Production of [N]ammonia from [C]methanol on a 7.5 MeV cyclotron using C(p, n)N reaction: Detection of myocardial infarction in a mouse model.

[N]Ammonia is commonly produced using O(p, α)N reaction but one of the limiting factor of this reaction is the relatively small nuclear cross-section at proton energies of <10 MeV. An alternative production method using C(p, n)N reaction, which has a higher nuclear cross-section at low proton energies, is more suitable for a preclinical PET imaging facility equipped with a <10 MeV cyclotron. Here, we report a novel method to produce [N]ammonia from [C]methanol for preclinical use on a 7.

Surface Modification of Liposomes by a Lipopolymer Targeting Prostate Specific Membrane Antigen for Theranostic Delivery in Prostate Cancer.

Prostate specific membrane antigen (PSMA) is a marker for diagnosis and targeted delivery of therapeutics to advanced/metastasized prostate cancer. We report a liposome-based system for theranostic delivery to PSMA-expressing (PSMA⁺) LNCaP cells. A lipopolymer (P³) comprising of PSMA ligand (PSMAL), polyethylene glycol (PEG), and palmitate was synthesized and post-inserted into the surface of preformed liposomes.

Ubiquitin Receptor RPN13 Mediates the Inhibitory Interaction of Diphenyldihaloketones CLEFMA and EF24 With the 26S Proteasome.

The proteasome is a validated target in drug discovery for diseases associated with unusual proteasomal activity. Here we report that two diphenyldihaloketones, CLEFMA and EF24, inhibit the peptidase activity of the 26S proteasome. The objective of this study was to investigate interaction of these compounds with the proteasome and identify a putative target within the protein components of the 26S proteasome.

Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24.

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock.

Imaging of isoproterenol-induced myocardial injury with F labeled fluoroglucaric acid in a rat model.

Unlabelled: Positron emission tomography (PET) of myocardial infarction (MI) by infarct avid imaging has the potential to reduce the time to diagnosis and improve diagnostic accuracy. The objective of this work was to synthesize F-labeled glucaric acid (FGA) for PET imaging of isoproterenol-induced cardiomyopathy in a rat model.

Methods: We synthesized F-FGA by controlled oxidation of F-fluorodeoxy glucose (FDG), mediated by 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in presence of NaBr and NaOCl in highly-buffered reaction conditions.

Stability study on an anti-cancer drug 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid (CLEFMA) using a stability-indicating HPLC method.

CLEFMA, 4-(3,5-bis(2-chlorobenzylidene)-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid, is a new chemical entity with anti-cancer and anti-inflammatory activities. Here, we report its stability in solution against stress conditions of exposure to acid/base, light, oxidant, high temperature, and plasma. The identity of the degradation products was ascertained by mass and proton nuclear magnetic resonance spectroscopy.

Folate-PEG Conjugates of a Far-Red Light-Activatable Paclitaxel Prodrug to Improve Selectivity toward Folate Receptor-Positive Cancer Cells.

We recently demonstrated the far-red light-activatable prodrug of paclitaxel (PTX), Pc-(L-PTX). Upon illumination with a 690 nm laser, Pc-(L-PTX) showed combinational cell killing from rapid photodynamic therapy damage by singlet oxygen, followed by sustained chemotherapy effects from locally released PTX. However, its high lipophilicity (log > 3.

Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy.

Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer.

Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen.

Photodynamic therapy (PDT) is a cancer treatment modality where photosensitizer (PS) is activated by visible and near IR light to produce singlet oxygen ((1)O2). However, (1)O2 has a short lifetime (<40 ns) and cannot diffuse (<20 nm) beyond the cell diameter (e.g.

Facile synthesis of para-[(18)F]fluorohippurate via iodonium ylide-mediated radiofluorination for PET renography.

para-[(18)F]fluorohippurate ([(18)F]PFH) is a renal tubular agent suitable for conducting positron emission tomography (PET) renography. [(18)F]PFH is currently synthesized by a four-step two-pot procedure utilizing a classical prosthetic group, N-succinimidyl-4-[(18)F]fluorobenzoate, followed by glycine conjugation. Considering the short half-life of fluorine-18 (110min), it is important to reduce the number of synthetic steps and overall production time for successful translation of any fluorine-18 radiopharmaceutical in to clinical practice.

Folate receptor-mediated enhanced and specific delivery of far-red light-activatable prodrugs of combretastatin A-4 to FR-positive tumor.

We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, light-activated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker.

Far-red light activatable, multifunctional prodrug for fluorescence optical imaging and combinational treatment.

We recently developed "photo-unclick chemistry", a novel chemical tool involving the cleavage of aminoacrylate by singlet oxygen, and demonstrated its application to visible light-activatable prodrugs. In this study, we prepared an advanced multifunctional prodrug, Pc-(L-CA4)2, composed of the fluorescent photosensitizer phthalocyanine (Pc), an SO-labile aminoacrylate linker (L), and a cytotoxic drug combretastatin A-4 (CA4). Pc-(L-CA4)2 had reduced dark toxicity compared with CA4.

Site-specific and far-red-light-activatable prodrug of combretastatin A-4 using photo-unclick chemistry.

Although tissue-penetrable light (red and NIR) has great potential for spatiotemporally controlled release of therapeutic agents, it has been hampered because of the lack of chemistry translating the photonic energy to the cleavage of a chemical bond. Recently, we discovered that an aminoacrylate group could be cleaved to release parent drugs after oxidation by SO and have called this "photo-unclick chemistry". We demonstrate its application to far-red-light-activated prodrugs.

Visible Light Controlled Release of Anticancer Drug through Double Activation of Prodrug.

We designed and synthesized a novel double activatable prodrug system (drug-linker-deactivated photosensitizer), containing a photocleavable aminoacrylate-linker and a deactivated photosensitizer, to achieve the spatiotemporally controlled release of parent drugs using visible light. Three prodrugs of CA-4, SN-38, and coumarin were prepared to demonstrate the activation of deactivated photosensitizer by cellular esterase and the release of parent drugs by visible light (540 nm) via photounclick chemistry. Among these prodrugs, nontoxic coumarin prodrug was used to quantify the release of parent drug in live cells.

Synthesis and in vitro biological evaluation of lipophilic cation conjugated photosensitizers for targeting mitochondria.

Mitochondria-specific photosensitizers were designed by taking advantage of the preferential localization of delocalized lipophilic cations (DLCs) in mitochondria. Three DLC-porphyrin conjugates: CMP-Rh (a core modified porphyrin-rhodamine B cation), CMP-tPP (a core modified porphyrin-mono-triphenyl phosphonium cation), CMP-(tPP)(2) (a core modified porphyrin-di-tPP cation) were prepared. The conjugates were synthesized by conjugating a monohydroxy core modified porphyrin (CMP-OH) to rhodamine B (Rh B), or either one or two tPPs, respectively, via a saturated hydrocarbon linker.

Click and photo-unclick chemistry of aminoacrylate for visible light-triggered drug release.

"Click and Photo-unclick Chemistry" of aminoacrylates is proposed for a new photo-labile linker. Adducts are built in 2 steps with good yields and cleaved rapidly by tissue penetrable visible light (690 nm) with a photosensitizer. Facile synthesis, release of mother drug, and stability and cleavage in medium are demonstrated.

Synthesis and singlet oxygen reactivity of 1,2-diaryloxyethenes and selected sulfur and nitrogen analogs.

1,2-Diaryloxyethene has recently been proposed as a linker in singlet oxygen-mediated drug release. Even though 1,2-diaryloxyethenes look very simple, their synthesis was not an easy task. Previous methods are limited to symmetric molecules, lengthy step and low yield.