Search

Developing a cancer theranostic nanoplatform with diagnosis and treatment capabilities to effectively treat tumors and reduce side effects is of great significance. Herein, we present a drug delivery strategy for photosensitizers based on a new liquid metal nanoplatform that leverages the tumor microenvironment to achieve photodynamic therapeutic effects in pancreatic cancer. Eutectic gallium indium (EGaIn) nanoparticles were successfully conjugated with a water-soluble cancer targeting ligand, hyaluronic acid, and a photosensitizer, benzoporphyrin derivative, creating EGaIn nanoparticles (EGaPs) via a simple green sonication method. The prepared sphere-shaped EGaPs, with a core-shell structure, presented high biocompatibility and stability. EGaPs had greater cellular uptake, manifested targeting competence, and generated significantly higher intracellular ROS. Further, near-infrared light activation of EGaPs demonstrated their potential to effectively eliminate cancer cells due to their single oxygen generation capability. Finally, from

Supplementary Methods Supplemental Figure 1: The MIA-PaCa-2 + PCAF model exhibits histologic features consistent with desmoplasia 90 days post implantation Supplemental Figure 2: 1 μM calcipitriol activates the vitamin D receptor (VDR) in cancer associated fibroblasts Supplemental Figure 3: VDAR activation + PDP enable a 75% dose reduction in nal-IRI Supplemental Figure 4: Inhibition of the CXCL12/CXCR7 by CAL+PDP is lost by day 90 post-implantation Supplemental Figure 5: Calcipotriol and photodynamic priming cytotoxicity curves Supplemental Figure 6: MRC-5 conditioned medium does not affect the baseline metabolic activity of PDAC cell lines Supplemental Figure 7: PDP increases intratumoral nal-IRI via increased vascular and parenchymal permeability Supplemental Figure 8: Treatment with CAL+PDP+5 mg/kg nal-IRI induces global transcriptomic shifts in pancreataic tumors that correlate with a less aggressive and more responsive treatment profile compared to treatment with PDP+20 mg/kg nal-IRI

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.

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment. Cancer Res; 76(5); 1066–77. ©2015 AACR.

(i) Supplementary Methods 1. Synthesis of L-BPD and L-IRI via freeze-thaw extrusion method 2. Pharmacokinetics and biodistribution of L-BPD and L-IRI 3. In-vitro quantification of changes in ABCG2 expression using immunofluorescence 4. Ultrasound Imaging 5. Histology and immunofluorescence of tumor samples 6. Quantification of H&E and immunofluorescence biomarkers 7. Determination of Synergism (ii) Supplementary Tables Supplementary Table S1. Comparison of PDT and irinotecan doses used in this study versus in clinic Supplementary Table S2. List of antibodies used for immunofluorescence Supplementary Table S3. The synergistic effect of combination PDT and L-IRI Supplementary Table S4. Physical parameters of L-BPD and L-IRI (iii) Supplementary Figures and Legends Supplementary Fig. S1. Treatment schedule and longitudinal monitoring of PanCa tumors in vivo Supplementary Fig. S2. Sub-cytotoxic PDT leads to decreased levels of ABCG2 and increased intracellular irinotecan in AsPC-1 cells Supplementary Fig. S3. Tumor growth kinetics of MIA PACa-2 and AsPC-1 in vivo Supplementary Fig. S4. Change in mouse body weight after combination treatment

Several molecular-targeted imaging and therapeutic agents are in clinical trials for image-guided surgery and photoimmunotherapy (PIT) of head and neck cancers. In this context, we have previously reported the development, characterization, and specificity of a dual function antibody conjugate (DFAC) for multi-modal imaging and photoimmunotherapy (PIT) of EGFR over-expressing cancer cells. The DFAC reported previously and used in the present study, comprises of 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 tumor presence 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 intra-operative setting.

Photoacoustic imaging using external contrast agents is emerging as a powerful modality for real-time molecular imaging of deep-seated tumors. There are several chromophores, such as indocyanine green and IRDye800, that can potentially be used for photoacoustic imaging; however, their use is limited due to several drawbacks, particularly photostability. There is, therefore, an urgent need to design agents to enhance contrast in photoacoustic imaging. Naphthalocyanine dyes have been demonstrated for their use as photoacoustic contrast agents; however, their low solubility in aqueous solvents and high aggregation propensity limit their application. In this study, we report the synthesis and characterization of silicon-centered naphthalocyanine dyes with high aqueous solubility and near infra-red (NIR) absorption in the range of 850–920 nm which make them ideal candidates for photoacoustic imaging. A series of Silicon-centered naphthalocyanine dyes were developed with varying axial and peripheral substitutions, all in an attempt to enhance their aqueous solubility and improve photophysical properties. We demonstrate that axial incorporation of charged ammonium mesylate group enhances water solubility. Moreover, the incorporation of peripheral 2-methoxyethoxy groups at the α-position modulates the electronic properties by altering the π-electron delocalization and enhancing photoacoustic signal amplitude. In addition, all the dyes were synthesized to incorporate an N-hydroxysuccinimidyl group to enable further bioconjugation. In summary, we report the synthesis of water-soluble silicon-centered naphthalocyanine dyes with a high photoacoustic signal amplitude that can potentially be used as contrast agents for molecular photoacoustic imaging.

Simple Summary A new approach of combined optoacoustic (OA) and fluorescence (FL) imaging for in vivo real-time tracing photosensitizer (PS) kinetics and functional vascular effects in the treated area was developed. FL monitoring using a photoactivatable multi-inhibitor liposomal (PMILs) platform, demonstrates enhancement of PS accumulation in tumor, 24 h post-treatment. OA monitoring revealed the alterations of the tumor vasculature structure after treatment, which is in good agreement with the histological data that shows five times higher percentage of hemorrhages in PMIL treated mice compared to the untreated group. Abstract The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between −14.9 ± 1.04 to −16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs’ therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.

The placenta is a highly vascularized organ with unique structural and metabolic complexities. As the primary conduit of fetal support, the placenta mediates transport of oxygen, nutrients, and waste between maternal and fetal blood. Thus, normal placenta anatomy and physiology is absolutely required for maintenance of maternal and fetal health during pregnancy. Moreover, impaired placental health can negatively impact offspring growth trajectories as well as increase the risk of maternal cardiovascular disease later in life. Despite these crucial roles for the placenta, placental disorders, such as preeclampsia, intrauterine growth restriction (IUGR), and preterm birth, remain incompletely understood. Effective noninvasive imaging and image analysis are needed to advance the obstetrician’s clinical reasoning toolkit and improve the utility of the placenta in interpreting maternal and fetal health trajectories. Current paradigms in placental imaging and image analysis aim to improve the traditional imaging techniques that may be time-consuming, costly, or invasive. In concert with conventional clinical approaches such as ultrasound (US), advanced imaging modalities can provide insightful information on the structure of placental tissues. Herein we discuss such imaging modalities, their specific applications in structural, vascular, and metabolic analysis of placental health, and emerging frontiers in image analysis research in both preclinical and clinical contexts.

The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ NIR molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with EGFR expression in U251, U87 and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson’s r= 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.

Background The autologous vein remains the standard conduit for lower extremity and coronary artery bypass grafting despite a 30%-50% 5-y failure rate, primarily attributable to intimal hyperplasia (IH) that develops in the midterm period (3-24 mo) of graft maturation. Our group discovered that externally strengthening vein grafts by cross-linking the adventitial collagen with photochemical tissue passivation (PTP) mitigates IH in an arteriovenous model at 4 wk. We now investigate whether this effect is retained in the midterm period follow-up. Methods Six Hanford miniature pigs received bilateral carotid artery interposition vein grafts. In each animal, the external surface of one graft was treated with PTP before grafting, whereas the opposite side served as the untreated control. The grafts were harvested after 3 mo. Ultrasound evaluation of all vein grafts was performed at the time of grafting and harvest. The grafts were also evaluated histomorphometrically and immunohistologically for markers of IH. Results All vein grafts were patent at 3 mo except one graft in the PTP-treated group because of early technical failure. The control vein grafts had significantly greater IH than PTP-treated grafts at 3 mo, as evidenced by the intimal area (2.6 ± 1.0 mm2 versus 1.4 ± 1.5 mm2, respectively, P = 0.045) and medial area (5.1 ± 1.9 mm2 versus 2.7 ± 2.4 mm2, respectively, P = 0.048). The control grafts had an increased presence and proliferation of mural myofibroblasts with greater smooth muscle actin and proliferating cell nuclear antigen staining. Conclusions PTP treatment to the external surface of the vein grafts decreases IH at 3 mo after arteriovenous grafting and may prevent future graft failure.

There is an increasing need for 3D ultrasound and photoacoustic (USPA) imaging technology for real-time monitoring of dynamic changes in vasculature or molecular markers in various malignancies. Current 3D USPA systems utilize expensive 3D transducer arrays, mechanical arms or limited-range linear stages to reconstruct the 3D volume of the object being imaged. In this study, we developed, characterized, and demonstrated an economical, portable, and clinically translatable handheld device for 3D USPA imaging. An off-the-shelf, low-cost visual odometry system (the Intel RealSense T265 camera equipped with simultaneous localization and mapping technology) to track free hand movements during imaging was attached to the USPA transducer. Specifically, we integrated the T265 camera into a commercially available USPA imaging probe to acquire 3D images and compared it to the reconstructed 3D volume acquired using a linear stage (ground truth). We were able to reliably detect 500 µm step sizes with 90.46% accuracy. Various users evaluated the potential of handheld scanning, and the volume calculated from the motion-compensated image was not significantly different from the ground truth. Overall, our results, for the first time, established the use of an off-the-shelf and low-cost visual odometry system for freehand 3D USPA imaging that can be seamlessly integrated into several photoacoustic imaging systems for various clinical applications.

BACKGROUND: Morbidity and mortality due to oral cancer in India are exacerbated by a lack of access to effective treatments among medically underserved populations. We developed a user-friendly low-cost, portable fibre-coupled LED system for photodynamic therapy (PDT) of early oral lesions, using a smartphone fluorescence imaging device for treatment guidance, and 3D printed fibreoptic attachments for ergonomic intraoral light delivery. METHODS: 30 patients with T(1)N(0)M(0) buccal mucosal cancer were recruited from the JN Medical College clinics, Aligarh, and rural screening camps. Tumour limits were defined by external ultrasound (US), white light photos and increased tumour fluorescence after oral administration of the photosensitising agent ALA (60 mg/kg, divided doses), monitored by a smartphone fluorescence imaging device. 100 J/cm(2) LED light (635 nm peak) was delivered followed by repeat fluorescence to assess photobleaching. US and biopsy were repeated after 7-17 days. This trial is registered with ClinicalTrials.gov, NCT03638622, and the study has been completed. FINDINGS: There were no significant complications or discomfort. No sedation was required. No residual disease was detected in 22 out of 30 patients who completed the study (26 of 34 lesions, 76% complete tumour response, 50 weeks median follow-up) with up to 7.2mm depth of necrosis. Treatment failures were attributed to large tumour size and/or inadequate light delivery (documented by limited photobleaching). Moderately differentiated lesions were more responsive than well-differentiated cancers. INTERPRETATION: This simple and low-cost adaptation of image-guided PDT is effective for treatment of early-stage malignant oral lesions and may have implications in global health. FUNDING: US National Cancer Institute

Photodynamic therapy (PDT) is a well-known cancer therapy that utilizes light to excite a photosensitizer and generate cytotoxic reactive oxygen species (ROS). The efficacy of PDT primarily depends on the photosensitizer and oxygen concentration in the tumor. Hypoxia in solid tumors promotes treatment resistance, resulting in poor PDT outcomes. Hence, there is a need to combat hypoxia while delivering sufficient photosensitizer to the tumor for ROS generation. Here we showcase our unique theranostic perfluorocarbon nanodroplets as a triple agent carrier for oxygen, photosensitizer, and indocyanine green that enables light triggered spatiotemporal delivery of oxygen to the tumors. We evaluated the characteristics of the nanodroplets and validated their ability to deliver oxygen via photoacoustic monitoring of blood oxygen saturation and subsequent PDT efficacy in a murine subcutaneous tumor model. The imaging results were validated with an oxygen sensing probe, which showed a 9.1 fold increase in oxygen content inside the tumor, following systemic administration of the nanodroplets. These results were also confirmed with immunofluorescence. In vivo studies showed that nanodroplets held higher rates of treatment efficacy than a clinically available benzoporphyrin derivative formulation. Histological analysis showed higher necrotic area within the tumor with perfluoropentane nanodroplets. Overall, the photoacoustic nanodroplets can significantly enhance image-guided PDT and has demonstrated substantial potential as a valid theranostic option for patient-specific photodynamic therapy-based treatments., Graphical Abstract ga1

Cholesteatoma is a potentially serious complication of chronic ear infections and requires surgical intervention for definitive management. Long-term complications include a frequent need for repeat surgical intervention for disease recurrence, and techniques to improve efficacy of single-stage surgery are an important area of continued research. This study investigates a novel application of the photosensitizer immune conjugate (PIC) cetuximab-benzoporphyrin derivative (Cet-BPD) for in vitro localization of human cholesteatoma tissue, coupled with an in vivo safety study for middle ear application of Cet-BPD in a murine model. In fresh human cholesteatoma tissues, Cet-BPD demonstrates selective localization to the hyperplastic squamous cell tissue associated with cholesteatoma, without localizing to other tissues such as middle ear mucosa. Applied to the murine middle ear, Cet-BPD does not demonstrate any deleterious effect on murine hearing when assessed by any of auditory brainstem response (ABR) thresholds, distortion product otoacoustic emission thresholds, or ABR wave I amplitudes. These findings demonstrate the technical promise and encouraging safety profile for the use of PICs for intraoperative localization and treatment of cholesteatoma.

Despite untiring efforts to develop therapies for pancreatic ductal adenocarcinoma (PDAC), survival statistics remain dismal, necessitating distinct approaches. Photodynamic priming (PDP), which improves drug delivery and combination regimens, as well as tumor photodestruction are key attributes of photodynamic therapy (PDT), making it a distinctive clinical option for PDAC. Localized, high-payload nanomedicine-assisted delivery of photosensitizers (PSs), with molecular specificity and controlled photoactivation, thus becomes critical in order to reduce collateral toxicity during more expansive photodynamic activation procedures with curative intent. As such, targeted photoactivable lipid-based nanomedicines are an ideal candidate but have failed to provide greater than two-fold cancer cell selectivity, if at all, due to their extensive multivariant physical, optical, and chemical complexity. Here, we report (1) a systematic multivariant tuning approach to engineer (Cet, anti-EGFR mAb) photoimmunonanoconjugates (PINs), and (2) stroma-rich heterotypic PDAC in vitro and in vivo models incorporating patient-derived pancreatic cancer-associated fibroblasts (PCAFs) that recapitulate the desmoplasia observed in the clinic. These offer a comprehensive, disease-specific framework for the development of Cet-PINs. Specificity-tuning of the PINs, in terms of PS lipid anchoring, electrostatic modulation, Cet orientation, and Cet surface densities, achieved ∼16-fold binding specificities and rapid penetration of the heterotypic organoids within 1 h, thereby providing a ∼16-fold enhancement in molecular targeted NIR photodestruction. As a demonstration of their inherent amenability for multifunctionality, encapsulation of high payloads of gemcitabine hydrochloride, 5-fluorouracil, and oxaliplatin within the Cet-PINs further improved their antitumor efficacy in the heterotypic organoids. In heterotypic desmoplastic tumors, the Cet-PINs efficiently penetrated up to 470 μm away from blood vessels, and photodynamic activation resulted in substantial tumor necrosis, which was not elicited in T47D tumors (low EGFR) or when using untargeted constructs in both tumor types. Photodynamic activation of the Cet-PINs in the heterotypic desmoplastic tumors resulted in collagen photomodulation, with a 1.5-fold reduction in collagen density, suggesting that PDP may also hold potential for conquering desmoplasia. The in vivo safety profile of photodynamic activation of the Cet-PINs was also substantially improved, as compared to the untargeted constructs. While treatment using the Cet-PINs did not cause any detriment to the mice's health or to healthy proximal tissue, photodynamic activation of untargeted constructs induced severe acute cachexia and weight loss in all treated mice, with substantial peripheral skin necrosis, muscle necrosis, and bowel perforation. This study is the first report demonstrating the true value of molecular targeting for NIR-activable PINs. These constructs integrate high payload delivery, efficient photodestruction, molecular precision, and collagen photomodulation in desmoplastic PDAC tumors in a single treatment using a single construct. Such combined PIN platforms and heterocellular models open up an array of further multiplexed combination therapies to synergistically control desmoplastic tumor progression and extend PDAC patient survival.

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, multi-modal molecular imaging probes enabling target visualization through complementary imaging technologies provides an attractive alternative. However, there are several challenges associated in designing molecular probes carrying contrast agents for complementary multi-modal 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 multi-modal infra-red (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 multi-modal 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 pre-clinical and clinical translation.

Low cost and high-power LED’s are replacing highly expensive and bulky Lasers in photoacoustic imaging (PAI) technology. LEDs bring the opportunity to image samples at a higher repetition rate (in kHz) compared to the conventional Q switched lasers (typically upto 20 Hz) and thus offer high frame rate and averaging power while maintain real-time imaging capability. In order to make a complete switch from Laser to LEDs, a proper understanding of this newly emerging class of LED arrays is important, for e.g., beam divergence, beam focus, coherence, time-dependent power and wavelength stability, penetration depth and sensitivity, etc. We performed characterization and optimization experiments on different tissue mimicking phantoms with various optical scattering and absorbing properties using a commercially available AcousticX PAI system with customized 3D printed holders for the LED array. The axial and lateral positions of LED arrays with respect to the acoustic probe to image deep lesions upto 1.5 cm were optimized. We also report the sensitivity of the system and Signal-to-noise-ratio (SNR) dependency of the LED arrays’ axial and lateral positions. Finally, we also demonstrate the adaptability of our custom designed, 3D printed variable angle and distance holder to perform deep tissue ultrasound and photoacoustic imaging probe on phantoms of with absorbers at different depth and in subcutaneous tumors and compare it with traditional laser based photoacoustic imaging systems.

This Conference Presentation, “Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy,” was recorded for the Photonics West 2021 Digital Forum.

In this study, we evaluated the capability of an LED-based photoacoustic imaging system (AcousticX, 7MHz ultrasound probe, 850 nm LED arrays) in imaging heterogenous vasculature of subcutaneous tumors in mice. For evaluating the functional imaging capability, we used AcousticX with dual-wavelength LED arrays (750/850 nm) and monitored oxygen saturation of the tumor volume. We also compared the tumor images acquired by AcousticX and a commercial laser-based photoacoustic imaging system. Our results show that LED-based photoacoustic imaging can obtain similar imaging performance as a laser-based system and thus holds good promise in preclinical cancer research in an affordable setting.

Here we present a dual function antibody conjugate with a photosensitizer (or a fluorophore) and a napthalocyanine dye conjugated on Cetuximab targeted towards Epidermal growth factor receptor. The in vitro therapeutic efficacy and in vivo molecular photoacoustic imaging capabilities of the conjugate are demonstrated in murine oral cancer models.

We report on a novel approach to monitor photodynamic therapy procedure based on the simultaneous fluorescence and optoacoustic imaging with the use of a liposome nanoconstructs contain benzoporphyrin derivatives and the fluorescent IRDye800 dye. We demonstrate the results of a preliminary in vivo study with combined fluorescence and optoacoustic custom-made setups on a NUDE mouse with human glioblastoma U-87.

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 have been created 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 got more uniform when coated with longer chain carboxylates. The AFM force distance (F-D) measurements are used to measure the stiffness of the carboxylate coated EGaIn CSN. In corroboration with DRIFTS analysis, the stiffness studies show that the alkyl chains undergo conformational changes upon compression.

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 dependent response to Benzoporphyrin Derivative photodynamic therapy (BPD-PDT) and irinotecan. Small tumors (5–35 mm(3)) were found to respond well to a single round of PDT, while large tumors (35–65 mm(3)) 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.