Erratum: Influence of structural moieties in squaraine dyes on optoacoustic signal shape and intensity.

[This corrects the article PMC11087056.].

Influence of structural moieties in squaraine dyes on optoacoustic signal shape and intensity.

Optoacoustic imaging has grown in clinical relevance due to inherent advantages in sensitivity, resolution, and imaging depth, but the development of contrast agents is lacking. This study assesses the influence of structural features of squaraine dyes on optoacoustic activity through computational models, in vitro testing, and in vivo experimentation. The squaraine scaffold was decorated with halogens and side-chain extensions. Extension of side chains and heavy halogenation of squaraines both increased optoacoustic signals individually, although they had a more significant effect in tandem. Density functional theory models suggest that the origin of the increased optoacoustic signal is the increase in transition dipole moment and vibrational entropy, which manifested as increased absorbance in near-infrared region (NIR) wavelengths and decreased fluorescence quantum yield. This study provides insight into the structure-function relationships that will lead guiding principles for optimizing optoacoustic contrast agents. Further developments of squaraines and other agents will further increase the relevance of optoacoustic imaging in a clinical setting.

Erratum: Influence of structural moieties in squaraine dyes on optoacoustic signal shape and intensity.

[This corrects the article PMC11087056.].

Dynamic 2-deoxy-D-glucose-enhanced multispectral optoacoustic tomography for assessing metabolism and vascular hemodynamics of breast cancer.

Clinical tools for measuring tumor vascular hemodynamics, such as dynamic contrast-enhanced MRI, are clinically important to assess tumor properties. Here we explored the use of multispectral optoacoustic tomography (MSOT), which has a high spatial and temporal resolution, to measure the intratumoral pharmacokinetics of a near-infrared-dye-labeled 2-Deoxyglucose, 2-DG-800, in orthotropic 2-LMP breast tumors in mice. As uptake of 2-DG-800 is dependent on both vascular properties, and glucose transporter activity - a widely-used surrogate for metabolism, we evaluate hemodynamics of 2-DG-MP by fitting the dynamic MSOT signal of 2-DG-800 into two-compartment models including the extended Tofts model (ETM) and reference region model (RRM). We showed that dynamic 2-DG-enhanced MSOT (DGE-MSOT) is powerful in acquiring hemodynamic rate constants, including Ktrans and Kep, via systemically injecting a low dose of 2-DG-800 (0.5 µmol/kg b.w.). In our study, both ETM and RRM are efficient in deriving hemodynamic parameters in the tumor. Area-under-curve (AUC) values (which correlate to metabolism), and Ktrans and Kep values, can effectively distinguish tumor from muscle. Hemodynamic parameters also demonstrated correlations to hemoglobin, oxyhemoglobin, and blood oxygen level (SO2) measurements by spectral unmixing of the MSOT data. Together, our study for the first time demonstrated the capability of DGE-MSOT in assessing vascular hemodynamics of tumors.

Intraoperative Imaging in Hepatopancreatobiliary Surgery.

Hepatopancreatobiliary surgery belongs to one of the most complex fields of general surgery. An intricate and vital anatomy is accompanied by difficult distinctions of tumors from fibrosis and inflammation; the identification of precise tumor margins; or small, even disappearing, lesions on currently available imaging. The routine implementation of ultrasound use shifted the possibilities in the operating room, yet more precision is necessary to achieve negative resection margins. Modalities utilizing fluorescent-compatible dyes have proven their role in hepatopancreatobiliary surgery, although this is not yet a routine practice, as there are many limitations. Modalities, such as photoacoustic imaging or 3D holograms, are emerging but are mostly limited to preclinical settings. There is a need to identify and develop an ideal contrast agent capable of differentiating between malignant and benign tissue and to report on the prognostic benefits of implemented intraoperative imaging in order to navigate clinical translation. This review focuses on existing and developing imaging modalities for intraoperative use, tailored to the needs of hepatopancreatobiliary cancers. We will also cover the application of these imaging techniques to theranostics to achieve combined diagnostic and therapeutic potential.

Advances in Imaging of Inflammation, Fibrosis, and Cancer in the Gastrointestinal Tract.

Gastrointestinal disease is prevalent and broad, manifesting itself in a variety of ways, including inflammation, fibrosis, infection, and cancer. However, historically, diagnostic technologies have exhibited limitations, especially with regard to diagnostic uncertainty. Despite development of newly emerging technologies such as optoacoustic imaging, many recent advancements have focused on improving upon pre-existing modalities such as ultrasound, computed tomography, magnetic resonance imaging, and endoscopy. These advancements include utilization of machine learning models, biomarkers, new technological applications such as diffusion weighted imaging, and new techniques such as transrectal ultrasound. This review discusses assessment of disease processes using imaging strategies for the detection and monitoring of inflammation, fibrosis, and cancer in the context of gastrointestinal disease. Specifically, we include ulcerative colitis, Crohn's disease, diverticulitis, celiac disease, graft vs. host disease, intestinal fibrosis, colorectal stricture, gastric cancer, and colorectal cancer. We address some of the most recent and promising advancements for improvement of gastrointestinal imaging, including unique discussions of such advancements with regard to imaging of fibrosis and differentiation between similar disease processes.

Nanotheranostics for Image-Guided Cancer Treatment.

Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to drug resistance. Imaging is one of the tools best poised to enable tailoring of cancer therapies. The field of image-guided nanotheranostics has the potential to harness the precision of modern imaging techniques and use this to direct, dictate, and follow site-specific drug delivery, all of which can be used to further tailor cancer therapies on both the individual and population level. The use of image-guided drug delivery has exploded in preclinical and clinical trials although the clinical translation is incipient. This review will focus on traditional mechanisms of targeted drug delivery in cancer, including the use of molecular targeting, as well as the foundations of designing nanotheranostics, with a focus on current clinical applications of nanotheranostics in cancer. A variety of specially engineered and targeted drug carriers, along with strategies of labeling nanoparticles to endow detectability in different imaging modalities will be reviewed. It will also introduce newer concepts of image-guided drug delivery, which may circumvent many of the issues seen with other techniques. Finally, we will review the current barriers to clinical translation of image-guided nanotheranostics and how these may be overcome.

Toxicity Assessment of Mesoporous Silica Nanoparticles upon Intravenous Injection in Mice: Implications for Drug Delivery.

Nanoparticles are popular tools utilized to selectively deliver drugs and contrast agents for identification and treatment of disease. To determine the usefulness and translational potential of mesoporous silica nanoparticles (MSNs), further evaluations of toxicity are required. MSNs are among the most utilized nano-delivery systems due to ease of synthesis, pore structure, and functionalization. This study aims to elucidate toxicity as a result of intravenous injection of 25 nm MSNs coated with chitosan (C) or polyethylene glycol (PEG) in mice. Following acute and chronic injections, blood was evaluated for standard blood chemistry and complete blood count analyses. Blood chemistry results primarily indicated that no abnormalities were present following acute or chronic injections of MSNs, or C/PEG-coated MSNs. After four weekly administered treatments, vital organs showed minor exacerbation of pre-existing lesions in the 35KPEG-MSN and moderate exacerbation of pre-existing lesions in uncoated MSN and 2KPEG-MSN treatment groups. In contrast, C-MSN treatment groups had minimal changes compared to controls. This study suggests 25 nm MSNs coated with chitosan should elicit minimal toxicity when administered as either single or multiple intravenous injections, but MSNs coated with PEG, especially 2KPEG may exacerbate pre-existing vascular conditions. Further studies should evaluate varying sizes and types of nanoparticles to provide a better overall understanding on the relation between nanoparticles and in vivo toxicity.

Differential expression of microRNA between triple negative breast cancer patients of African American and European American descent.

There are racial disparities in the outcome of triple negative breast cancer (TNBC) patients between women of African ancestry and women of European ancestry, even after accounting for lifestyle, socioeconomic and clinical factors. MicroRNA (miRNA) are non-coding molecules whose level of expression is associated with cancer suppression, proliferation and drug resistance; therefore, these have potential for biomarker applications in cancers including TNBC. Historically, miRNAs up-regulated in African American (AA) patients have received less attention than for patients of European ancestry. Using laser capture microdissection (LCM) to acquire ultrapure tumor cell samples, miRNA expression was evaluated in 15 AA and 15 European American (EA) TNBC patients. Tumor sections were evaluated using RNA extraction followed by miRNA analysis and profiling. Results were compared based on ethnicity and method of tissue fixation. miRNAs that showed high differential expression in AA TNBC patients compared to EA included: miR-19a, miR-192, miR-302a, miR-302b, miR-302c, miR-335, miR-520b, miR-520f and miR-645. LCM is a useful technique for isolation of tumor cells. We found a greater abundance of RNA in frozen samples compared to formalin fixed, paraffin embedded samples. miRNA appears to be a useful biomarker for TNBC to improve diagnosis and treatment.

Active Targeting Significantly Outperforms Nanoparticle Size in Facilitating Tumor-Specific Uptake in Orthotopic Pancreatic Cancer.

Nanoparticles are widely studied as theranostic vehicles for cancer; however, clinical translation has been limited due to poor tumor specificity. Features that maximize tumor uptake remain controversial, particularly when using clinically relevant models. We report a systematic study that assesses two major features for the impact on tumor specificity, i.e., active vs passive targeting and nanoparticle size, to evaluate relative influences in vivo. Active targeting via the V7 peptide is superior to passive targeting for uptake by pancreatic tumors, irrespective of nanoparticle size, observed through in vivo imaging. Size has a secondary effect on uptake for actively targeted nanoparticles in which 26 nm nanoparticles outperform larger 45 and 73 nm nanoparticles. Nanoparticle size had no significant effect on uptake for passively targeted nanoparticles. Results highlight the superiority of active targeting over nanoparticle size for tumor uptake. These findings suggest a framework for optimizing similar nonaggregate nanoparticles for theranostic treatment of recalcitrant cancers.

Mesoporous Silica Nanoparticles: Properties and Strategies for Enhancing Clinical Effect.

Due to the theragnostic potential of mesoporous silica nanoparticles (MSNs), these were extensively investigated as a novel approach to improve clinical outcomes. Boasting an impressive array of formulations and modifications, MSNs demonstrate significant in vivo efficacy when used to identify or treat myriad malignant diseases in preclinical models. As MSNs continue transitioning into clinical trials, a thorough understanding of the characteristics of effective MSNs is necessary. This review highlights recent discoveries and advances in MSN understanding and technology. Specific focus is given to cancer theragnostic approaches using MSNs. Characteristics of MSNs such as size, shape, and surface properties are discussed in relation to effective nanomedicine practice and projected clinical efficacy. Additionally, tumor-targeting options used with MSNs are presented with extensive discussion on active-targeting molecules. Methods for decreasing MSN toxicity, improving site-specific delivery, and controlling release of loaded molecules are further explained. Challenges facing the field and translation to clinical environments are presented alongside potential avenues for continuing investigations.

Improved pentamethine cyanine nanosensors for optoacoustic imaging of pancreatic cancer.

Optoacoustic imaging is a new biomedical imaging technology with clear benefits over traditional optical imaging and ultrasound. While the imaging technology has improved since its initial development, the creation of dedicated contrast agents for optoacoustic imaging has been stagnant. Current exploration of contrast agents has been limited to standard commercial dyes that have already been established in optical imaging applications. While some of these compounds have demonstrated utility in optoacoustic imaging, they are far from optimal and there is a need for contrast agents with tailored optoacoustic properties. The synthesis, encapsulation within tumor targeting silica nanoparticles and applications in in vivo tumor imaging of optoacoustic contrast agents are reported.

Molecular Imaging of Inflammatory Disease.

Inflammatory diseases include a wide variety of highly prevalent conditions with high mortality rates in severe cases ranging from cardiovascular disease, to rheumatoid arthritis, to chronic obstructive pulmonary disease, to graft vs. host disease, to a number of gastrointestinal disorders. Many diseases that are not considered inflammatory per se are associated with varying levels of inflammation. Imaging of the immune system and inflammatory response is of interest as it can give insight into disease progression and severity. Clinical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally limited to the visualization of anatomical information; then, the presence or absence of an inflammatory state must be inferred from the structural abnormalities. Improvement in available contrast agents has made it possible to obtain functional information as well as anatomical. In vivo imaging of inflammation ultimately facilitates an improved accuracy of diagnostics and monitoring of patients to allow for better patient care. Highly specific molecular imaging of inflammatory biomarkers allows for earlier diagnosis to prevent irreversible damage. Advancements in imaging instruments, targeted tracers, and contrast agents represent a rapidly growing area of preclinical research with the hopes of quick translation to the clinic.

Development of Multispectral Optoacoustic Tomography as a Clinically Translatable Modality for Cancer Imaging.

The use of optoacoustic imaging takes advantage of the photoacoustic effect to generate high-contrast, high-resolution medical images at penetration depths of up to 5 cm. Multispectral optoacoustic tomography (MSOT) is a type of optoacoustic imaging system that has seen promising preclinical success with a recent emergence into the clinic. Multiwavelength illumination of tissue allows for the mapping of multiple chromophores, which are generated endogenously or exogenously. However, translation of MSOT to the clinic is still in its preliminary stages. For successful translation, MSOT requires refinement of probes and data-acquisition systems to tailor to the human body, along with more intuitive, real-time visualization settings. The possibilities of optoacoustic imaging, namely MSOT, in the clinic are reviewed here. ©RSNA, 2020.

Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo.

Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment of pancreatic cancer. Tumor-specific uptake, biodistribution, efficacy of nanodelivered echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of pancreatic cancer. In these autophagic-dependent pancreatic cancer models, echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g., caspase activation and chromatin fragmentation, or necrosis, e.g., plasma membrane degradation and chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9 tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these findings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer.

Squaraine Dyes: Molecular Design for Different Applications and Remaining Challenges.

Squaraine dyes are a class of organic dyes with strong and narrow absorption bands in the near-infrared. Despite high molar absorptivities and fluorescence quantum yields, these dyes have been less explored than other dye scaffolds due to their susceptibility to nucleophilic attack. Recent strategies in probe design including encapsulation, conjugation to biomolecules, and new synthetic modifications have seen squaraine dyes emerging into the forefront of biomedical imaging and other applications. Herein, we provide a concise overview of (1) the synthesis of symmetrical and unsymmetrical squaraine dyes, (2) the relationship between structure and photophysical properties of squaraine dyes, and (3) current applications of squaraine dyes in the literature. Given the recent successes at overcoming the limitations of squaraine dyes, they show high potential in biological imaging, in photodynamic and photothermal therapies, and as molecular sensors.