Publications by authors named "Mingfeng Bai"

48 Publications

Simultaneous exposure to intracellular and extracellular photosensitizers for the treatment of infections.

Antimicrob Agents Chemother 2021 Sep 13:AAC0091921. Epub 2021 Sep 13.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are underway to develop therapies that target essential biological processes in . Antimicrobial photodynamic therapy is effective alternative to antibiotics, therefore we developed an approach to simultaneously expose to intracellular and extracellular photoactivators. A near infrared photosensitizer was conjugated to human monoclonal antibodies (mAbs) that target the Isd heme acquisition proteins. Additionally, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial PDT treatment of drug-resistant exposed to VU0038882 and conjugated anti-Isd mAbs proved to be an effective antibacterial strategy and in a murine model of SSTIs.
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http://dx.doi.org/10.1128/AAC.00919-21DOI Listing
September 2021

Photosensitizer IR700DX-6T- and IR700DX-mbc94-mediated photodynamic therapy markedly elicits anticancer immune responses during treatment of pancreatic cancer.

Pharmacol Res 2021 Oct 12;172:105811. Epub 2021 Aug 12.

Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Background/aims: IR700DX-6T and IR700DX-mbc94 are two chemically synthesized photosensitizers (PSs) that target the translocator protein (TSPO) and type 2 cannabinoid receptor (CBR), respectively, for photodynamic therapy (PDT) of cancer. Recently, we found that IR700DX-6T and IR700DX-mbc94 exhibited high selectivity and efficiency in PDT for breast cancer and malignant astrocytoma. Yet, the phototherapeutic effects of the PSs on pancreatic cancer and underlying mechanisms remain unknown. This study investigated the effect of IR700DX-6T- or IR700DX-mbc94-PDT on pancreatic cancer and whether the treatment involves eliciting anticancer immune responses in support of superior therapeutic efficacy.

Methods: Four pancreatic cancer cell lines were used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies regarding the therapeutic effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT on pancreatic cancer. The immunostimulatory or immunosuppressive effects of IR700DX-6T-PDT and IR700DX-mbc94-PDT were examined by detecting CD8 T cells, regulatory T cells (T), and dendritic cells (DCs) using flow cytometry and immunohistochemistry (IHC).

Results: TSPO and CBR were markedly upregulated in pancreatic cancer cells and tissues. Both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. Notably, assessment of anticancer immune responses revealed that both IR700DX-6T-PDT and IR700DX-mbc94-PDT significantly induced CD8 T cells, promoted maturation of DCs, and suppressed T, with stronger effects exerted by IR700DX-6T-PDT compared to IR700DX-mbc94-PDT.

Conclusions: IR700DX-6T-PDT and IR700DX-mbc94-PDT involves eliciting anticancer immune responses. Our study has also implicated that PDT in combination with immunotherapy holds promise to improve therapeutic efficacy for patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.phrs.2021.105811DOI Listing
October 2021

Translocator protein-targeted photodynamic therapy for direct and abscopal immunogenic cell death in colorectal cancer.

Acta Biomater 2021 Jul 27. Epub 2021 Jul 27.

Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we induced ICD in colorectal cancer (CRC) cell lines in vitro and in vivo by targeting the 18 kDa translocator protein (TSPO), a mitochondrial receptor overexpressed in CRC. Photodynamic therapy (PDT) using a TSPO-targeted photosensitizer, IR700DX-6T, caused effective apoptotic cell death in fourteen CRC cell lines. In a syngeneic immunocompetent CRC mouse model, the growth of tumors subjected to TSPO-PDT was greatly suppressed. Remarkably, untreated tumors in the opposing flank also showed marked growth suppression. Dendritic and CD8 T cells were activated after TSPO-PDT treatment, accompanied by decreased Treg cells in both treated and non-treated tumors. In addition, a cancer vaccine developed from TSPO-PDT produced a significant tumor inhibition effect. These results indicate that TSPO-PDT could not only directly suppress tumor growth but also dramatically provoke host anti-tumor immunity, highlighting the potential of TSPO-PDT as a successful therapeutic for CRC that exhibits systemic effects. STATEMENT OF SIGNIFICANCE: Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we report a new therapeutic approach that can reduce the growth of multiple CRC cell lines by inducing ICD. Notably, a direct and abscopal effect was observed in mouse tumor-derived MC38 cells when injected into syngeneic immunocompetent mice. If comparable effects could be achieved in humans, it would establish a novel paradigm for treating micro- and macro-metastasis.
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http://dx.doi.org/10.1016/j.actbio.2021.07.052DOI Listing
July 2021

Translocator protein (TSPO)-Targeted agents for photodynamic therapy of cancer.

Photodiagnosis Photodyn Ther 2021 Jun 6;34:102209. Epub 2021 Feb 6.

Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN, 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. Electronic address:

Photodynamic therapy (PDT) is a clinically approved therapeutic strategy that combines a specific wavelength of light and light-activated photosensitizers (PSs). The usage of PDT for cancer treatment is often hampered by the lack of tumor selectivity of PSs, which may cause photodamage to surrounding normal tissues. Recently, translocator protein (TSPO) has attracted great interest as a tumor biomarker, whose expression correlates with tumor aggressiveness. In this study, we report the development of a series of novel TSPO-PSs based on quinazoline, pyrazolopyrimidine, and tetrahydrocarbazole structures. These TSPO-PSs bind to TSPO with nanomolar affinities and demonstrated efficient and target-specific PDT effect upon light irradiation. Therefore, they may have great potential in the treatment of tumors associated with high-TSPO expression.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102209DOI Listing
June 2021

Novel TSPO-targeted Doxorubicin Prodrug for Colorectal Carcinoma Cells.

Anticancer Res 2020 Oct;40(10):5371-5378

Interventional Oncology Translational Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.

Background/aim: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability.

Materials And Methods: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay.

Results: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h.

Conclusion: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.
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http://dx.doi.org/10.21873/anticanres.14545DOI Listing
October 2020

TSPO-targeted PET and Optical Probes for the Detection and Localization of Premalignant and Malignant Pancreatic Lesions.

Clin Cancer Res 2020 11 15;26(22):5914-5925. Epub 2020 Sep 15.

Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, Tennessee.

Purpose: Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic "incidentalomas," particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions.

Experimental Design: Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. imaging was performed with [F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated.

Results: TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS.

Conclusions: We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669725PMC
November 2020

Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)--(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors.

J Med Chem 2019 07 28;62(13):6083-6101. Epub 2019 Jun 28.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science , Chinese Academy of Sciences , Hefei , Anhui 230031 , China.

Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00280DOI Listing
July 2019

Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors.

Ther Adv Med Oncol 2019 17;11:1758835919849757. Epub 2019 May 17.

High Magnetic Field Laboratory, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.

Background: cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells.

Methods: The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib.

Results: Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants and GIST preclinical models.

Conclusion: Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.
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http://dx.doi.org/10.1177/1758835919849757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535728PMC
May 2019

Discovery of ( E)- N-(3-Fluorophenyl)- N-(3-(2-(pyridin-2-yl)vinyl)-1 H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs).

J Med Chem 2019 05 14;62(10):5006-5024. Epub 2019 May 14.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology , Hefei Institutes of Physical Science, Chinese Academy of Sciences , Hefei , Anhui 230031 , P. R. China.

Gain-of-function mutations of c-KIT kinase play crucial pathological roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiological functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT wt. Compound 24 displays good antiproliferative effects against c-KIT T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theoretically can render a better therapeutic window.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00176DOI Listing
May 2019

Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models.

Cancer Lett 2019 04 24;447:105-114. Epub 2019 Jan 24.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China. Electronic address:

Despite of the great success of imatinib as the first-line treatment for GISTs, the majority of patients will develop drug-acquired resistance due to secondary mutations in the cKIT kinase. Sunitinib and regorafenib have been approved as the second and third line therapies to overcome some of these drug-resistance mutations; however, their limited clinical response, toxicity and resistance of the activation loop mutants still makes new therapies bearing different cKIT mutants activity spectrum profile highly demanded. Through a drug repositioning approach, we found that cabozantinib exhibited higher potency than imatinib against primary gain-of-function mutations of cKIT. Moreover, cabozantinib was able to overcome cKIT gatekeeper T670I mutation and the activation loop mutations that are resistant to imatinib or sunitinib. Cabozantinib demonstrated good efficacy in vitro and in vivo in the cKIT mutant-driven preclinical models of GISTs while displaying a long-lasting effect after treatment withdrawal. Furthermore, it also exhibited dose-dependent anti-proliferative efficacy in the GIST patient derived primary cells. Considering clinical safety and PK profile of cabozantinib, this report provides the basis for the future clinical applications of cabozantinib as an alternative anti-GISTs therapy in precision medicine.
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http://dx.doi.org/10.1016/j.canlet.2019.01.024DOI Listing
April 2019

Light-activatable cannabinoid prodrug for combined and target-specific photodynamic and cannabinoid therapy.

J Biomed Opt 2018 10;23(10):1-9

University of Pittsburgh, Department of Radiology, Pittsburgh, Pennsylvania, United States.

Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers. Upon the 690-nm light irradiation, the PS produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. We found that this unique multifunctional prodrug design offered dramatically improved therapeutic efficacy, and therefore provided a new strategy for targeted, controlled, and effective antitumor cannabinoid therapy.
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http://dx.doi.org/10.1117/1.JBO.23.10.108001DOI Listing
October 2018

Photostable, hydrophilic, and near infrared quaterrylene-based dyes for photoacoustic imaging.

Mater Sci Eng C Mater Biol Appl 2018 Dec 5;93:1012-1019. Epub 2018 Sep 5.

Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine & Heart and Vascular Institute, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh and UPMC, Pittsburgh, PA 15219, USA. Electronic address:

Novel near-infrared contrast agents based on the quaterrylene structure were strategically developed and tested for high photo-stability. Both a dendrimeric quaterrylene molecule, QR-G2-COOH, and a small molecule cationic quaterrylene dye, QR-4PyC4, remain optically stable and continue to generate a competitive photoacoustic response when irradiated by short near-infrared laser pulses for a relatively long time in an in-vitro cell study, unlike indocyanine green that rapidly decreases photoacoustic signal amplitude. The small molecule dye, QR-4PyC4 exhibits not only significantly higher cellular uptake rate than QR-G2-COOH and indocyanine green, but also low toxicity at a concentration of up to 10 μM. The dendrimeric dye, QR-G2-COOH that has surface functional groups available for conjugation with targeting and therapeutic agents shows the highest photoacoustic amplitude with high optical stability. Therefore, QR-4PyC4 can be a promising universal, sensitive and reliable photoacoustic contrast agent and QR-G2-COOH has great potential as a nano-platform with stable photoacoustic imaging capability.
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http://dx.doi.org/10.1016/j.msec.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172961PMC
December 2018

Combined CB2 receptor agonist and photodynamic therapy synergistically inhibit tumor growth in triple negative breast cancer.

Photodiagnosis Photodyn Ther 2018 Dec 18;24:185-191. Epub 2018 Sep 18.

Department of Radiology, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA, 15219, USA; Department of Medicine, University of Pittsburgh, 3501 Fifth Ave, Pittsburgh, PA, 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA. Electronic address:

Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CBR agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CBR agonists for cancer.
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http://dx.doi.org/10.1016/j.pdpdt.2018.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289793PMC
December 2018

Molecular Imaging of Pancreatic Duct Adenocarcinoma Using a Type 2 Cannabinoid Receptor-Targeted Near-Infrared Fluorescent Probe.

Transl Oncol 2018 Oct 9;11(5):1065-1073. Epub 2018 Jul 9.

Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address:

Imaging probes targeting type 2 cannabinoid receptor (CBR) overexpressed in pancreatic duct adenocarcinoma (PDAC) tissue have the potential to improve early detection and surgical outcome of PDAC. The aim of our study was to evaluate the molecular imaging potential of a CBR-targeted near-infrared (NIR) fluorescent probe (NIR760-XLP6) for PDAC. CBR overexpression was observed in both PDAC patient tissues and various pancreatic cancer cell lines. In vitro fluorescence imaging indicated specific binding of NIR760-XLP6 to CBR in human PDAC PANC-1 cells. In a xenograft mouse tumor model, NIR760-XLP6 showed remarkable 50- (ex vivo) and 3.2-fold (in vivo) tumor to normal contrast enhancement with minimal liver and kidney uptake. In a PDAC lymph node metastasis model, significant signal contrast was observed in bilateral axillary lymph nodes with PDAC metastasis after injection of the probe. In conclusion, NIR760-XLP6 exhibits promising characteristics for imaging PDAC, and CBR appears to be an attractive target for PDAC imaging.
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http://dx.doi.org/10.1016/j.tranon.2018.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043890PMC
October 2018

Mechanistic insight into the interaction of gastrointestinal mucus with oral diblock copolymers synthesized via ATRP method.

Int J Nanomedicine 2018 15;13:2839-2856. Epub 2018 May 15.

Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, China.

Introduction: Nanoparticles are increasingly used as drug carriers for oral administration. The delivery of drug molecules is largely dependent on the interaction of nanocarriers and gastrointestinal (GI) mucus, a critical barrier that regulates drug absorption. It is therefore important to understand the effects of physical and chemical properties of nanocarriers on the interaction with GI mucus. Unfortunately, most of the nanoparticles are unable to be prepared with satisfactory structural monodispersity to comprehensively investigate the interaction. With controlled size, shape, and surface chemistry, copolymers are ideal candidates for such purpose.

Materials And Methods: We synthesized a series of diblock copolymers via the atom transfer radical polymerization method and investigated the GI mucus permeability in vitro and in vivo.

Results: Our results indicated that uncharged and hydrophobic copolymers exhibited enhanced GI absorption.

Conclusion: These results provide insights into developing optimal nanocarriers for oral administration.
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http://dx.doi.org/10.2147/IJN.S160651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960240PMC
June 2018

Synthesis and Evaluation of a Tetra[6,7]quinoxalinoporphyrazine-based Near Infrared Photosensitizer.

RSC Adv 2017 30;7(80):50555-50561. Epub 2017 Oct 30.

Department of Radiology, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA.

Here we report a near infrared, water-soluble, functional and dendrimeric photosensitizer (PS) based on quinoxalinoporphyrazine structure. The photophysical properties and photodynamic therapy results suggest that this quinoxalinoporphyrazine-based dendrimer may serve as an efficient near infrared (NIR) PS platform.
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http://dx.doi.org/10.1039/C7RA06348BDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810975PMC
October 2017

Multilayer photodynamic therapy for highly effective and safe cancer treatment.

Acta Biomater 2017 05 9;54:271-280. Epub 2017 Mar 9.

Department of Radiology, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA; Department of Medicine, University of Pittsburgh, 3501 Fifth Ave, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. Electronic address:

Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CBR-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CBR- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects.

Statement Of Significance: Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.
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http://dx.doi.org/10.1016/j.actbio.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415343PMC
May 2017

Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.

J Med Chem 2016 09 30;59(18):8456-72. Epub 2016 Aug 30.

High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.

cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00902DOI Listing
September 2016

Tumor mitochondria-targeted photodynamic therapy with a translocator protein (TSPO)-specific photosensitizer.

Acta Biomater 2015 Dec 30;28:160-170. Epub 2015 Sep 30.

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15219, USA.

Unlabelled: Photodynamic therapy (PDT) has been proven to be a minimally invasive and effective therapeutic strategy for cancer treatment. It can be used alone or as a complement to conventional cancer treatments, such as surgical debulking and chemotherapy. The mitochondrion is an attractive target for developing novel PDT agents, as it produces energy for cells and regulates apoptosis. Current strategy of mitochondria targeting is mainly focused on utilizing cationic photosensitizers that bind to the negatively charged mitochondria membrane. However, such an approach is lack of selectivity of tumor cells. To minimize the damage on healthy tissues and improve therapeutic efficacy, an alternative targeting strategy with high tumor specificity is in critical need. Herein, we report a tumor mitochondria-specific PDT agent, IR700DX-6T, which targets the 18kDa mitochondrial translocator protein (TSPO). IR700DX-6T induced apoptotic cell death in TSPO-positive breast cancer cells (MDA-MB-231) but not TSPO-negative breast cancer cells (MCF-7). In vivo PDT study suggested that IR700DX-6T-mediated PDT significantly inhibited the growth of MDA-MB-231 tumors in a target-specific manner. These combined data suggest that this new TSPO-targeted photosensitizer has great potential in cancer treatment.

Statement Of Significance: Photodynamic therapy (PDT) is an effective and minimally invasive therapeutic technique for treating cancers. Mitochondrion is an attractive target for developing novel PDT agents, as it produces energy to cells and regulates apoptosis. Current mitochondria targeted photosensitizers (PSs) are based on cationic molecules, which interact with the negatively charged mitochondria membrane. However, such PSs are not specific for cancerous cells, which may result in unwanted side effects. In this study, we developed a tumor mitochondria-targeted PS, IR700DX-6T, which binds to translocator protein (TSPO). This agent effectively induced apoptosis in TSPO-positive cancer cells and significantly inhibited tumor growth in TSPO-positive tumor-bearing mice. These combined data suggest that IR700DX-6T could become a powerful tool in the treatment of multiple cancers that upregulate TSPO.
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http://dx.doi.org/10.1016/j.actbio.2015.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648641PMC
December 2015

Synthesis of a reactive oxygen species responsive heterobifunctional thioketal linker.

Tetrahedron Lett 2015 Sep;56(37):5242-5244

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15219, USA.

A new heterobifunctional reactive oxygen species (ROS) responsive thioketal linker and its synthesis are described. This linker allows for developing new ROS-responsive agents with two distinct functionalities using universal bioconjugation methods. The reaction kinetics of the thioketal cleavage in the presence of ROS is also described.
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http://dx.doi.org/10.1016/j.tetlet.2015.07.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545510PMC
September 2015

In vivo inflammation imaging using a CB2R-targeted near infrared fluorescent probe.

Am J Nucl Med Mol Imaging 2015 15;5(3):246-58. Epub 2015 Feb 15.

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh Pittsburgh, PA 15219, USA ; Department of Bioengineering, University of Pittsburgh Pittsburgh, PA 15261, USA ; University of Pittsburgh Cancer Institute Pittsburgh, PA 15232, USA.

Chronic inflammation is considered as a critical cause of a host of disorders, such as cancer, rheumatoid arthritis, atherosclerosis, and neurodegenerative diseases, although the exact mechanism is yet to be explored. Imaging tools that can specifically target inflammation are therefore important to help reveal the role of inflammation in disease progression, and allows for developing new therapeutic strategies to ultimately improve patient care. The purpose of this study was to develop a new in vivo inflammation imaging approach by targeting the cannabinoid receptor type 2 (CB2R), an emerging inflammation biomarker, using a unique near infrared (NIR) fluorescent probe. Herein, we report the first in vivo CB2R-targeted NIR inflammation imaging study using a synthetic fluorescent probe developed in our laboratory, NIR760-mbc94. In vitro binding assay and fluorescence microscopy study indicate NIR760-mbc94 specifically binds towards CB2R in mouse RAW264.7 macrophage cells. Furthermore, in vivo imaging was performed using a Complete Freund's Adjuvant (CFA)-induced inflammation mouse model. NIR760-mbc94 successfully identified inflamed tissues and the probe uptake was blocked by a CB2R ligand, SR144528. Additionally, immunofluorescence staining in cryosectioned tissues validated the NIR760-mbc94 uptake in inflamed tissues. In conclusion, this study reports the first in vivo CB2R-targeted inflammation imaging using an NIR fluorescent probe. Specific targeting of NIR760-mbc94 has been demonstrated in macrophage cells, as well as a CFA-induced inflammation mouse model. The combined evidence indicates that NIR760-mbc94 is a promising inflammation imaging probe. Moreover, in vivo CB2R-targeted fluorescence imaging may have potential in the study of inflammation-related diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446393PMC
June 2015

A novel near-infrared fluorescence imaging probe that preferentially binds to cannabinoid receptors CB2R over CB1R.

Biomaterials 2015 Jul 28;57:169-78. Epub 2015 Apr 28.

Department of Radiology, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. Electronic address:

The type 2 cannabinoid receptors (CB2R) have gained much attention recently due to their important regulatory role in a host of pathophysiological processes. However, the exact biological function of CB2R and how this function might change depending on disease progression remains unclear and could be better studied with highly sensitive and selective imaging tools for identifying the receptors. Here we report the first near infrared fluorescence imaging probe (NIR760-XLP6) that binds preferentially to CB2R over the type 1 cannabinoid receptors (CB1R). The selectivity of the probe was demonstrated by fluorescence microscopy using DBT-CB2 and DBT-CB1 cells. Furthermore, in mouse tumor models, NIR760-XLP6 showed significantly higher uptake in DBT-CB2 than that in DBT-CB1 tumors. These findings indicate that NIR760-XLP6 is a promising imaging tool for the study of CB2R regulation.
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http://dx.doi.org/10.1016/j.biomaterials.2015.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426855PMC
July 2015

Phosphorescence monitoring of hypoxic microenvironment in solid-tumors to evaluate chemotherapeutic effects using the hypoxia-sensitive iridium (III) coordination compound.

PLoS One 2015 18;10(3):e0121293. Epub 2015 Mar 18.

The Key Laboratory of Biomedical Information Engineering, Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China.

Objectives: To utilize phosphorescence to monitor hypoxic microenvironment in solid-tumors and investigate cancer chemotherapeutic effects in vivo.

Methods: A hypoxia-sensitive probe named BTP was used to monitor hypoxic microenvironment in solid-tumors. The low-dose metronomic treatment with cisplatin was used in anti-angiogenetic chemotherapeutic programs. The phosphorescence properties of BTP were detected by a spectrofluorometer. BTP cytotoxicity utilized cell necrosis and apoptosis, which were evaluated by trypan blue dye exclusion and Hoechst33342 plus propidium iodide assays. Tumor-bearing mouse models of colon adenocarcinoma were used for tumor imaging in vivo. Monitoring of the hypoxic microenvironment in tumors was performed with a Maestro 2 fluorescence imaging system. Tumor tissues in each group were harvested regularly and treated with pathological hematoxylin and eosin and immunohistochemical staining to confirm imaging results.

Results: BTP did not feature obvious cytotoxicity for cells, and tumor growth in low-dose metronomic cisplatin treated mice was significantly inhibited by chemotherapy. Hypoxic levels significantly increased due to cisplatin, as proven by the expression level of related proteins. Phosphorescence intensity in the tumors of mice in the cisplatin group was stronger and showed higher contrast than that in tumors of saline treated mice.

Conclusions: We develop a useful phosphorescence method to evaluate the chemotherapeutic effects of cisplatin. The proposed method shows potential as a phosphorescence imaging approach for evaluating chemotherapeutic effects in vivo, especially anti-angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121293PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365010PMC
February 2016

Antibody-functionalized peptidic membranes for neutralization of allogeneic skin antigen-presenting cells.

Acta Biomater 2014 Nov 10;10(11):4759-4767. Epub 2014 Aug 10.

Division of Pharmaceutical Sciences, Duquesne University, PA, USA. Electronic address:

We report herein application of an in situ material strategy to attenuate allograft T cell responses in a skin transplant mouse model. Functionalized peptidic membranes were used to impede trafficking of donor antigen-presenting cells (dAPCs) from skin allografts in recipient mice. Membranes formed by self-assembling peptides (SAPs) presenting antibodies were found to remain underneath grafted skins for up to 6 days. At the host-graft interface, dAPCs were targeted by using a monoclonal antibody that binds to a class II major histocompatibility complex (MHC) molecule (I-A(d)) expressed exclusively by donor cells. Using a novel cell labeling near-infrared nanoemulsion, we found more dAPCs remained in allografts treated with membranes loaded with anti-I-A(d) antibodies than without. In vitro, dAPCs released from skin explants were found adsorbed preferentially on anti-I-A(d) antibody-loaded membranes. Recipient T cells from these mice produced lower concentrations of interferon-gamma cultured ex vivo with donor cells. Taken together, the data indicate that the strategy has the potential to alter the natural course of rejection immune mechanisms in allogeneic transplant models.
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http://dx.doi.org/10.1016/j.actbio.2014.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186902PMC
November 2014

Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe.

J Biomed Opt 2014 ;19(7):76016

University of Pittsburgh, Molecular Imaging Laboratory, Department of Radiology, Pittsburgh, Pennsylvania 15219dUniversity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, United StateseUniversity of Pittsburgh, Department of Bioengineering.

Cannabinoid CB2 receptors (CB2R) hold promise as therapeutic targets for treating diverse diseases, such as cancers, neurodegenerative diseases, pain, inflammation, osteoporosis, psychiatric disorders, addiction, and immune disorders. However, the fundamental role of CB2R in the regulation of diseases remains unclear, largely due to a lack of reliable imaging tools for the receptors. The goal of this study was to develop a CB2R-targeted molecular imaging probe and evaluate the specificity of the probe using human tumor cells that naturally overexpress CB2R. To synthesize the CB2R-targeted probe (NIR760-Q), a conjugable CB2R ligand based on the quinolone structure was first prepared, followed by bioconjugation with a near-infrared (NIR) fluorescent dye, NIR760. In vitro fluorescence imaging and competitive binding studies showed higher uptake of NIR760-Q than free NIR760 dye in Jurkat human acute T-lymphoblastic leukemia cells. In addition, the high uptake of NIR760-Q was significantly inhibited by the blocking agent, 4-quinolone-3-carboxamide, indicating specific binding of NIR760-Q to the target receptors. These results indicate that the NIR760-Q has potential in diagnostic imaging of CB2R positive cancers and elucidating the role of CB2R in the regulation of disease progression.
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http://dx.doi.org/10.1117/1.JBO.19.7.076016DOI Listing
February 2015

Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth.

Mol Pharm 2014 Jun 8;11(6):1919-29. Epub 2014 May 8.

Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University , Shanghai 200438, P. R. China.

The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment. IR700DX-mbc94 was prepared by conjugating a photosensitizer, IR700DX, to mbc94, whose binding specificity to CB2R has been previously demonstrated. We found that phototherapy treatment using IR700DX-mbc94 greatly inhibited the growth of CB2R positive tumors but not CB2R negative tumors. In addition, phototherapy treatment with nontargeted IR700DX did not show significant therapeutic effect. Similarly, treatment with IR700DX-mbc94 without light irradiation or light irradiation without the photosensitizer showed no tumor-inhibitory effect. Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment.
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http://dx.doi.org/10.1021/mp5001923DOI Listing
June 2014

Synthesis and optical properties of water-soluble biperylene-based dendrimers.

Chem Commun (Camb) 2014 May;50(42):5648-51

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15219, USA.

We report the synthesis and photophysical properties of three biperylene-based dendrimers, which show red fluorescence in water. A fluorescence microscopy study demonstrated uptake of biperylene-based dendrimers in living cells. Our results indicate that these biperylene-based dendrimers are promising candidates in fluorescence imaging applications with the potential as therapeutic carriers.
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http://dx.doi.org/10.1039/c4cc01742kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037920PMC
May 2014

Perfluorocarbon nanoemulsions with fluorescent, colloidal and magnetic properties.

Biomaterials 2014 Jun 25;35(18):4958-68. Epub 2014 Mar 25.

Molecular Imaging Laboratory, Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. Electronic address:

Bimodal imaging agents that combine magnetic resonance imaging (MRI) and nearinfrared (NIR) imaging formulated as nanoemulsions became increasingly popular for imaging inflammation in vivo. Quality of in vivo imaging using nanoemulsions is directly dependent on their integrity and stability. Here we report the design of nanoemulsions for bimodal imaging, where both photostability and colloidal stability are equally addressed. A highly chemically and photo stable quaterrylenediimide dye was introduced into perfluoro-15-crown-5 ether (PCE) nanoemulsions. The nanoemulsions were prepared with PCE and Miglyol 812N mixed at 1:1 v/v ratio as internal phase stabilized by non-ionic surfactants. Data shows exceptional colloidal stability demonstrated as unchanged droplet size (~130 nm) and polydispersity (<0.15) after 182 days follow up at both 4 and 25 °C. Nanoemulsions also sustained the exposure to mechanical and temperature stress, and prolonged exposure to light without changes in droplet size, (19)F signal or fluorescence signal. No toxicity was observed in vitro in model inflammatory cells upon 24 h exposure while confocal microscopy showed that nanoemulsions droplets accumulated in the cytoplasm. Overall, our data demonstrates that design of bimodal imaging agents requires consideration of stability of each imaging component and that of the nanosystem as a whole to achieve excellent imaging performance.
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http://dx.doi.org/10.1016/j.biomaterials.2014.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058911PMC
June 2014

Targeted zwitterionic near infrared fluorescent probe for improved imaging of type 2 cannabinoid receptors.

J Biomed Opt 2014 Mar;19(3):36006

University of Pittsburgh, Department of Radiology, Molecular Imaging Laboratory, Pittsburgh, Pennsylvania 15219dUniversity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232.

Recent studies indicate that the type 2 cannabinoid receptors (CB2R) have become an attractive target for treating a variety of pathologies, including cancers, neurodegenerative diseases, inflammation, pain, osteoporosis, immunological disorders and drug abuse. In addition, it appears that many of these diseases have up-regulated CB2R expression. However, the precise role of CB2R in the regulation of diseases remains unclear. The ability to specifically image CB2R would contribute to develop reliable CB2R-based therapeutic approaches with a better understanding of the mechanism of CB2R action in these diseases. We developed a CB2R-targeted zwitterionic near-infrared (NIR) fluorescent probe, ZW760-mbc94. When compared with a previously reported CB2R probe (NIR760-mbc94) with the same targeting moiety but a charged NIR fluorescent dye, ZW760-mbc94 showed improved binding specificity in vitro and ex vivo. Overall, ZW760-mbc94 appears to have great potential as a CB2R-targeted contrast agent.
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http://dx.doi.org/10.1117/1.JBO.19.3.036006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019425PMC
March 2014

Target-selective phototherapy using a ligand-based photosensitizer for type 2 cannabinoid receptor.

Chem Biol 2014 Mar 27;21(3):338-44. Epub 2014 Feb 27.

Department of Radiology, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15219, USA; University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. Electronic address:

Phototherapy is a powerful, noninvasive approach for cancer treatment, with several agents currently in clinical use. Despite the progress and promise, most current phototherapy agents have serious side effects as they can lead to damage to healthy tissue, even when the photosensitizers are fused to targeting molecules due to nonspecific light activation of the unbound photosensitizer. To overcome these limitations, we developed a phototherapy agent that combines a functional ligand and a near infrared phthalocyanine dye. Our target is type 2 cannabinoid receptor (CB2R), considered an attractive therapeutic target for phototherapy given it is overexpressed by many types of cancers that are located at a surface or can be reached by an endoscope. We show that our CB2R-targeted phototherapy agent, IR700DX-mbc94, is specific for CB2R and effective only when bound to the target receptor. Overall, this opens up the opportunity for development of an alternative treatment option for CB2R-positive cancers.
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http://dx.doi.org/10.1016/j.chembiol.2014.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989837PMC
March 2014
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