conclusions and Relevance This study is a thorough nationwide estimate of the incidence of NMSC and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States. This study also demonstrates equal incidence rates for BCC and SCC in the Medicare population.
1,700 citations
TL;DR: The current status of PDT with an emphasis on the contributions of physics, biophysics and technology, and the challenges remaining in the optimization and adoption of this treatment modality are reviewed.
Abstract: Photodynamic therapy (PDT) uses light-activated drugs to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections. This paper reviews the current status of PDT with an emphasis on the contributions of physics, biophysics and technology, and the challenges remaining in the optimization and adoption of this treatment modality. A theme of the review is the complexity of PDT dosimetry due to the dynamic nature of the three essential components—light, photosensitizer and oxygen. Considerable progress has been made in understanding the problem and in developing instruments to measure all three, so that optimization of individual PDT treatments is becoming a feasible target. The final section of the review introduces some new frontiers of research including low dose rate (metronomic) PDT, two-photon PDT, activatable PDT molecular beacons and nanoparticle-based PDT.
885 citations
TL;DR: It is shown here that transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome, demonstrating that SHH is sufficient to induce basal cell carcinomas in mice, suggesting thatSHH may have a role in human tumorigenesis.
Abstract: Mutations in the tumor suppressor gene PATCHED (PTC) are found in human patients with the basal cell nevus syndrome, a disease causing developmental defects and tumors, including basal cell carcinomas. Gene regulatory relationships defined in the fruit fly Drosophila suggest that overproduction of Sonic hedgehog (SHH), the ligand for PTC, will mimic loss of ptc function. It is shown here that transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome, demonstrating that SHH is sufficient to induce basal cell carcinomas in mice. These data suggest that SHH may have a role in human tumorigenesis.
727 citations
"Photodynamic Therapy-Induced Microv..." refers background in this paper
...Transgenic K5-Gli mice overexpress the Gli2 transcription factor in the epidermal basal layer and outer root sheath of the hair follicles, developing spontaneous basal cell carcinomas (BCC) histologically similar to human BCCs [26]....
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...Transgenic K5-Gli mice, which develop spontaneous BCCs, were acquired from Dr. Andrezj Dlugosz at the University of Michigan and bred in our domestic colony [24]....
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...Overexpression of Gli2 leads to increased activation of the Sonic hedgehog (Shh) pathway and increased activation of Shh has been associated with BCCs in both human tumors and animal models [25]....
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