Publications by authors named "Hak Soo Choi"

161 Publications

Phototheranostics for multifunctional treatment of cancer with fluorescence imaging.

Adv Drug Deliv Rev 2022 Aug 6;189:114483. Epub 2022 Aug 6.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Phototheranostics stem from the recent advances in nanomedicines and bioimaging to diagnose and treat human diseases. Since tumors' diversity, heterogeneity, and instability limit the clinical application of traditional diagnostics and therapeutics, phototheranostics, which combine light-induced therapeutic and diagnostic modalities in a single platform, have been widely investigated. Numerous efforts have been made to develop phototheranostics for efficient light-induced antitumor therapeutics with minimal side effects. Herein, we review the fundamentals of phototheranostic nanomedicines with their biomedical applications. Furthermore, the progress of near-infrared fluorescence imaging and cancer treatments, including photodynamic therapy and photothermal therapy, along with chemotherapy, immunotherapy, and gene therapy, are summarized. This review also discusses the opportunities and challenges associated with the clinical translation of phototheranostics in pan-cancer research. Phototheranostics can pave the way for future research, improve the quality of life, and prolong cancer patients' survival times.
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http://dx.doi.org/10.1016/j.addr.2022.114483DOI Listing
August 2022

NIR fluorescence imaging and treatment for cancer immunotherapy.

J Immunother Cancer 2022 07;10(7)

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

Cancer immunotherapy has emerged as one of the most powerful anticancer therapies. However, the details on the interaction between tumors and the immune system are complicated and still poorly understood. Optical fluorescence imaging is a technique that allows for the visualization of fluorescence-labeled immune cells and monitoring of the immune response during immunotherapy. To this end, near-infrared (NIR) light has been adapted for optical fluorescence imaging because it is relatively safe and simple without hazardous ionizing radiation and has relatively deeper tissue penetration into living organisms than visible fluorescence light. In this review, we discuss state-of-the-art NIR optical imaging techniques in cancer immunotherapy to observe the dynamics, efficacy, and responses of the immune components in living organisms. The use of bioimaging labeling techniques will give us an understanding of how the immune system is primed and ultimately developed.
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http://dx.doi.org/10.1136/jitc-2022-004936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305898PMC
July 2022

A small molecule redistributes iron in ferroportin-deficient mice and patient-derived primary macrophages.

Proc Natl Acad Sci U S A 2022 06 22;119(26):e2121400119. Epub 2022 Jun 22.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109.

Deficiencies of the transmembrane iron-transporting protein ferroportin (FPN1) cause the iron misdistribution that underlies ferroportin disease, anemia of inflammation, and several other human diseases and conditions. A small molecule natural product, hinokitiol, was recently shown to serve as a surrogate transmembrane iron transporter that can restore hemoglobinization in zebrafish deficient in other iron transporting proteins and can increase gut iron absorption in FPN1-deficient flatiron mice. However, whether hinokitiol can restore normal iron physiology in FPN1-deficient animals or primary cells from patients and the mechanisms underlying such targeted activities remain unknown. Here, we show that hinokitiol redistributes iron from the liver to red blood cells in flatiron mice, thereby increasing hemoglobin and hematocrit. Mechanistic studies confirm that hinokitiol functions as a surrogate transmembrane iron transporter to release iron trapped within liver macrophages, that hinokitiol-Fe complexes transfer iron to transferrin, and that the resulting transferrin-Fe complexes drive red blood cell maturation in a transferrin-receptor-dependent manner. We also show in FPN1-deficient primary macrophages derived from patients with ferroportin disease that hinokitiol moves labile iron from inside to outside cells and decreases intracellular ferritin levels. The mobilization of nonlabile iron is accompanied by reductions in intracellular ferritin, consistent with the activation of regulated ferritin proteolysis. These findings collectively provide foundational support for the translation of small molecule iron transporters into therapies for human diseases caused by iron misdistribution.
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http://dx.doi.org/10.1073/pnas.2121400119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245668PMC
June 2022

Neuroimaging Modalities in Alzheimer's Disease: Diagnosis and Clinical Features.

Int J Mol Sci 2022 May 28;23(11). Epub 2022 May 28.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Alzheimer's disease (AD) is a neurodegenerative disease causing progressive cognitive decline until eventual death. AD affects millions of individuals worldwide in the absence of effective treatment options, and its clinical causes are still uncertain. The onset of dementia symptoms indicates severe neurodegeneration has already taken place. Therefore, AD diagnosis at an early stage is essential as it results in more effective therapy to slow its progression. The current clinical diagnosis of AD relies on mental examinations and brain imaging to determine whether patients meet diagnostic criteria, and biomedical research focuses on finding associated biomarkers by using neuroimaging techniques. Multiple clinical brain imaging modalities emerged as potential techniques to study AD, showing a range of capacity in their preciseness to identify the disease. This review presents the advantages and limitations of brain imaging modalities for AD diagnosis and discusses their clinical value.
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http://dx.doi.org/10.3390/ijms23116079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181385PMC
May 2022

Image-guided drug delivery of nanotheranostics for targeted lung cancer therapy.

Theranostics 2022 13;12(9):4147-4162. Epub 2022 May 13.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School; Boston, MA 02114, USA.

Enormous efforts have been made to integrate various therapeutic interventions into multifunctional nanoplatforms, resulting in the advance of nanomedicine. Image-guided drug delivery plays a pivotal role in this field by providing specific targeting as well as image navigation for disease prognosis. We demonstrate image-guided surgery and drug delivery for the treatment of lung cancer using nanotheranostic H-dots loaded with gefitinib and genistein. The surgical margin for lung tumors is determined by image guidance for precise tumor resection, while targeted anti-cancer drugs function simultaneously for synergistic combination therapy. Compared to conventional chemotherapies, H-dot complexes could improve the therapeutic efficacy of drugs while reducing the risk of adverse effects and drug resistance owing to their ideal biodistribution profiles, high targetability, low nonspecific tissue uptake, and fast renal excretion. These H-dot complexes have unlocked a unique framework for integrating multiple therapeutic and diagnostic modalities into one nanoplatform.
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http://dx.doi.org/10.7150/thno.72803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169367PMC
May 2022

3D cell-printing of gradient multi-tissue interfaces for rotator cuff regeneration.

Bioact Mater 2023 Jan 11;19:611-625. Epub 2022 May 11.

Department of Mechanical Engineering, Pohang University of Science and Technology, 77 Cheongam-ro, Nam-gu, Gyeongsangbuk-do, Pohang, 37673, South Korea.

Owing to the prevalence of rotator cuff (RC) injuries and suboptimal healing outcome, rapid and functional regeneration of the tendon-bone interface (TBI) after RC repair continues to be a major clinical challenge. Given the essential role of the RC in shoulder movement, the engineering of biomimetic multi-tissue constructs presents an opportunity for complex TBI reconstruction after RC repair. Here, we propose a gradient cell-laden multi-tissue construct combined with compositional gradient TBI-specific bioinks via 3D cell-printing technology. studies demonstrated the capability of a gradient scaffold system in zone-specific inducibility and multi-tissue formation mimicking TBI. The regenerative performance of the gradient scaffold on RC regeneration was determined using a rat RC repair model. In particular, we adopted nondestructive, consecutive, and tissue-targeted near-infrared fluorescence imaging to visualize the direct anatomical change and the intricate RC regeneration progression in real time . Furthermore, the 3D cell-printed implant promotes effective restoration of shoulder locomotion function and accelerates TBI healing . In summary, this study identifies the therapeutic contribution of cell-printed constructs towards functional RC regeneration, demonstrating the translational potential of biomimetic gradient constructs for the clinical repair of multi-tissue interfaces.
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http://dx.doi.org/10.1016/j.bioactmat.2022.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109128PMC
January 2023

Topical pH Sensing NIR Fluorophores for Intraoperative Imaging and Surgery of Disseminated Ovarian Cancer.

Adv Sci (Weinh) 2022 07 14;9(20):e2201416. Epub 2022 May 14.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Fluorescence-guided surgery (FGS) aids surgeons with real-time visualization of small cancer foci and borders, which improves surgical and prognostic efficacy of cancer. Despite the steady advances in imaging devices, there is a scarcity of fluorophores available to achieve optimal FGS. Here, 1) a pH-sensitive near-infrared fluorophore that exhibits rapid signal changes in acidic tumor microenvironments (TME) caused by the attenuation of intramolecular quenching, 2) the inherent targeting for cancer based on chemical structure (structure inherent targeting, SIT), and 3) mitochondrial and lysosomal retention are reported. After topical application of PH08 on peritoneal tumor regions in ovarian cancer-bearing mice, a rapid fluorescence increase (< 10 min), and extended preservation of signals (> 4 h post-topical application) are observed, which together allow for the visualization of submillimeter tumors with a high tumor-to-background ratio (TBR > 5.0). In addition, PH08 is preferentially transported to cancer cells via organic anion transporter peptides (OATPs) and colocalizes in the mitochondria and lysosomes due to the positive charges, enabling a long retention time during FGS. PH08 not only has a significant impact on surgical and diagnostic applications but also provides an effective and scalable strategy to design therapeutic agents for a wide array of cancers.
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http://dx.doi.org/10.1002/advs.202201416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286000PMC
July 2022

Reversal of genetic brain iron accumulation by N,N'-bis(2-mercaptoethyl)isophthalamide, a lipophilic metal chelator, in mice.

Arch Toxicol 2022 07 21;96(7):1951-1962. Epub 2022 Apr 21.

Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA, USA.

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic metal chelator and antioxidant used in mercury poisoning. Recent studies have suggested that NBMI may also bind to other metals such as lead and iron. Since NBMI can enter the brain, we evaluated if NBMI removes excess iron from the iron-loaded brain and ameliorates iron-induced oxidative stress. First, NBMI exhibited preferential binding to ferrous (Fe) iron with a negligible binding affinity to ferric (Fe) iron, indicating a selective chelation of labile iron. Second, NBMI protected SH-SY5Y human neuroblastoma cells from the cytotoxic effects of high iron. NBMI also decreased cellular labile iron and lessened the production of iron-induced reactive oxygen species in these cells. Deferiprone (DFP), a commonly used oral iron chelator, failed to prevent iron-induced cytotoxicity or labile iron accumulation. Next, we validated the efficacy of NBMI in Hfe H67D mutant mice, a mouse model of brain iron accumulation (BIA). Oral gavage of NBMI for 6 weeks decreased iron accumulation in the brain as well as liver, whereas DFP showed iron chelation only in the liver, but not in the brain. Notably, depletion of brain copper and anemia were observed in BIA mice treated with DFP, but not with NBMI, suggesting a superior safety profile of NBMI over DFP for long-term use. Collectively, our study demonstrates that NBMI provides a neuroprotective effect against BIA and has therapeutic potential for neurodegenerative diseases associated with BIA.
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http://dx.doi.org/10.1007/s00204-022-03287-1DOI Listing
July 2022

Injectable Thermosensitive Hydrogels for a Sustained Release of Iron Nanochelators.

Adv Sci (Weinh) 2022 05 27;9(15):e2200872. Epub 2022 Mar 27.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Deferoxamine (DFO) is an FDA-approved iron-chelating agent which shows good therapeutic efficacy, however, its short blood half-life presents challenges such as the need for repeated injections or continuous infusions. Considering the lifelong need of chelating agents for iron overload patients, a sustained-release formulation that can reduce the number of chelator administrations is essential. Here, injectable hydrogel formulations prepared by integrating crosslinked hyaluronic acid into Pluronic F127 for an extended release of DFO nanochelators are reported. The subcutaneously injected hydrogel shows a thermosensitive sol-gel transition at physiological body temperature and provides a prolonged release of renal clearable nanochelators over 2 weeks, resulting in a half-life 47-fold longer than that of the nanochelator alone. In addition, no chronic toxicity of the nanochelator-loaded hydrogel is confirmed by biochemical and histological analyses. This injectable hydrogel formulation with DFO nanochelators has the potential to be a promising formulation for the treatment of iron overload disorders.
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http://dx.doi.org/10.1002/advs.202200872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130884PMC
May 2022

QuatCy-I and MHI-I in Photodynamic Therapy.

ACS Med Chem Lett 2022 Mar 18;13(3):470-474. Epub 2022 Feb 18.

Department of Chemistry, Texas A&M University, Box 30012, College Station, Texas 77842, United States.

MHI-I () and QuatCy-I () were compared in terms of properties important for early-stage photodynamic therapy preclinical candidates. Thus, experiments were performed to monitor dark cytotoxicities, light/dark cytotoxicity ratios, selectivity of localization in tumors over other organs, and clearance from the plasma.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919274PMC
March 2022

Highly sensitive near-infrared SERS nanoprobes for in vivo imaging using gold-assembled silica nanoparticles with controllable nanogaps.

J Nanobiotechnology 2022 Mar 12;20(1):130. Epub 2022 Mar 12.

Department of Bioscience and Biotechnology, Konkuk University, Seoul, 05029, South Korea.

Background: To take advantages, such as multiplex capacity, non-photobleaching property, and high sensitivity, of surface-enhanced Raman scattering (SERS)-based in vivo imaging, development of highly enhanced SERS nanoprobes in near-infrared (NIR) region is needed. A well-controlled morphology and biocompatibility are essential features of NIR SERS nanoprobes. Gold (Au)-assembled nanostructures with controllable nanogaps with highly enhanced SERS signals within multiple hotspots could be a breakthrough.

Results: Au-assembled silica (SiO) nanoparticles (NPs) ([email protected]@Au NPs) as NIR SERS nanoprobes are synthesized using the seed-mediated growth method. [email protected]@Au NPs using six different sizes of Au NPs ([email protected]@[email protected]@Au) were prepared by controlling the concentration of Au precursor in the growth step. The nanogaps between Au NPs on the SiO surface could be controlled from 4.16 to 0.98 nm by adjusting the concentration of Au precursor (hence increasing Au NP sizes), which resulted in the formation of effective SERS hotspots. [email protected]@Au NPs with a 0.98-nm gap showed a high SERS enhancement factor of approximately 3.8 × 10 under 785-nm photoexcitation. [email protected]@Au nanoprobes showed detectable in vivo SERS signals at a concentration of 16 μg/mL in animal tissue specimen at a depth of 7 mm. [email protected]@Au NPs with 14 different Raman label compounds exhibited distinct SERS signals upon subcutaneous injection into nude mice.

Conclusions: [email protected]@Au NPs showed high potential for in vivo applications as multiplex nanoprobes with high SERS sensitivity in the NIR region.
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http://dx.doi.org/10.1186/s12951-022-01327-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917682PMC
March 2022

Fast and Durable Intraoperative Near-infrared Imaging of Ovarian Cancer Using Ultrabright Squaraine Fluorophores.

Angew Chem Int Ed Engl 2022 04 26;61(17):e202117330. Epub 2022 Feb 26.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The residual tumor after surgery is the most significant prognostic factor of patients with epithelial ovarian cancer. Near-infrared (NIR) fluorescence-guided surgery is actively utilized for tumor localization and complete resection during surgery. However, currently available contrast-enhancing agents display low on-target binding, unfavorable pharmacokinetics, and toxicity, thus not ideal for clinical use. Here we report ultrabright and stable squaraine fluorophores with optimal pharmacokinetics by introducing an asymmetric molecular conformation and surface charges for rapid transporter-mediated cellular uptake. Among the tested, OCTL14 shows low serum binding and rapid distribution into cancer tissue via organic cation transporters (OCTs). Additionally, the charged squaraine fluorophores are retained in lysosomes, providing durable intraoperative imaging in a preclinical murine model of ovarian cancer up to 24 h post-injection. OCTL14 represents a significant departure from the current bioconjugation approach of using a non-targeted fluorophore and would provide surgeons with an indispensable tool to achieve optimal resection.
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http://dx.doi.org/10.1002/anie.202117330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007913PMC
April 2022

Near-Infrared Fluorescence Imaging of Carotid Plaques in an Atherosclerotic Murine Model.

Biomolecules 2021 11 24;11(12). Epub 2021 Nov 24.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Successful imaging of atherosclerosis, one of the leading global causes of death, is crucial for diagnosis and intervention. Near-infrared fluorescence (NIRF) imaging has been widely adopted along with multimodal/hybrid imaging systems for plaque detection. We evaluate two macrophage-targeting fluorescent tracers for NIRF imaging (TLR4-ZW800-1C and Feraheme-Alexa Fluor 750) in an atherosclerotic murine cohort, where the left carotid artery (LCA) is ligated to cause stenosis, and the right carotid artery (RCA) is used as a control. Imaging performed on dissected tissues revealed that both tracers had high uptake in the diseased vessel compared to the control, which was readily visible even at short exposure times. In addition, ZW800-1C's renal clearance ability and Feraheme's FDA approval puts these two tracers in line with other NIRF tracers such as ICG. Continued investigation with these tracers using intravascular NIRF imaging and larger animal models is warranted for clinical translation.
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http://dx.doi.org/10.3390/biom11121753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698491PMC
November 2021

Novel Quantification of Real-Time Lymphatic Clearance: Immediate Lymphatic Reconstruction in a Large-Animal Model.

Plast Reconstr Surg 2022 Jan;149(1):130-141

From the Division of Plastic and Reconstructive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School; and Gordon Center for Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School.

Background: The real-time quantification of lymphatic flow remains elusive. Efforts to provide a metric of direct lymphatic function are not clinically translatable and lack reproducibility. Early reports demonstrate the promise of immediate lymphatic reconstruction (immediate lymphovenous bypass after lymphadenectomy) to reduce the risk of lymphedema development. However, there remains a heightened need to appraise this technique in a clinically translatable large-animal model. The aim of the authors' experiment was to evaluate the role of molecular imaging in the quantification of real-time lymphatic flow after lymphadenectomy, and lymphadenectomy with lymphovenous bypass using novel fluorophores in a swine model.

Methods: A lymphadenectomy or lymphadenectomy with subsequent lymphovenous bypass was performed in 10 female swine. After subdermal fluorophore injection, near-infrared molecular imaging of blood samples was used to evaluate change in lymphatic flow after lymphadenectomy versus after lymphadenectomy with lymphovenous bypass. Continuous imaging evaluating fluorescence of the superficial epigastric vein in the torso and adjacent skin was performed throughout all experiments. Findings between modalities were correlated.

Results: The near-infrared dye signal in central and peripheral blood samples was often difficult to separate from background and proved challenging for reliable quantification. Venous and skin near-infrared imaging demonstrated a lymphatic clearance rate decrease of 70 percent after lymphadenectomy versus a decrease by only 30 percent after lymphadenectomy with immediate lymphovenous bypass.

Conclusions: In this article, the authors describe a noninvasive, swine, large-animal model to quantify lymphatic clearance using skin imaging. The authors' findings were consistent with results yielded from real-time imaging of the vein. The authors believe this model may have important implications for eventual direct translation to the clinical setting.
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http://dx.doi.org/10.1097/PRS.0000000000008631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8691163PMC
January 2022

Tumor-Associated Immune-Cell-Mediated Tumor-Targeting Mechanism with NIR-II Fluorescence Imaging.

Adv Mater 2022 Feb 18;34(8):e2106500. Epub 2022 Jan 18.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

The strategy of structure-inherent tumor targeting (SITT) with cyanine-based fluorophores is receiving more attention because no chemical conjugation of targeting moieties is required. However, the targeting mechanism behind SITT has not yet been well explained. Here, it is demonstrated that heptamethine-cyanine-based fluorophores possess not only targetability of tumor microenvironments without the need for additional targeting ligands but also second near-infrared spectral window (NIR-II) imaging capabilities, i.e., minimum scattering and ultralow autofluorescence. The new SITT mechanism suggests that bone-marrow-derived and/or tissue-resident/tumor-associated immune cells can be a principal target for cancer detection due to their abundance in tumoral tissues. Among the tested, SH1 provides ubiquitous tumor targetability and a high tumor-to-background ratio (TBR) ranging from 9.5 to 47 in pancreatic, breast, and lung cancer mouse models upon a single bolus intravenous injection. Furthermore, SH1 can be used to detect small cancerous tissues smaller than 2 mm in diameter in orthotopic lung cancer models. Thus, SH1 could be a promising cancer-targeting agent and have a bright future for intraoperative optical imaging and image-guided cancer surgery.
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http://dx.doi.org/10.1002/adma.202106500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881361PMC
February 2022

Endogenous Stem Cell-Based In Situ Tissue Regeneration Using Electrostatically Interactive Hydrogel with a Newly Discovered Substance P Analog and VEGF-Mimicking Peptide.

Small 2021 10 4;17(40):e2103244. Epub 2021 Sep 4.

Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Korea.

The use of chemoattractants to promote endogenous stem cell-based in situ tissue regeneration has recently garnered much attention. This study is the first to assess the endogenous stem cell migration using a newly discovered substance P (SP) analog (SP1) by molecular dynamics simulations as an efficient chemoattractant. Further, a novel strategy based on electrostatic interaction using cationic chitosan (Ch) and anionic hyaluronic acid (HA) to prepare an SP1-loaded injectable C/H formulation without SP1 loss is developed. The formulation quickly forms an SP1-loaded C/H hydrogel in situ through in vivo injection. The newly discovered SP1 is found to possess human mesenchymal stromal cells (hMSCs) migration-inducing ability that is approximately two to three times higher than that of the existing SP. The designed VEGF-mimicking peptide (VP) chemically reacts with the hydrogel (C/H-VP) to sustain the release of VP, thus inducing vasculogenic differentiation of the hMSCs that migrate toward the C/H-VP hydrogel. Similarly, in animal experiments, SP1 attracts a large number of hMSCs toward the C/H-VP hydrogel, after which VP induces vasculogenic differentiation. Collectively, these findings indicate that SP1-loaded C/H-VP hydrogels are a promising strategy to facilitate endogenous stem cell-based in situ tissue regeneration.
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http://dx.doi.org/10.1002/smll.202103244DOI Listing
October 2021

Fluorescent nanodiamond - hyaluronate conjugates for target-specific molecular imaging.

RSC Adv 2021 29;11(37):23073-23081. Epub 2021 Jun 29.

Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH) 77 Cheongam-ro, Nam-gu, Pohang Gyeongbuk KR 37673 Korea +82 54 279 2399 +82 54 279 2159.

Despite wide investigation on molecular imaging contrast agents, there are still strong unmet medical needs to enhance their signal-to background ratio, brightness, photostability, and biocompatibility with multimodal imaging capability. Here, we assessed the feasibility of fluorescent nanodiamonds (FNDs) as carbon based photostable and biocompatible materials for molecular imaging applications. Because FNDs have negatively charged nitrogen vacancy (NV) centers, they can emit bright red light. FNDs were conjugated to hyaluronate (HA) for target-specific molecular imaging. HA is a biocompatible, biodegradable, and linear polysaccharide with abundant HA receptors in the liver, enabling liver targeted molecular imaging. cell viability tests revealed the biocompatibility of HA-FND conjugates and the competitive cellular uptake test confirmed their target-specific intracellular delivery to HepG2 cells with HA receptors. In addition, fluorescence lifetime (FLT) assessment revealed the imaging capability of FNDs and HA-FND conjugates. After that, we could confirm the statistically significant liver-targeted delivery of HA-FND conjugates by imaging system (IVIS) analysis and biodistribution tests in various organs. The renal clearance test and histological analysis corroborated the biocompatibility and safety of HA-FND conjugates. All these results demonstrated the feasibility of HA-FND conjugates for further molecular imaging applications.
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http://dx.doi.org/10.1039/d1ra03936aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240508PMC
June 2021

Non-invasive in vivo monitoring of transplanted stem cells in 3D-bioprinted constructs using near-infrared fluorescent imaging.

Bioeng Transl Med 2021 May 26;6(2):e10216. Epub 2021 Mar 26.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem North Carolina USA.

Cell-based tissue engineering strategies have been widely established. However, the contributions of the transplanted cells within the tissue-engineered scaffolds to the process of tissue regeneration remain poorly understood. Near-infrared (NIR) fluorescence imaging systems have great potential to non-invasively monitor the transplanted cell-based tissue constructs. In this study, labeling mesenchymal stem cells (MSCs) using a lipophilic pentamethine indocyanine (CTNF127, emission at 700 nm) as a NIR fluorophore was optimized, and the CTNF127-labeled MSCs (NIR-MSCs) were printed embedding in gelatin methacryloyl bioink. The NIR-MSCs-loaded bioink showed excellent printability. In addition, NIR-MSCs in the 3D constructs showed high cell viability and signal stability for an extended period in vitro. Finally, we were able to non-invasively monitor the NIR-MSCs in constructs after implantation in a rat calvarial bone defect model, and the transplanted cells contributed to tissue formation without specific staining. This NIR-based imaging system for non-invasive cell monitoring in vivo could play an active role in validating the cell fate in cell-based tissue engineering applications.
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http://dx.doi.org/10.1002/btm2.10216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126817PMC
May 2021

ZW800-PEG: A Renal Clearable Zwitterionic Near-Infrared Fluorophore for Potential Clinical Translation.

Angew Chem Int Ed Engl 2021 06 17;60(25):13847-13852. Epub 2021 May 17.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.

Near-infrared (NIR) fluorescence imaging has advanced medical imaging and image-guided interventions during the past three decades. Despite tremendous advances in imaging devices, surprisingly only a few dyes are currently available in the clinic. Previous fluorophores, ZW800-1A and ZW800-1C, significantly improved the poor performance of the FDA-approved indocyanine green. However, ZW800-1A is not stable in serum and ZW800-1C induces severe stacking in aqueous media. To solve such dilemmas, ZW800-PEG was designed by introducing a flexible yet stable thiol PEG linker. ZW800-PEG shows high solubility in both aqueous and organic solvents, thus improving renal clearance with minimal binding to serum proteins during systemic circulation. The sulfide group on the meso position of the heptamethine core improves serum stability and physicochemical properties including the maximum emission wavelength shift to 800 nm, enabling the use of ZW800-PEG for image-guided interventions and augmenting photothermal therapy.
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http://dx.doi.org/10.1002/anie.202102640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428668PMC
June 2021

Enhancement of Wound Healing Efficacy by Increasing the Stability and Skin-Penetrating Property of bFGF Using 30Kc19α-Based Fusion Protein.

Adv Biol (Weinh) 2021 01 4;5(1):e2000176. Epub 2021 Jan 4.

School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

The instability of recombinant basic fibroblast growth factor (bFGF) is a major disadvantage for its therapeutic use and means frequent applications to cells or tissues are required for sustained effects. Originating from silkworm hemolymph, 30Kc19α is a cell-penetrating protein that also has protein stabilization properties. Herein, it is investigated whether fusing 30Kc19α to bFGF can enhance the stability and skin penetration properties of bFGF, which may consequently increase its therapeutic efficacy. The fusion of 30Kc19α to bFGF protein increases protein stability, as confirmed by ELISA. 30Kc19α-bFGF also retains the biological activity of bFGF as it facilitates the migration and proliferation of fibroblasts and angiogenesis of endothelial cells. It is discovered that 30Kc19α can improve the transdermal delivery of a small molecular fluorophore through the skin of hairless mice. Importantly, it increases the accumulation of bFGF and further facilitates its translocation into the skin through follicular routes. Finally, when applied to a skin wound model in vivo, 30Kc19α-bFGF penetrates the dermis layer effectively, which promotes cell proliferation, tissue granulation, angiogenesis, and tissue remodeling. Consequently, the findings suggest that 30Kc19α improves the therapeutic functionalities of bFGF, and would be useful as a protein stabilizer and/or a delivery vehicle in therapeutic applications.
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http://dx.doi.org/10.1002/adbi.202000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996635PMC
January 2021

Small Molecules for Multi-Wavelength Near-Infrared Fluorescent Mapping of Regional and Sentinel Lymph Nodes in Colorectal Cancer Staging.

Front Oncol 2020 17;10:586112. Epub 2020 Dec 17.

Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.

Assessing lymph node (LN) status during tumor resection is fundamental for the staging of colorectal cancer. Current guidelines require a minimum of 12 LNs to be harvested during resection and ultra-staging regional lymph nodes by sentinel lymph node (SLN) assessment is being extensively investigated. The current study presents novel near-infrared (NIR) fluorescent dyes for simultaneous pan lymph node (PanLN; regional) and SLN mapping. PanLN-Forte was intravenously injected in mice and assessed for accumulation in regional LNs. SLN800 was injected intradermally in mice, after which the collection and retention of fluorescence in SLNs were measured using indocyanine green (ICG) and its precursor, SLN700, as references. LNs in the cervical, inguinal, jejunal, iliac, and thoracic basins could clearly be distinguished after a low dose intravenous injection of PanLN-Forte. Background fluorescence was significantly lower compared to the parent compound ZW800-3A (p < 0.001). SLN700 and SLN800 specifically targeted SLNs with fluorescence being retained over 40-fold longer than the current clinically used agent ICG. Using SLN700 and SLN800, absolute fluorescence in SLN was at least 10 times higher than ICG in second-tier nodes, even at 1 hour post-injection. Histologically, the fluorescent signal localized in the LN medulla (PanLN-Forte) or sinus entry (SLN700/SLN800). PanLN-Forte and SLN800 appear to be optimal for real-time NIR fluorescence imaging of regional and SLNs, respectively.
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http://dx.doi.org/10.3389/fonc.2020.586112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774022PMC
December 2020

3D Printing and NIR Fluorescence Imaging Techniques for the Fabrication of Implants.

Materials (Basel) 2020 Oct 28;13(21). Epub 2020 Oct 28.

Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Three-dimensional (3D) printing technology holds great potential to fabricate complex constructs in the field of regenerative medicine. Researchers in the surgical fields have used 3D printing techniques and their associated biomaterials for education, training, consultation, organ transplantation, plastic surgery, surgical planning, dentures, and more. In addition, the universal utilization of 3D printing techniques enables researchers to exploit different types of hardware and software in, for example, the surgical fields. To realize the 3D-printed structures to implant them in the body and tissue regeneration, it is important to understand 3D printing technology and its enabling technologies. This paper concisely reviews 3D printing techniques in terms of hardware, software, and materials with a focus on surgery. In addition, it reviews bioprinting technology and a non-invasive monitoring method using near-infrared (NIR) fluorescence, with special attention to the 3D-bioprinted tissue constructs. NIR fluorescence imaging applied to 3D printing technology can play a significant role in monitoring the therapeutic efficacy of 3D structures for clinical implants. Consequently, these techniques can provide individually customized products and improve the treatment outcome of surgeries.
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http://dx.doi.org/10.3390/ma13214819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662749PMC
October 2020

Ultrabright and Serum-Stable Squaraine Dyes.

J Med Chem 2020 09 19;63(17):9436-9445. Epub 2020 Aug 19.

Department of Chemistry, Georgia State University, 145 Piedmont Avenue SE, Atlanta, Georgia 30303, United States.

Highly stable symmetric and asymmetric squaraine fluorophores have been synthesized featuring an internal salt bridge between a quaternary ammonium cation and the central oxycyclobutenolate ring of the chromophore. Some of our newly synthesized symmetric and asymmetric compounds display increased molar absorptivity, quantum yield in serum, and thermal/photochemical stability over previously reported squaraine-based dyes. Consequently, both classes show great promise in resurfacing the normal environment-labile squaraine dyes as novel imaging agents and scaffolds for fluorescence sensing. Furthermore, incorporating a covalent attachment point away from the conjugated system allows for biological tagging applications without disturbing the optimum optical characteristics of the newly designed fluorophore.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428814PMC
September 2020

NIR fluorescence for monitoring in vivo scaffold degradation along with stem cell tracking in bone tissue engineering.

Biomaterials 2020 11 6;258:120267. Epub 2020 Aug 6.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. Electronic address:

Stem cell-based tissue engineering has the potential to use as an alternative for autologous tissue grafts; however, the contribution of the scaffold degradation along with the transplanted stem cells to in vivo tissue regeneration remains poorly understood. Near-infrared (NIR) fluorescence imaging has great potential to monitor implants while avoiding autofluorescence from the adjacent host tissue. To utilize NIR imaging for in vivo monitoring of scaffold degradation and cell tracking, we synthesized 800-nm emitting NIR-conjugated PCL-ran-PLLA-ran-PGA (ZW-PCLG) copolymers with three different degradation rates and labeled 700-nm emitting lipophilic pentamethine (CTNF127) on the human placental stem cells (CT-PSCs). The 3D bioprinted hybrid constructs containing the CT-PSC-laden hydrogel together with the ZW-PCLG scaffolds demonstrate that NIR fluorescent imaging enables tracking of in vivo scaffold degradation and stem cell fate for bone regeneration in a rat calvarial bone defect model. This NIR-based monitoring system can be effectively utilized to study cell-based tissue engineering applications.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484145PMC
November 2020

In Vivo Imaging of Click-Crosslinked Hydrogel Depots Following Intratympanic Injection.

Materials (Basel) 2020 Jul 9;13(14). Epub 2020 Jul 9.

Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea.

In this study, we developed injectable intratympanic hyaluronic acid (HA) depots for the treatment of hearing loss. We prepared an injectable click-crosslinking formulation by modifying HA with tetrazine (HA-TET) and trans-cyclooctene (HA-TCO), which crosslinked to form an HA depot (Cx-HA). Preparation of the click-crosslinking HA formulation was facile, and Cx-HA depot formation was reproducible. Additionally, the Cx-HA hydrogel was significantly stiffer than HA hydrogel. To monitor the degradation pattern of hydrogels, we mixed a zwitterionic near-infrared (NIR) fluorophore (e.g., ZW800-1C) in the click-crosslinking HA formulation. Then, HA-TET and HA-TCO solutions containing ZW800-1C were loaded separately into the compartments of a dual-barrel syringe for intratympanic injection. The Cx-HA depots formed quickly, and an extended residence time in the tympanic cavity was confirmed by performing NIR fluorescence imaging. We have successfully prepared an injectable click-crosslinking HA formulation that has promise as an intratympanic drug depot.
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http://dx.doi.org/10.3390/ma13143070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412526PMC
July 2020

Near-infrared fluorescence imaging in immunotherapy.

Adv Drug Deliv Rev 2020 12 21;167:121-134. Epub 2020 Jun 21.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Near-infrared (NIR) light possesses many suitable optophysical properties for medical imaging including low autofluorescence, deep tissue penetration, and minimal light scattering, which together allow for high-resolution imaging of biological tissue. NIR imaging has proven to be a noninvasive and effective real-time imaging methodology that provides a high signal-to-background ratio compared to other potential optical imaging modalities. In response to this, the use of NIR imaging has been extensively explored in the field of immunotherapy. To date, NIR fluorescence imaging has successfully offered reliable monitoring of the localization, dynamics, and function of immune responses, which are vital in assessing not only the efficacy but also the safety of treatments to design immunotherapies optimally. This review aims to provide an overview of the current research on NIR imaging of the immune response. We expect that the use of NIR imaging will expand further in response to the recent success in cancer immunotherapy. We will also offer our insights on how this technology will meet rapidly growing expectations in the future.
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http://dx.doi.org/10.1016/j.addr.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450770PMC
December 2020

Facile formulation of a long-wavelength cyanine for optical imaging in the second near-infrared window.

Biomater Sci 2020 Aug 9;8(15):4199-4205. Epub 2020 Jun 9.

Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.

The second near-infrared window (NIR-II) beyond 1000 nm has attracted attention for optical contrast imaging in small animals. We sought to assess whether commercially available NIR-II dyes could be easily formulated for this purpose. 13 hydrophobic NIR-II dyes were purchased and screened by formulating them in simple solubilizing agents with established use in humans: propylene glycol, Cremaphor EL, Kolliphor HS15 (HS15), Tween 80, and cyclodextrin. Based on the absorption at 1064 nm (matching the Nd:YAG laser output commonly used in photoacoustic imaging), three of the dyes were further assessed at varying dye and surfactant concentrations. Of these, benzo indole butyl diphenylaminocyclopentene heptamethine (BIBDAH) tetrafluoroborate in HS15 generally showed the most favorable NIR-II character. 1 mg mL BIBDAH in 25% HS15 exhibited a single absorption peak at 1030 nm with a calculated intensity greater than 100, which was relatively stable for weeks in storage. Following intravenous administration to mice, determination of BIBDAH pharmacokinetics was possible by absorption measurements of sampled plasma, revealing a circulating half-life of about one hour. Most of the dye was taken up by the liver. BIBDAH was used in vitro and in vivo as a photoacoustic contrast imaging agent and its accumulation could be detected in subcutaneous tumors in mice. BIBDAH was used for fluorescence imaging of blood vessels in mice, including in the brain (through intact skull), and dye clearance from blood to the liver was visualized. Taken together, this study confirms that accessible, strongly-absorbing dye can readily be formulated for injection by simply dissolving them in biocompatible surfactants and used for high-contrast preclinical optical imaging in the second NIR window.
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http://dx.doi.org/10.1039/d0bm00572jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390685PMC
August 2020

Combating iron overload: a case for deferoxamine-based nanochelators.

Nanomedicine (Lond) 2020 May 20. Epub 2020 May 20.

Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115, USA.

While iron is a nutrient metal, iron overload can result in multiple organ failures. Iron chelators, such as deferoxamine, are commonly used to ameliorate iron overload conditions. However, their uses are limited due to poor pharmacokinetics and adverse effects. Many novel chelator formulations have been developed to overcome these drawbacks. In this review, we have discussed various nanochelators, including linear and branched polymers, dendrimers, polyrotaxane, micelles, nanogels, polymeric nanoparticles and liposomes. Although these research efforts have mainly been focused on nanochelators with longer half-lives, prolonged residence of polymers in the body could raise potential safety issues. We also discussed recent advances in nanochelation technologies, including mechanism-based, long-acting nanochelators.
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http://dx.doi.org/10.2217/nnm-2020-0038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304435PMC
May 2020

Chemical Modulation of Bioengineered Exosomes for Tissue-Specific Biodistribution.

Adv Ther (Weinh) 2019 Nov 13;2(11). Epub 2019 Sep 13.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

The physicochemical properties of nanomaterials play a key role in tissue-specific targeting by reducing nonspecific background uptake as well as controlling biodistribution and clearance. Due to the strong influence of surface chemistry, chemical modulation of bioinert exosomes with chargeable and traceable small molecule fluorophores has a significant effect on the targeting, stability, and toxicity of the final conjugates. In this study, charge-variable exosomes are designed by conjugating their surface proteins with near-infrared fluorophores to control the in vivo fate of exosomes. Interestingly, zwitterionic fluorophore-labeled exosomes show rapid renal clearance with minimum to none nonspecific tissue uptake, whereas anionic exosomes are excreted through the hepatobiliary route with high uptake in the liver. The biodistribution and pharmacokinetics of exosome conjugates are comparable to their corresponding free fluorophores, demonstrating that the surface characteristics govern the fate of final conjugates in the living organism. Such unique surface properties of chemically modulated exosomes are confirmed in the lymphatic system after intradermal administration, which results in distinctive kinetic profiles in the secondary lymphoid tissues. This finding can subsequently serve as the foundation for developing tissue-specific exosome-based therapeutics.
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http://dx.doi.org/10.1002/adtp.201900111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172497PMC
November 2019

Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors.

iScience 2020 Apr 25;23(4):101006. Epub 2020 Mar 25.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Design of tissue-specific contrast agents to delineate tumors from background tissues is a major unmet clinical need for ultimate surgical interventions. Bioconjugation of fluorophore(s) to a ligand has been mainly used to target overexpressed receptors on tumors. However, the size of the final targeted ligand can be large, >20 kDa, and cannot readily cross the microvasculature to meet the specific tissue, resulting in low targetability with a high background. Here, we report a small and hydrophilic phenoxazine with high targetability and retention to pancreatic neuroendocrine tumor. This bioengineered fluorophore permits sensitive detection of ultrasmall (<0.5 mm) ectopic tumors within a few seconds after a single bolus injection, highlighting every tumor in the pancreas from the surrounding healthy tissues with reasonable half-life. The knowledge-based approach and validation used to develop structure-inherent tumor-targeted fluorophores have a tremendous potential to improve treatment outcome by providing definite tumor margins for image-guided surgery.
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http://dx.doi.org/10.1016/j.isci.2020.101006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139119PMC
April 2020
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