Near-infrared Optical Imaging Research Articles

Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation.

Second near-infrared (NIR-II) optical imaging technology has emerged as a powerful tool for diagnostic and image-guided surgery due to its higher imaging contrast. However, a general strategy for efficiently designing NIR-II organic molecules is still lacking, because NIR-II dyes are usually difficult to synthesize, which has impeded the rapid development of NIR-II bioprobes. Herein, based on the theoretical calculations on 62 multiaryl-pyrrole (MAP) systems with spectra ranging from the visible to the NIR-II region, a continuous red shift of the spectra toward the NIR-II region could be achieved by adjusting the type and site of substituents on the MAPs. Two descriptors (ΔEgs and μgs) were identified as exhibiting strong correlations with the maximum absorption/emission wavelengths, and the descriptors could be used to predict the emission spectrum in the NIR-II region only if ΔEgs ≤ 2.5 eV and μgs ≤ 22.55 D. The experimental absorption and emission spectra of ten MAPs fully confirmed the theoretical predictions, and biological imaging in vivo of newly designed MAP23-BBT showed high spatial resolution in the NIR-II region in deep tissue angiography. More importantly, both descriptors of ΔEgs and μgs have shown general applicability to most of the reported donor-acceptor-donor-type non-MAP NIR-II dyes. These results have broad implications for the efficient design of NIR-II dyes.

Abstract 6166: A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes

Abstract Objective With the recent discovery of the fallopian tube (FT) origin of the most common and lethal type of ovarian cancer, high grade serous cancer (HGSC), engineering solutions to overcome the limitations of standard histopathology to more reliably identify incipient HGSCs and their serous tubal intraepithelial carcinoma (STIC) precursors are much needed. This investigation tests the potential of whole-organ ex vivo optical imaging of freshly excised FTs to label and sample abnormal tubal epithelium prior to formalin fixation and paraffin embedding for standard histopathology. Methods This investigation prototyped “OVASEEK”, a whole-organ, near-infrared optical imaging platform for identification of STICs. This prospective biospecimen protocol with annotated clinical data was approved by the IRB. Following salpingectomy at the time of hysterectomy for benign indications, FTs from study participants are longitudinally bivalved. Half of the FT is retained for routine evaluation using the Sectioning and Extensively Examining the Fimbriated end (SEE-FIM) protocol by Johns Hopkins gynecologic pathologists (Gyn Path), while the other half is sent overnight in organ transplant media to MIT for imaging on OVASEEK. Hyperspectral “label free” first pass imaging is performed using a series of band-pass filters. Second pass fluorescence imaging is then performed using nanoparticles tagged with anti-LAMC1 antibodies targeting laminin γ1, a known STIC surface marker. Abnormal signal(s) on OVASEEK imaging of the FT epithelium are tattooed with black ink, the tissue is formalin fixed and returned to Gyn Path for serial sectioning. Research findings are reported in an addendum to the formal pathology report in the electronic medical record and discussed with the patient by the gynecologic oncologist co-investigator. Results OVASEEK enabled non-destructive imaging over a wide field-of-view ~ 12×12 cm, with features of interest in the 1,050-1,550 nm range. In this pilot study, OVASEEK identified histopathologic abnormalities missed by standard SEE-FIM in 20% of FTs (n=2 out of 10). In each case, OVASEEK found microscopic (~200 µm) foci of salpingitis, a lymphoplasmacytic infiltrate consistent with inflammation. Performance of serial sectioning and histopathologic examination of the tattooed epithelium yielded this diagnosis. Conclusion Work is ongoing to improve the resolution, speed and sensitivity of OVASEEK for STIC detection. Identification of µm-sized foci of inflammation using OVASEEK is proof-of-principle that whole-organ ex vivo imaging of freshly excised FTs may be an innovation that improves the diagnostic performance of routine histopathology. Accurate and reproducible diagnosis of STIC and concurrent microscopic HGSC is imperative to the understanding of the early pathogenesis of HGSC in clinically actionable ways. Citation Format: Neelkanth M. Bardhan, Vivek Rastogi, Rebecca L. Stone, Angela M. Belcher. A whole-organ ex vivo optical imaging technique for non-destructive, more precise identification of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6166.

Optical properties of Y dwarfs observed with the Gran Telescopio Canarias

Our science goals are to characterise the optical properties of Y dwarfs and to study their consistency with theoretical models. A sample of five Y dwarfs was observed with three optical and near-infrared instruments at the 10.4\,m Gran Telescopio Canarias. Deep near-infrared ($J$- or $H$-band) and multicolour optical images ($z$-, $i$-, $r$-, $g$-, $u$-bands) of the five targets and a low-resolution far-red optical spectrum for one of the targets were obtained. One of the Y dwarfs, WISE J173835.53+273258.9 (Y0), was clearly detected in the optical ($z$- and $i$-bands) and another, WISE J182831.08+265037.7 (Y2), was detected only in the $z$-band. We measured the colours of our targets and found that the $z-J$ and $i-z$ colours of the Y dwarfs are bluer than those of mid- and late-T dwarfs. This optical blueing has been predicted by models, but our data indicates that it is sharper and happens at temperatures about 150 K warmer than expected. The culprit is the K I resonance doublet, which weakens more abruptly in the T- to Y-type transition than expected. Moreover, we show that the alkali resonance lines (Cs I and K I) are weaker in Y dwarfs than in T dwarfs; the far-red optical spectrum of WISE J173835.53+273258.9 is similar to that of late-T dwarfs, but with stronger methane and water features; and we noted the appearance of new absorption features that we propose could be due to hydrogen sulphide. Last but not least, in 2014, WISE J173835.53+273258.9 presented a bluer $i-z$ colour than in 2021 by a factor of 2.8 (significance of 2.5sigma ). Thanks to our deep optical images, we found that the 2014 $i$-band spectrum was contaminated by a galaxy bluer than the Y dwarf. The optical properties of Y dwarfs presented here pose new challenges to the modelling of grain sedimentation in extremely cool objects. The weakening of the very broad K I resonance doublet due to condensation in dust grains is more abrupt than theoretically anticipated. Consequently, the observed blueing of the $z-J$ and $i-z$ colours of Y dwarfs with respect to T dwarfs is more pronounced than predicted by models and could boost the potential of upcoming deep large-area optical surveys regarding their ability to detect extremely cool objects.

Theranostic potential of a novel aptamer specifically targeting HER2 in breast cancer cells.

The overexpression of HER2 is correlated with poorer outcomes and therapeutic resistance in breast cancer patients. While HER2-targeted therapies have shown improvement, prognosis remains poor for HER2-positive breast cancer patients, and these treatments have limitations. Therefore, it is crucial to explore effective molecular strategies for early detection and treatment of HER2-positive breast cancers. In this study, we employed the cell-SELEX method to generate a selective aptamer capable of recognizing HER2 in its native conformation within breast cancer cells, for theranostic applications. Utilizing an adherent cell-SELEX approach, we developed and explored a DNA aptamer, named HMAP7, which can specifically target HER2 in the MDA-MB-453 and SK-BR-3 human breast cancer cell lines. After sequencing, the binding affinities of 10 candidate aptamers to HER2 receptors were evaluated by measuring fluorescence intensities within intact cells using near-infrared optical imaging. The dissociation constant of HMAP7 was determined to be in the nanomolar range in both cell lines. The cell-SELEX-derived aptamer sequence, HMAP7 (41-mer), exhibited the highest binding affinity and specificity for HER2. HMAP7 was rapidly internalized into breast cancer cells overexpressing HER2 but showed no uptake in the HER2 receptor-deficient breast cancer cell line MDA-MB-231. Moreover, HMAP7 demonstrated remarkable selectivity for HER2, rendering it suitable for use in complex biological systems. Our findings suggest that the novel DNA aptamer HMAP7 holds promise for both therapeutic and diagnostic applications, enabling selective delivery of therapeutic agents or imaging of HER2-positive breast tumors.

Novel affibody molecules as potential agents in molecular imaging for MAGE-A3-positive tumor diagnosis

BackgroundThe cancer-testis protein melanoma antigen A3 (MAGE-A3) is highly expressed in a broad range of malignant tumor forms. It has been confirmed that affibody molecules, a novel family of small (∼6.5 kDa) targeting proteins, are useful agents for molecular imaging and targeted tumor treatment. As a novel agent for in vivo molecular imaging detection of MAGE-A3-positive tumors, the efficacy of affibody molecules was assessed in this research. MethodsIn this study, three cycles of phage display library screening resulted in the isolation of two new affibody molecules (ZMAGE-A3:172 and ZMAGE-A3:770) that attach to MAGE-A3. These molecules were then expressed in bacteria and purified. The affibody molecules with high affinity and specificity were evaluated using western blotting, immunohistochemistry, indirect immunofluorescence, surface plasmon resonance, and near-infrared optical imaging of tumor-bearing nude mice. ResultsThe selected ZMAGE-A3 affibodies can precisely bind to the MAGE-A3 protein in living cells and display high-affinity binding to the MAGE-A3 protein at the molecular level. Furthermore, the accumulation of DyLight755-labeled ZMAGE-A3:172 or ZMAGE-A3:770 in MAGE-A3-positive tumors was achieved as early as 30 min and disappeared at 48 h post-injection. ConclusionOur findings support the potential of the two MAGE-A3 protein-binding affibody molecules for their use as molecular imaging agents.

Real-time Fluorescent ICG and 99m-Tc Nanocolloid Tracer Navigation in Bilateral Sentinel Lymph Node Mapping of Vulvar Cancer

The effectiveness of sentinel lymph node (SLN) biopsy has been validated by two prospective trials, GROINS VI and GOG 1731-2. According to ESGO guideline in patients with unifocal tumors with a diameter of <4 cm, in the absence of suspected inguinal lymph nodes, SLN biopsy is recommended. The use of a radioactive tracer is mandatory.2 Using Indocyanine green (ICG) increase the detection of the vulvar sentinel node from 89.7 to 100%3. Aim of this video is to share our experience about the feasibility, safety and usefulness of the surgical identification of SLN in vulvar cancer using real-time fluorescent indocyanine green with 99m-technetium nanocolloid. Stepwise demonstration of the technique with narrated video footage. Tertiary level hospital "IRCCS Istituto Nazionale dei Tumori", Milano, Italy. A 50-year-old woman was diagnosed with vulvar cancer on biopsy of 1.5 cm size vulvar lesion under the clitoris area and referred to our Operative Unit. F-18 fluorodeoxyglucose positron-emission tomography-computed tomography (PET) showed no extra-vulvar disease. The patient was scheduled for radical vulvectomy and bilateral inguinal sentinel lymph-node biopsy (SLN). In this video the surgical procedure involved double location of SLN, first with the 99m-technetium detector followed by ICG identification. We used an ICG dilution of 2.5 mg/mL in sterile water and injected 4 mL around the tumor 5-10 min before visualization. First a handheld gamma probe used to identify the location of the SLN(s) with 99m-technetium. The fluorescence imaging was performed by the quest imaging system (FLUOPTICS©, Middenmeer, The Netherlands) that combine autofluorescence and fluorescence perfusion imaging. Second, we carried out the SLN biopsy using a dark mood procedure to identify the IGC tracer. The fluorescence imaging enables the detection of these markers through some millimeters of tissue and ICG has the advantage that is visible through the skin4. This video shows a successful combined 99m-technetium and ICG fluorescence image-guided bilateral SLN biopsy in a vulvar cancer patient using a near-infrared (NIR) optical imaging system (FLUOPTICS©). ICG for SLN mapping appears to be safe in women with vulvar cancer with a satisfactory detection rate. This may help in retaining surgical radicality while minimizing operative complications.

Combining seeded region growing and k-nearest neighbours for the segmentation of routinely acquired spatio-temporal image data

PurposeThe acquisition conditions of medical imaging are often precisely defined, leading to a high homogeneity among different data sets. Nonetheless, outliers or artefacts still appear and need to be reliably detected to ensure a reliable diagnosis. Thus, the algorithms need to handle small sample sizes especially, when working with domain specific imaging modalities.MethodsIn this work, we suggest a pipeline for the detection and segmentation of light pollution in near-infrared fluorescence optical imaging (NIR-FOI), based on a small sample size. NIR-FOI produces spatio-temporal data with two spatial and one temporal dimension. To calculate a two-dimensional light pollution map for the entire image stack, we combine region growing and k-nearest neighbours (kNN), which classifies pixels into fore- and background by its entire temporal component. Thus, decision-making on reduced data is omitted.ResultsWe achieved a F_1 score of 0.99 for classifying a data set as light polluted or pollution-free. Additionally, we reached a total F_1 score of 0.90 for detecting regions of interest within the polluted data sets. Finally, an average Dice’s coefficient measuring the segmentation performance over all polluted data sets of 0.80 was accomplished.ConclusionsA Dice’s coefficient of 0.80 for the area segmentation does not seem perfect. However, there are two main factors, besides true prediction errors, lowering the score: Segmentation mistakes on small areas lead to a rapid decrease in the score and labelling errors due to complex data. However, in combination with the light-polluted data set and pollution area detection, these results can be considered successful and play a key role in our general goal: Exploiting NIR-FOI for the early detection of arthritis within hand joints.

The early stage of adult ocular dominance plasticity revealed by near-infrared optical imaging of intrinsic signals

Long term monocular deprivation is considered to be necessary for the induction of significant ocular dominance plasticity in the adult visual cortex. In this study, we subjected adult mice to monocular deprivation for various durations and screened for changes in ocular dominance using dual-wavelength intrinsic signal optical imaging. We found that short-term deprivation was sufficient to cause a shift in ocular dominance and that these early-stage changes were detected only by near-infrared illumination. In addition, single-unit recordings showed that these early-stage changes primarily occurred in deep cortical layers. This early-stage ocular dominance shift was abolished by the blockade of NMDA receptors. In summary, our findings reveal an early phase of adult ocular dominance plasticity and provide the dynamics of adult plasticity.

Lower Energy Excitation of Water Soluble Near-Infrared Emitting Mixed-Ligand Metallacrowns.

By combining advantages of two series of lanthanide(III)/zinc(II) metallacrowns (MCs) assembled using pyrazine- (pyzHA2- ) and quinoxaline- (quinoHA2- ) hydroximate building blocks ligands, we created here water-soluble mixed-ligand MCs with extended absorption to the visible range. The YbIII analogue demonstrated improved photophysical properties in the near-infrared (NIR) range in cell culture media, facilitating its application for NIR optical imaging in living HeLa cells.

A FRET-Based Ratiometric H2S Sensor for Sensitive Optical Molecular Imaging in Second Near-Infrared Window.

Second near-infrared (NIR-II) window optical molecular imaging kicks off a new revolution in high-quality imaging invivo, but always suffers from the hurdles of inevitable tissue autofluorescence background and NIR-II probe development. Here, we prepare a Förster resonance energy transfer-based ratiometric NIR-II window hydrogen sulfide (H2S) sensor through the combination of an H2S-responsive NIR-II cyanine dye (acceptor, LET-1055) and an H2S-inert rhodamine hybrid polymethine dye (donor, Rh930). This sensor not only exhibits high sensitivity and selectivity, but also shows rapid reaction kinetics (~20 min) and relatively low limit of detection (~96 nM) toward H2S, allowing invivo ratiometric NIR-II fluorescence imaging of orthotopic liver and colon tumors and visualization of the drug-induced hepatic H2S fluctuations. Our findings provide the potential for advancing the feasibility of NIR-II activity-based sensing for invivo clinical diagnosis.

Targeted Treatment of Inappropriate Sinoatrial Node Tachycardia Based on Electrophysiological and Structural Mechanisms

The purpose of this review is to determine the causal mechanisms and treatment of inappropriate sinoatrial tachycardia (IST), defined as a non-physiological elevation in resting heart rate. IST is defined as a resting daytime sinus rate >100 beats/minute and an average 24-hour heart rate >90 beats/minute. Potential causal mechanisms include sympathetic receptor hypersensitivity, blunted parasympathetic tone, or enhanced intrinsic automaticity within the sinoatrial node (SAN) pacemaker-conduction complex. These anomalies may coexist in the same patient. Recent ex-vivo near-infrared transmural optical imaging of the SAN in human and animal hearts provides important insights into the functional and molecular features of this complex structure. In particular, it reveals the existence of preferential sinoatrial conduction pathways that ensure robust SAN activation with electrical conduction. The mechanism of IST is debated because even high-resolution electroanatomical mapping approaches cannot reveal intramural conduction in the 3-dimensional SAN complex. It may be secondary to enhanced automaticity, intranodal re-entry, or sinoatrial conduction pathway re-entry. Different pharmacological approaches can target these mechanisms. Long-acting β blockers in IST can act on both primarily increased automaticity and dysregulated autonomic system. Ivabradine targets sources of increased SAN automaticity. Conventional or hybrid ablation may target all the described abnormalities. This review provides a state-of-the-art overview of putative IST mechanisms. In conclusion, based on current knowledge, pharmacological and ablation approaches for IST, including the novel hybrid SAN sparing ablation, are discussed.

PSMA-targeted NIR probes for image-guided detection of prostate cancer

Tumour-targeted near-infrared (NIR) optical imaging is an emerging tool for the detection of malignant tissues. This modality can be useful in both diagnosis and intraoperative visualisation, to help defining tumour margins and allow a more precise removal of all the cancerous mass during surgery. In this context, we have developed a series of NIR fluorescent probes that target the prostate-specific membrane antigen (PSMA), an established biomarker overexpressed in prostate cancer. Four new NIR imaging agents were prepared by conjugating the well-known urea-based PSMA targeting module to the NIR fluorophore Cy7.5, with linkers of 7, 10, 17 and 24 atoms. The affinity of each probe for PSMA was assessed through competitive binding and IC50 measurement in prostate cancer cells, using a previously reported PSMA-targeted NIR probe (i.e. PSMA-IRDye800CW) as reference. The NIR probe PSMA-Cy7.5_2 demonstrated a high affinity for PSMA (i.e. IC50 = 58.8 nM) and was further studied in mouse xenograft models of prostate cancer, to assess its ability to image PSMA positive tumour tissues. While PSMA-Cy7.5_2 out-performed PSMA-IRDye800CW in vitro, its tumour accumulation in vivo was not as evident. Further micellar aggregation studies indicated that the relatively higher hydrophobic property of PSMA-Cy7.5_2 may lower its bioavailability and tissue distribution following systemic injection, limiting its ability of targeting PSMA tumour in vivo. Nevertheless, the excellent binding capability of PSMA-Cy7.5_2 renders this probe a valid lead for further structural optimisation to develop imaging analogues with high affinity and specificity for PSMA, as required for effective NIR fluorescence-guided applications pre-clinically and clinically.

Development of Intraoperative Near-Infrared Fluorescence Imaging System Using a Dual-CMOS Single Camera.

We developed a single-camera-based near-infrared (NIR) fluorescence imaging device using indocyanine green (ICG) NIR fluorescence contrast agents for image-induced surgery. In general, a fluorescent imaging system that simultaneously provides color and NIR images uses two cameras, which is disadvantageous because it increases the imaging head of the system. Recently, a single-camera-based NIR optical imaging device with quantum efficiency partially extended to the NIR region was developed to overcome this drawback. The system used RGB_NIR filters for camera sensors to provide color and NIR images simultaneously; however, the sensitivity and resolution of the infrared images are reduced by 1/4, and the exposure time and gain cannot be set individually when acquiring color and NIR images. Thus, to overcome these shortcomings, this study developed a compact fluorescent imaging system that uses a single camera with two complementary metal–oxide semiconductor (CMOS) image sensors. Sensitivity and signal-to-background ratio were measured according to the concentrations of ICG solution, exposure time, and camera gain to evaluate the performance of the imaging system. Consequently, the clinical applicability of the system was confirmed through the toxicity analysis of the light source and in vivo testing.

Safety of use of the ENDOSWIR near-infrared optical imaging device on human tissues: prospective blind study.

Cancer surgery requires removing the tumor tissue in necessary and sufficient quantities. Spectral optical imaging in the short-wave infrared (900-1700nm) could provide an intraoperative guidance to the surgeon based on the absorption of the tissues without contrast agent. Our objective was to ensure the safety of our ENDOSWIR device on human tissues. Histological analysis of fresh human tonsils exposed to the SWIR light or not was compared and showed no histological differences. This demonstrates the safety of using the SWIR device on human tissues and allows us to initiate a clinical study for the resection of tumors intraoperatively.

Near-infrared excitation/emission microscopy with lanthanide-based nanoparticles.

Near-infrared optical imaging offers some advantages over conventional imaging, such as deeper tissue penetration, low or no autofluorescence, and reduced tissue scattering. Lanthanide-doped nanoparticles (LnNPs) have become a trend in the field of photoactive nanomaterials for optical imaging due to their unique optical features and because they can use NIR light as excitation and/or emission light. This review is focused on NaREF4 NPs and offers an overview of the state-of-the-art investigation in their use as luminophores in optical microscopy, time-resolved imaging, and super-resolution nanoscopy based on, or applied to, LnNPs. Secondly, whenever LnNPs are combined with other nanomaterial or nanoparticle to afford nanohybrids, the characterization of their physical and chemical properties is of current interest. In this context, the latest trends in optical microscopy and their future perspectives are discussed.

Numerical Study of Near-Infrared Light Propagation in Aqueous Alumina Suspensions Using the Steady-State Radiative Transfer Equation and Dependent Scattering Theory

Understanding light propagation in liquid phantoms, such as colloidal suspensions, involves fundamental research of near-infrared optical imaging and spectroscopy for biological tissues. Our objective is to numerically investigate light propagation in the alumina colloidal suspensions with the mean alumina particle diameter of 55 nm at the volume fraction range 1–20%. We calculated the light scattering properties using the dependent scattering theory (DST) on a length scale comparable to the optical wavelength. We calculated the steady-state radiative transfer and photon diffusion equations (RTE and PDE) using the DST results based on the finite difference method in a length scale of the mean free path. The DST calculations showed that the scattering and reduced scattering coefficients become more prominent at a higher volume fraction. The anisotropy factor is almost zero at all the volume fractions, meaning the scattering is isotropic. The comparative study of the RTE with the PDE showed that the diffusion approximation holds at the internal region with all the volume fractions and the boundary region with the volume fraction higher than 1%. Our findings suggest the usefulness of the PDE as a light propagation model for the alumina suspensions rather than the RTE, which provides accurate but complicated computation.

Tuning the photophysical properties of lanthanide(iii)/zinc(ii) 'encapsulated sandwich' metallacrowns emitting in the near-infrared range.

A family of Zn16Ln(HA)16 metallacrowns (MCs; Ln = YbIII, ErIII, and NdIII; HA = picoline- (picHA2−), pyrazine- (pyzHA2−), and quinaldine- (quinHA2−) hydroximates) with an ‘encapsulated sandwich’ structure possesses outstanding luminescence properties in the near-infrared (NIR) and suitability for cell imaging. Here, to decipher which parameters affect their functional and photophysical properties and how the nature of the hydroximate ligands can allow their fine tuning, we have completed this Zn16Ln(HA)16 family by synthesizing MCs with two new ligands, naphthyridine- (napHA2−) and quinoxaline- (quinoHA2−) hydroximates. Zn16Ln(napHA)16 and Zn16Ln(quinoHA)16 exhibit absorption bands extended into the visible range and efficiently sensitize the NIR emissions of YbIII, ErIII, and NdIII upon excitation up to 630 nm. The energies of the lowest singlet (S1), triplet (T1) and intra-ligand charge transfer (ILCT) states have been determined. LnIII-centered total (QLLn) and intrinsic (QLnLn) quantum yields, sensitization efficiencies (ηsens), observed (τobs) and radiative (τrad) luminescence lifetimes have been recorded and analyzed in the solid state and in CH3OH and CD3OD solutions for all Zn16Ln(HA)16. We found that, within the Zn16Ln(HA)16 family, τrad values are not constant for a particular LnIII. The close in energy positions of T1 and ILCT states in Zn16Ln(picHA)16 and Zn16Ln(quinHA)16 are preferred for the sensitization of LnIII NIR emission and ηsens values reach 100% for NdIII. Finally, the highest values of QLLn are observed for Zn16Ln(quinHA)16 in the solid state or in CD3OD solutions. With these data at hand, we are now capable of creating MCs with desired properties suitable for NIR optical imaging.

Targeted Fluorogenic Cyanine Carbamates Enable In Vivo Analysis of Antibody-Drug Conjugate Linker Chemistry.

Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker between the antibody and the drug payload plays an essential role in the efficacy and tolerability of these agents. New methods that quantitatively assess the cleavage efficiency in complex tissue settings could provide valuable insights into the ADC design process. Here we report the development of a near-infrared (NIR) optical imaging approach that measures the site and extent of linker cleavage in mouse models. This approach is enabled by a superior variant of our recently devised cyanine carbamate (CyBam) platform. We identify a novel tertiary amine-containing norcyanine, the product of CyBam cleavage, that exhibits a dramatically increased cellular signal due to an improved cellular permeability and lysosomal accumulation. The resulting cyanine lysosome-targeting carbamates (CyLBams) are ∼50× brighter in cells, and we find this strategy is essential for high-contrast in vivo targeted imaging. Finally, we compare a panel of several common ADC linkers across two antibodies and tumor models. These studies indicate that cathepsin-cleavable linkers provide dramatically higher tumor activation relative to hindered or nonhindered disulfides, an observation that is only apparent with in vivo imaging. This strategy enables quantitative comparisons of cleavable linker chemistries in complex tissue settings with implications across the drug delivery landscape.

Decreasing hyaluronic acid combined with drug-loaded nanoprobes improve the delivery and efficacy of chemotherapeutic drugs for pancreatic cancer.

Pancreatic cancer is one of the common malignant tumors of the digestive system, and its clinical treatment is still very challenging. Most of the pancreatic cancer chemotherapeutic drugs have poor plasma stability, low cell uptake efficiency, and are prone to developing drug resistance and toxic side effects. Besides, pancreatic cancer often has a dense extracellular matrix, which consists of collagens, hyaluronic acid, and other proteoglycans. Among them, hyaluronic acid is a key component of the dense matrix, which results in vascular compression and insufficient perfusion, and hinders the delivery of chemotherapeutic drugs. In this study, we explore using hyaluronidase in tumor-bearing mice to eliminate the hyaluronic acid barrier, to reduce blood vessel compression and reshape the tumor microenvironment. In addition, we evaluate using doxorubicin-loaded nanoprobes to improve the stability and local tumor-killing effect of the drug. The nanoprobes have the characteristics of near-infrared optical imaging, which are used to monitor the tumor size in real-time during the treatment process, and dynamically observe the tumor inhibitory effect. The results show that elimination of the hyaluronic acid barrier combined with the doxorubicin-loaded nanoprobes can greatly increase drug penetration into tumor tissue and improve the effectiveness of chemotherapy drugs. This study provides a novel strategy for the treatment of pancreatic cancer.

Abstract 10382: Large Lipid-Rich Plaque Predicts Intra-Stent Thrombus Formation After Primary Pci in Patients with Acute Coronary Syndrome: Insights from Near-infrared Spectroscopy and Optical Coherence Tomography Imaging Analysis

Backgrounds: The formation of intrastent thrombus is a PCI-related complication in subjects with ACS, which infrequently causes acute stent thrombosis. Given that lipid-rich plaque, a substrate for ACS, activates inflammation inducing prothrombotic state, the degree of lipidic plaque materials may associate with intrastent thrombus formation. Methods: Culprit lesions in 70 ACS subjects (=STEMI/NSTEMI/uAP=28/27/15) receiving newer-generation DES implantation were evaluated by both near-infrared spectroscopy (NIRS) and optical coherence tomography (OCT) imaging. NIRS-derived 4-mm maximum lipid-core-burden index (maxLCBI 4mm ) at culprit lesion was measured prior to PCI. OCT-derived intrastent thrombus-burden index (ITBI) after stent implantation were calculated as follows: [Σ(every 1-mm cross sectional thrombus-arc score: 1=1-90°,2=91-180°,3=181-270°,4=271-360°)/analyzed length]x(averaged longitudinal length). ITBI was compared between subjects with maxLCBI 4mm &lt;400 and ≥400. Result: The averaged maxLCBI 4mm was 525±236, and dual-antiplatelet therapy with aspirin and clopidogrel, and aspirin and prasugrel was used in 43 and 56%, respectively. On OCT imaging analysis, maxLCBI 4mm was significantly associated with ITBI (r=0.55, p &lt;0.001, Figure), whereas there were no significant relationships of minimum stent area (MSA) (r=0.18, p=0.13) and stent malapposition diameter with ITBI (r=0.00. p=0.97). Multivariate analysis demonstrated maxLCBI 4mm as an independent predictor of higher ITBI even after adjusting MSA, stent malapposition and other clinical characteristics (Table). Conclusions: The presence of lipid-rich plaque was associated with intrastent thrombus formation in the setting of ACS. Our findings suggest the potential importance to modulate activated prothrombotic cascade by using more potent antiplatelet agent in ACS patients exhibiting lipid-rich plaques.