Preclinical Evaluation of an Integrin αβ-Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) is a minimally invasive treatment in which an external light source activates an injected photosensitizer (PS) to generate reactive oxygen species, causing localized cell death. Although the first PDT received FDA approval in 1995, clinical adoption has been limited, in part due to the limited tumor selectivity of PSs. The goal of this study was to develop a PS with improved tumor selectivity by incorporating a targeting peptide that selectively binds to the integrin αβ.

Evaluation of [F]AlF NOTA-5G, an Aluminum [F]fluoride Labeled Peptide Targeting the Cell Surface Receptor Integrin Alpha(v)beta(6) for PET Imaging.

Purpose: Peptide-based probes targeting integrin αβ have shown promise in clinical trials for cancer imaging based on the high over-expression of this epithelial-specific cell surface receptor in many cancerous tissues. Recently, the αβ-targeting gallium-68 labeled DOTA-5G peptide, [Ga]Ga DOTA-5G, demonstrated diagnostic value in patients with metastatic pancreatic cancer. To facilitate adoption at sites without access to gallium-68 and take advantage of the characteristics of fluorine-18 through convenient [F]fluoride chelation chemistry, this study evaluated the fluorine-18 labeled analog, [F]AlF NOTA-5G, in vitro and in vivo in a tumor mouse model, and compared it to [Ga]Ga DOTA-5G.

Synthesis and Evaluation of a Monomethyl Auristatin E─Integrin αβ Binding Peptide-Drug Conjugate for Tumor Targeted Drug Delivery.

Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin αβ are emerging as powerful tools to overcome these challenges. The development of an integrin αβ-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αβ-binding peptide (αβ-BP) and with the ability of positron emission tomography (PET) imaging by copper-64.

Preclinical Evaluation of Ga- and Lu-Labeled Integrin αβ-Targeting Radiotheranostic Peptides.

The integrin αβ, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αβ-targeting peptide, DOTA-5G () radiolabeled with Ga, for PET/CT imaging and Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G ().

Primary Hemiarthroplasty for the Treatment of Basicervical Femoral Neck Fractures.

Purpose Basicervical femoral neck fractures are uncommon injuries that occur at the extracapsular base of the femoral neck at its transition with the intertrochanteric line. Controversy remains in the orthopedic literature as to the optimal method of treatment for this fracture type given the inherent instability and greater rate of implant failure with traditional fixation constructs. The purpose of this study is to quantify the incidence and preferred treatment methods of basicervical hip fractures at a single, regional, Level 1 trauma center and to identify differences in postoperative complications between treatment options.

A Comparison of Evans Blue and 4-(-Iodophenyl)butyryl Albumin Binding Moieties on an Integrin αβ Binding Peptide.

Serum albumin binding moieties (ABMs) such as the Evans blue (EB) dye fragment and the 4-(p-iodophenyl)butyryl (IP) have been used to improve the pharmacokinetic profile of many radiopharmaceuticals. The goal of this work was to directly compare these two ABMs when conjugated to an integrin αvβ6 binding peptide (αvβ6-BP); a peptide that is currently being used for positron emission tomography (PET) imaging in patients with metastatic cancer. The ABM-modified αvβ6-BP peptides were synthesized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) chelator for radiolabeling with copper-64 to yield [64Cu]Cu DOTA-EB-αvβ6-BP ([64Cu]1) and [64Cu]Cu DOTA-IP-αvβ6-BP ([64Cu]2).

Repurposing an atherosclerosis targeting peptide for tumor imaging.

Cancer and atherosclerosis are chronic diseases that share common characteristics at both early and advanced stages and can arise from multiple factors. Both diseases are characterized by uncontrolled cell proliferation, inflammation, angiogenesis and apoptosis. Herein we investigated the ability of a peptide (CTHRSSVVC), that was previously reported to bind atherosclerotic lesions to home in the tumor microenvironment.

Evaluation of Copper-64-Labeled αβ-Targeting Peptides: Addition of an Albumin Binding Moiety to Improve Pharmacokinetics.

The incorporation of non-covalent albumin binding moieties (ABMs) into radiotracers results in increased circulation time, leading to a higher uptake in the target tissues such as the tumor, and, in some cases, reduced kidney retention. We previously developed [F]AlF NOTA-K(ABM)-αβ-BP, where αβ-BP is a peptide with high affinity for the cell surface receptor integrin αβ that is overexpressed in several cancers, and the ABM is an iodophenyl-based moiety. [F]AlF NOTA-K(ABM)-αβ-BP demonstrated prolonged blood circulation compared to the non-ABM parent peptide, resulting in high, αβ-targeted uptake with continuously improving detection of αβ(+) tumors using PET/CT.

αβ-Targeted Molecular PET/CT Imaging of the Lungs After SARS-CoV-2 Infection.

The true impact and long-term damage to organs such as the lungs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain to be determined. Noninvasive molecularly targeted imaging may play a critical role in aiding visualization and understanding of the systemic damage. We have identified αβ as a molecular target; an epithelium-specific cell surface receptor that is low or undetectable in healthy adult epithelium but upregulated in select injured tissues, including fibrotic lung.

The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αβ-Selective Peptide Labeled with Aluminum [F]Fluoride.

Purpose: The αβ-BP peptide selectively targets the integrin αβ, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life.

Procedures: The peptides NOTA-αβ-BP (1) and NOTA-K(ABM)-αβ-BP (2) were synthesized on solid phase, radiolabeled with aluminum [F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [αβ(+)]/DX3puro [αβ(-)], and for [F]AlF 2, BxPC-3 [αβ(+)] cell xenografts (PET imaging, biodistribution).

Fully automated peptide radiolabeling from [F]fluoride.

The biological properties of receptor-targeted peptides have made them popular diagnostic imaging and therapeutic agents. Typically, the synthesis of fluorine-18 radiolabeled receptor-targeted peptides for positron emission tomography (PET) imaging is a time consuming, complex, multi-step synthetic process that is highly variable based on the peptide. The complexity associated with the radiolabeling route and lack of robust automated protocols can hinder translation into the clinic.

Identification, Characterization, and Optimization of Integrin αβ₆-Targeting Peptides from a One-Bead One-Compound (OBOC) Library: Towards the Development of Positron Emission Tomography (PET) Imaging Agents.

The current translation of peptides identified through the one-bead one-compound (OBOC) technology into positron emission tomography (PET) imaging agents is a slow process, with a major delay between ligand identification and subsequent lead optimization. This work aims to streamline the development process of F-peptide based PET imaging agents to target the integrin αβ₆. By directly identify αβ₆⁻targeting peptides from a 9-mer 4-fluorobenzoyl peptide library using the on-bead two-color (OBTC) cell-screening assay, a total of 185 peptide beads were identified and 5 beads sequenced for further evaluation.

Preclinical Development and First-in-Human Imaging of the Integrin αβ with [F]αβ-Binding Peptide in Metastatic Carcinoma.

Purpose: The study was undertaken to develop and evaluate the potential of an integrin αβ-binding peptide (αβ-BP) for noninvasive imaging of a diverse range of malignancies with PET.

Experimental Design: The peptide αβ-BP was prepared on solid phase and radiolabeled with 4-[F]fluorobenzoic acid. testing included ELISA, serum stability, and cell binding studies using paired αβ-expressing and αβ-null cell lines.

N,N,N-Trimethyl-5-[(2,3,5,6-tetrafluorophenoxy)carbonyl]pyridin-2-aminium trifluoromethanesulfonate a precursor for the synthesis of 2,3,5,6-tetrafluorophenyl 6-[F]-fluoronicotinate.

The synthesis, recrystallization, and X-ray deterimination of N,N,N-trimethyl-5-[(2,3,5,6-tetrafluorophenoxy)carbonyl]pyridin-2-aminium trifluoromethanesulfonate (PyTFP-precursor), CHFNO·CFSO, is described. This triflate salt precursor is required for the synthesis of 2,3,5,6-tetrafluorophenyl 6-[F]-fluoronicotinate ([F]FPyTFP), a prosthetic group used to radiolabel peptides for positron emission tomography (PET), as peptides are increasingly being used as PET-imaging probes in nuclear medicine. Radiolabeling of peptides is typically done using a `prosthetic group', a small synthon to which the radioisotope is attached in the first step, followed by attachment to the peptide in the second step.

In Vivo Tracking of Copper-64 Radiolabeled Nanoparticles in Lactuca sativa.

Engineered nanoparticles (NPs) are increasingly used in commercial products including automotive lubricants, clothing, deodorants, sunscreens, and cosmetics and can potentially accumulate in our food supply. Given their size it is difficult to detect and visualize the presence of NPs in environmental samples, including crop plants. New analytical tools are needed to fill the void for detection and visualization of NPs in complex biological and environmental matrices.

Solid-phase synthesis and fluorine-18 radiolabeling of cycloRGDyK.

Solid-phase peptide synthesis, head-to-tail cyclization, and subsequent radiolabeling provided a reproducible, simple, rapid synthetic method to generate the cyclic peptide radiotracer cRGDyK([F]FBA). Herein is reported the first on-resin cyclization and F-radiolabeling of a cyclic peptide (cRGDyK) in an overall peptide synthesis yield of 88% (cRGDyK(NH)) and subsequent radiolabeling yield of 14 ± 2% (decay corrected, n = 4). This approach is generally applicable to the development of an automated process for the synthesis of cyclic radiolabeled peptides for positron emission tomography (PET).

Synthesis of cholesteryl-α-D-lactoside via generation and trapping of a stable β-lactosyl iodide.

The generation of β-lactosyl iodide was carried out under non-in situ-anomerization, metal free conditions by reacting commercially available β-per--acetylated lactose with trimethylsilyl iodide (TMSI). The β-iodide was surprisingly stable as evidenced by NMR spectroscopy. Introduction of octanol or cholesterol under microwave conditions gave high yields of α-linked glycoconjugates.

Synthesis and structural characterization of three unique Helicobacter pylori α-cholesteryl phosphatidyl glucosides.

Steryl glycosides produced by bacteria play important biological roles in the evasion and modulation of host immunity. Step-economical syntheses of three cholesteryl-6-O-phosphatidyl-α-D-glucopyranosides (αCPG) unique to Helicobacter pylori have been achieved. The approach relies upon regioselective deprotection of per-O-trimethylsilyl-α-D-cholesterylglucoside at C6 followed by phosphoramidite coupling.

Tandem glycosyl iodide glycosylation and regioselective enzymatic acylation affords 6-O-tetradecanoyl-α-d-cholesterylglycosides.

A generalized synthesis of α-d-cholesterylglycosides has been achieved using one-pot per-O-trimethylsilyl glycosyl iodide glycosidation. Both cholesteryl α-d-glucopyranoside (αCG) and cholesteryl α-d-galactopyranoside were prepared in high yield. These compounds were further esterified using regioselective enzymatic acylation with tetradecanoyl vinyl ester to afford 6-O-tetradecanoyl-α-d-cholesteryl glucopyranoside (αCAG) of Helicobacter pylori and the corresponding galactose analogue in 66-78% overall yields from free sugars.

Two-step functionalization of oligosaccharides using glycosyl iodide and trimethylene oxide and its applications to multivalent glycoconjugates.

Oligosaccharide conjugates, such as glycoproteins and glycolipids, are potential chemotherapeutics and also serve as useful tools for understanding the biological roles of carbohydrates. With many modern isolation and synthetic technologies providing access to a wide variety of free sugars, there is increasing need for general methodologies for carbohydrate functionalization. Herein, we report a two-step methodology for the conjugation of per-O-acetylated oligosaccharides to functionalized linkers that can be used for various displays.

A fused [3.3.0]-neoglycoside lactone derived from glucuronic acid.

The bridged next-generation aminoglycoside (neoglycoside), 1-deoxy-1-[(methoxy)methylamino)]-2,5-di-O-triethylsilyl-β-D-glucofuranurono-γ-lactone {systematic name: (3S,3aS,5R,6R,6aS)-5-[methoxy(methyl)amino]-3,6-bis[(triethylsilyl)oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-2-one}, C20H41NO6Si2, was synthesized in a one-pot manner from commercially available D-glucuronic acid. This structure supports the properties associated with the anomeric effect for furanosides and can be employed to provide insight into the mechanisms by which alkoxyamine-appended natural products derive their enhanced biological activity. To the best of our knowledge, this is the first published crystal structure of a bicyclic neoglycoside and is the first neoglycoside to be completely and unambiguously characterized.

Chemoenzymatic synthesis of cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside: a product of host cholesterol efflux promoted by Helicobacter pylori.

In a three-step protocol involving regioselective enzymatic acylation, per-O-trimethylsilylation, and a one-pot α-glycosidation-deprotection sequence, cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside (α-CAG) of Helicobacter pylori is afforded starting from glucose in an overall yield of 45%. The production of CAG can be scaled to make purified quantities available to the biological community for the first time.

(5S)-4-(2,2-Dimethyl-prop-yl)-5-isopropyl-1,3,4-oxadiazinan-2-one.

The title compound, C(11)H(22)N(2)O(2), has one chiral center and packs in the monoclinic space group P2(1). The asymmetric unit has five crystallographically independent mol-ecules, four of which engage in inter-molecular N-H⋯O hydrogen bonding.

Gene expression changes in children with autism.

The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression).