Image-Based Quantification of Gold Nanoparticle Uptake and Localization in 3D Tumor Models to Inform Radiosensitization Schedule.

Gold nanoparticles (GNPs) have shown particular promise as radiosensitizing agents and as complementary drug delivery agents to improve therapeutic index in cancer treatment. Optimal implementation, however, depends critically on the localization of GNPs at the time of irradiation, which, in turn, depends on their size, shape, and chemical functionalization, as well as organism-level pharmacokinetics and interactions with the tumor microenvironment. Here, we use in vitro 3D cultures of A549 lung carcinoma cells, which recapitulate interaction with extracellular matrix (ECM) components, combined with quantitative fluorescence imaging to study how time-dependent localization of ultrasmall GNPs in tumors and ECM impacts the degree of damage enhancement to tumor cells. Confocal imaging of fluorescence-labeled GNPs in 3D culture reveals that nanoparticles are initially embedded in ECM and only gradually accumulate in cancer cells over multiple days. Furthermore, the timing of GNP redistribution from ECM to cellular compartments directly impacts efficacy, with major damage enhancement when irradiation is performed after GNPs have accumulated significantly in 3D tumor nodules. These results underscore the importance of the timing and scheduling in treatment planning to ensure optimal radiosensitization, as well as the necessity of studying these effects in model systems that recapitulate elements of tumor microenvironment interaction.

Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitro photodynamic therapy efficacy (Erratum).

The erratum corrects an error in the y-axis labels of Fig. 4 and Fig. S2.

Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitro photodynamic therapy efficacy.

Photodynamic therapy (PDT), a spatially localized phototoxic therapy that involves irradiation of a photosensitizer (PS) with specific wavelengths of light, has shown exceptional promise in impacting cancer treatment outcomes, particularly oral cancer. To reduce PDT outcome variability, attempts toward image-guided personalized PDT are being pursued by monitoring PS uptake either via fluorescence or photoacoustic imaging (PAI), a nonionizing modality dependent on optical absorption properties of the tissue. PAI-guided PDT requires a near-infrared contrast agent for deep tissue imaging with minimal photobleaching effect. We evaluate the impact of PDT agent, benzoporphyrin derivative (BPD), on PAI agent indocyanine green (ICG) and vice versa, given that they have different optical absorption properties and singlet oxygen quantum yields for PDT. Specifically, we demonstrate in two oral squamous cell carcinoma lines (FaDu and SCC4) that ICG has minimal effect on BPD PDT efficacy when irradiated with either a continuous or pulsed laser. Furthermore, the impact of BPD on ICG photodegradation was monitored with PAI in tissue-mimicking phantoms. These studies inform us that the combination of BPD and ICG can be utilized for PAI-guided PDT. However, researchers need to consider the photodegradation effects of ICG in the presence of BPD when designing their drug delivery strategies for PAI-guided PDT.

Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids.

Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinically-approved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporally-spaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanistically-distinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer.

Digital holographic microscopy for longitudinal volumetric imaging of growth and treatment response in three-dimensional tumor models.

We report the use of digital holographic microscopy (DHM) as a viable microscopy approach for quantitative, nondestructive longitudinal imaging of in vitro three-dimensional (3-D) tumor models. Following established methods, we prepared 3-D cultures of pancreatic cancer cells in overlay geometry on extracellular matrix beds and obtained digital holograms at multiple time points throughout the duration of growth. The holograms were digitally processed and the unwrapped phase images were obtained to quantify the nodule thickness over time under normal growth and in cultures subject to chemotherapy treatment. In this manner, total nodule volumes are rapidly estimated and demonstrated here to show contrasting time-dependent changes during growth and in response to treatment. This work suggests the utility of DHM to quantify changes in 3-D structure over time and suggests the further development of this approach for time-lapse monitoring of 3-D morphological changes during growth and in response to treatment that would otherwise be impractical to visualize.

Lymphatic drainage, regional metastases and surgical management of papillary thyroid carcinoma arising in pyramidal lobe--a single institution experience.

Papillary thyroid carcinoma (PTC) arising in pyramidal lobe (PL) is very rare. The aim of this study was to determine the incidence of single PTC focus in PL and its lymphonodal metastases, as well as to present a single surgeon experience in management of PL PTC. We performed a retrospective analysis of records of all patients surgically treated for PTC in our institution from year 2003 to 2013. Only patients with single PTC focus in PL were included. Out of total 753 patients, majority (66.52%) had PTC focus in one of the lobes, while only 3 patients (0.4%) had solitary PTC focus in PL. They were all females, aged 36, 41 and 22. During surgery, methylene-blue dye was injected peritumorally. After frozen section analysis of excised PL and isthmus and confirmation of malignancy, we performed total thyroidectomy with central neck dissection, as well as sentinel lymph node biopsy in both jugulo-carotid regions. Pathology showed encapsulated PTC stage T1 and solitary metastasis in Delphian lymph node of the youngest patient. All patients were disease free in the follow-up. PTC single focus in PL is very rare and only individual experiences can be discussed regarding the extent of the surgery.