Dual-Function Antibody Conjugate-Enabled Photoimmunotherapy Complements Fluorescence and Photoacoustic Imaging of Head and Neck Cancer Spheroids.

Several molecular-targeted imaging and therapeutic agents are in clinical trials for image-guided surgery and photoimmunotherapy (PIT) for head and neck cancers. In this context, we have previously reported the development, characterization, and specificity of a dual-function antibody conjugate (DFAC) for multimodal imaging and photoimmunotherapy (PIT) of EGFR-overexpressing cancer cells. The DFAC reported previously and used in the present study comprises an EGFR-targeted antibody, cetuximab, conjugated to benzoporphyrin derivative (BPD) for fluorescence imaging and PIT and a Si-centered naphthalocyanine dye for photoacoustic imaging. We report here the evaluation and performance of DFAC in detecting microscopic cancer spheroids by fluorescence and photoacoustic imaging along with their treatment by PIT. We demonstrate that while fluorescence imaging can detect spheroids with volumes greater than 0.049 mm3, photoacoustic imaging-based detection was possible even for the smallest spheroids (0.01 mm3) developed in the study. When subjected to PIT, the spheroids showed a dose-dependent response, with smaller spheroids (0.01 and 0.018 mm3) showing a complete response with no recurrence when treated with 100 J/cm2. Together our results demonstrate the complementary imaging and treatment capacity of DFAC. This potentially enables fluorescence imaging to assess the presence of tumor on a macroscopic scale, followed by photoacoustic imaging for delineating tumor margins guiding surgical resection and elimination of any residual microscopic disease by PIT, in a single intraoperative setting.

Dual Function Antibody Conjugates for Multimodal Imaging and Photoimmunotherapy of Cancer Cells.

Precision imaging, utilizing molecular targeted agents, is an important tool in cancer diagnostics and guiding therapies. While there are limitations associated with single mode imaging probes, multimodal molecular imaging probes enabling target visualization through complementary imaging technologies provides an attractive alternative. However, there are several challenges associated with designing molecular probes carrying contrast agents for complementary multimodal imaging. Here, we propose a dual function antibody conjugate (DFAC) comprising an FDA approved photosensitizer Benzoporphyrin derivative (BPD) and a naphthalocyanine-based photoacoustic dye (SiNc(OH)) for multimodal infrared (IR) imaging. While fluorescence imaging, through BPD, provides sensitivity, complementing it with photoacoustic imaging, through SiNc(OH), provides a depth-resolved spatial resolution much beyond the optical diffusion limits of fluorescence measurements. Through a series of in vitro experiments, we demonstrate the development and utilization of DFACs for multimodal imaging and photodynamic treatment of squamous cell carcinoma (A431) cell line. The proposed DFACs have potential use in precision imaging applications such as guiding tumor resection surgeries and photodynamic treatment of residual microscopic disease thereby minimizing local recurrence. The data demonstrated in this study merits further investigation for its preclinical and clinical translation.

Vitamin D Receptor Activation and Photodynamic Priming Enables Durable Low-dose Chemotherapy.

Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.

Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance.

Imaging modalities play an important role in the clinical management of cancer, including screening, diagnosis, treatment planning and therapy monitoring. Owing to increased research efforts during the past two decades, photoacoustic imaging (a non-ionizing, noninvasive technique capable of visualizing optical absorption properties of tissue at reasonable depth, with the spatial resolution of ultrasound) has emerged. Ultrasound-guided photoacoustics is noted for its ability to provide in vivo morphological and functional information about the tumor within the surrounding tissue. With the recent advent of targeted contrast agents, photoacoustics is now also capable of in vivo molecular imaging, thus facilitating further molecular and cellular characterization of cancer. This review examines the role of photoacoustics and photoacoustic-augmented imaging techniques in comprehensive cancer detection, diagnosis and treatment guidance.

Development and applications of photo-triggered theranostic agents.

Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases.

Photoacoustic technique to measure beam profile of pulsed laser systems.

The beam profiles of pulsed lasers are currently measured using either complementary metal oxide semiconductor (CMOS) or charge coupled device (CCD) cameras. Despite providing high-resolution beam profiles, these devices cannot work with high power lasers. If additional optical attenuators are used, beam distortions may occur. In this paper we demonstrate a high-resolution photoacoustic technique capable of measuring the beam profile of pulsed lasers. The beam profiles of a pulsed neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and a pulsed optical parametric oscillator (OPO) laser system were measured using a polydimethylsiloxane film and a single element high-frequency ultrasonic transducer. The advantages and limitations of the developed photoacoustic technique are discussed.