Size‐dependent Tumor Response to Photodynamic Therapy and Irinotecan Monotherapies Revealed by Longitudinal Ultrasound Monitoring in an Orthotopic Pancreatic Cancer Model

Longitudinal monitoring of tumor size in vivo can provide important biological information about disease progression and treatment efficacy that is not captured by other modes of quantification. Ultrasound enables high‐throughput evaluation of orthotopic mouse models via fast acquisition of three‐dimensional tumor images and calculation of volume with a reasonable degree of accuracy. Herein, we compare orthotopic pancreatic tumor volume measurements determined by ultrasound with volume measured by calipers and tumor weight, and found strong correlations between the three modalities over a large range of tumor sizes, suggesting ultrasound can accurately quantify tumor volumes in this model. Furthermore, we demonstrate the unique ability of longitudinal treatment monitoring to reveal a tumor size‐dependent response to Benzoporphyrin Derivative photodynamic therapy (BPD‐PDT) and irinotecan. Small tumors (5–35 mm³) were found to respond well to a single round of PDT, while large tumors (35–65 mm³) showed no response to the same treatment. These results highlight the role that tumor size can play in preclinical interpretation of treatment response and more generally suggest that careful evaluation of subtle biological features such as this must be carefully considered in order to grant a more comprehensive understanding of disease biology in vivo.     

Surfaces and Interfaces of Liquid Metal Core–Shell Nanoparticles under the Microscope

Eutectic gallium indium (EGaIn), a Ga-based liquid metal alloy holds great promise for designing next-generation core–shell nanoparticles (CSNs). A shearing-assisted ligand-stabilization method has shown promise as a synthetic method for these CSNs; however, determining the role of the ligand on stabilization demands an understanding of the surface chemistry of the ligand–nanoparticle interface. EGaIn CSNs are created and functionalized with aliphatic carboxylates of different chain length, allowing a fundamental investigation on ligand stabilization of EGaIn CSNs. Raman and diffuse reflectance Fourier transform spectroscopies (DRIFTS) confirm reaction of the ligand with the oxide shell of the EGaIn nanoparticles. Changing the length of the alkyl chain in the aliphatic carboxylates (C2–C18) may influence the size and structural stability of EGaIn CSNs, which is easily monitored using atomic force microscopy (AFM). No matter how large the carboxylate ligand, there is no obvious effect on the size of the EGaIn CSNs, except the particle size getting more uniform when coated with longer chain carboxylates. The AFM force–distance measurements are used to measure the stiffness of the carboxylate-coated EGaIn CSNs. In corroboration with DRIFTS analysis, the stiffness studies show that the alkyl chains undergo conformational changes upon compression.     

Utility of biodegradable plasmonic nanoclusters in photoacoustic imaging

Plasmonic metal nanoparticles are used in photoacoustic imaging as contrast agents because of their resonant optical absorption properties in the visible and near-IR regions. However, the nanoparticles could accumulate and result in long-term toxicity in vivo, because they are generally not biodegradable. Recently, biodegradable plasmonic gold nanoclusters, consisting of sub-5 nm primary gold nanoparticles and biodegradable polymer stabilizer, were introduced. In this Letter, we demonstrate the feasibility of biodegradable nanoclusters as a photoacoustic contrast agent. We performed photoacoustic and ultrasound imaging of a tissue-mimicking phantom with inclusions containing nanoclusters at various concentrations. The results indicate that the biodegradable gold nanoclusters can be used as effective contrast agents in photoacoustic imaging.     

Role of Ultrasound and Photoacoustic Imaging in Photodynamic Therapy for Cancer

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.