Leland Stanford Junior University

The University of Texas System

University of California

Incanthera Limited

Zymera, Inc.

Jianghong Rao

Jeffrey D Cirillo

Hexin Xie

Yunfeng Cheng

Adam Shuhendler

Min-kyung So

Roger Y Tsien

Sanjiv Sam Gambhir

James C Sacchettini

Andreas M Loening

Kanyi Pu

Chenjie Xu

Daniel Sobek

Christopher H Contag

Stephen Howard Thorne

Paul Loadman

David Francis Ackerley

Jason Gill

Heike E Daldrup-Link

Bin Shen

Robert Falconer

A C Matin

Lina Cui

Hequan Yao

Yoram Barak

Jianghang Xie

Min Chen

Deju Ye

Frederick Te-Ning Chin

Jongho Jeon

Haibin Shi

Nan Ma

Jinghang Xie

Susan V Lynch

Zixin Chen

Embodiments of the synthesis, radiolabeling and biological applications of an activatable tracer that undergoes intramolecular cyclization and aggregation upon activation by cleavage of a blocking moiety are provided. The probes of the disclosure allow for target-controlled self-assembly of small molecules in living subjects for imaging and drug delivery. The aggregated nanoprobes of the disclosure may be detectable optically, by PET detection, magnetic resonance imaging, and the like depending on the detectable reporter attached to the nanoprobe.

Caspase-3-triggered molecular self-assembling PET probes and uses thereof

The present invention discloses a probe useful for the selective detection of metallo-beta-lactamases, in particular carbapenemases, thereby distinguishing those species of bacteria that are carbapenem-resistant from bacterial strains that are sensitive. Cephalospori based probes that have the 6,7 R,R configuration are susceptible to cleavage by beta-lactamases but cannot distinguish between cleavage by metallo-beta-lactamases and other beta-lactamases. By modifying a side group of the cephalosporin, selectivity can be introduced allowing the probes to distinguish between various types of metallo-beta-lactamases.

6,7-trans cephalosporin-based probes for detecting bacteria expressing a metallo-beta-lactamase

The compositions of the present disclosure provide novel fluorogenic probes for use in the specific imaging and detection of mycobacteria species, and in particular &#x3b2;-lactam-antibiotic resistant. Specificity for mycobacteria is conferred on these probes by incorporating a moiety that specifically targets the unique trapping mechanism of the DprE1 found in in mycobacteria. Accordingly, only Mycobacteria species that express both a &#x3b2;-lactamase and DprE1 enable both the activation of the caged fluorescent probe, and the affixing of the released fluorescent probes to the bacteria cells through the functioning reduction-covalent binding mechanism. Advantageously, such a probe is able, at its most sensitive, to allow singledetection.

Probes for rapid and specific detection of mycobacteria

&#x3b2;-Lactamase substrates and methods for using the substrates to detect &#x3b2;-lactamase and to diagnose tuberculosis.

2,7-disubstituted cephalosporin derivatives as &#x3b2;-lactamase substrates and methods for their use for the diagnosis of tuberculosis

The present inventors have harnessed the targeting of nanoparticles to tumor sites, combined with the tumor site specific elevated MMP-14 activity within one conjugate to simultaneously deliver a vascular disrupting agent (VDA) and a MRI contrast agent to a tumor site. The MMP activatable conjugate of the present invention provides both therapeutic and diagnostic functions&#x2014;and is referred to as a 'theranostic'. The theranostic conjugate of the present invention achieves the benefits of tumor site specificity, VDA delivery and MRI contrast agent delivery in a single theranostic conjugate. Consequently, the present invention provides a cancer 'theranostic' which improves therapeutic efficacy while simultaneously reducing dose-limiting systemic toxicities and provides a tool for rapidly and non-invasively identifying tumor location, monitoring drug delivery and pharmacodynamics.

Tumour-targeted theranostic

Provided are embodiments of a small molecule tracer for positron emission tomography (PET) imaging of the enzyme activity of PARP-1 that is responsible for DNA-damage sensing and critically involved in radiation therapy and some chemotherapy response mechanisms. These PARP-1 tracers are derivatives of nicotinamide adenine dinucleotide (NAD), which is the natural substrate for PARP-1. Provided are NAD derivatives that include a linker moiety to which may be attached a label moiety such as a PET detectable fluorine to generate a 6N-(triazo-PEG2-F)-NAD. Especially advantageous for use in PET and MRI scanning detection systems is the attachment of a chelating agent that allows for the formation of a chelator-metal ion complex.

Probe for imaging PARP-1 activity

Encompassed are embodiments of activatable nanoprobes useful for in vivo longitudinal imaging of drug hepatotoxicity with oxidative and nitrosative stress as the safety biomarkers. Both HOand ONOOare important mediators of radical stress. Two channels of optical detection, intrinsically free from cross-talk, were engineered into superconducting polymer nanoparticles to generate chemiluminescence resonance energy transfer between the conjugated polymer matrix of the nanoparticle and an incorporated chemiluminescent substrate allowing for the luminescent detection of HOand fluorescence resonance energy transfer between the polymer matrix and an oxidation-degradable fluorophore for ratiometric detection of ONOO These nanoprobes have been applied for real-time in vivo monitoring of hepatotoxicity resulting from challenges from drugs. In addition to the ability of imaging the dose-dependence of oxidative and nitrosative stress, the positive detection of radical stress that precedes histological changes allow the early and longitudinal detection of drug-induced hepatotoxicity in vivo.

Discrete imaging of hepatic oxidative and nitrosative stress with two-channel nanoparticles for in vivo drug safety screening

2,7-disubstituted cephalosporin derivatives as beta-lactamase substrates and methods for their use for the diagnosis of tuberculosis

&#x3b2;-Lactamase substrates and methods for using the substrates to detect &#x3b2;-lactamase diagnose tuberculosis.

&#x3b2;-lactamase substrates and methods of their use for the diagnosis of tuberculosis

For whole animal in-situ and real-time imaging of inflammation, a dual-color fluorescent nanoprobe is provided for the detection of reactive oxygen and nitrogen species (RONS) in inflammatory microenvironments. The nanoprobes of the disclosure are a RONS-responsive energy transferring nanosystem of a fluorescent conjugated polymer core and a PEG-shell linked with RONS-sensing antennae as a FRET acceptor. These nanoprobes allow in vivo imaging of the entire process of inflammation from the release of local tissue distress signals, to the action of leukocytes and macrophages late in the process of inflammation, through to restitution, allowing in whole-body diagnosis and monitoring of inflammatory diseases.

Nanoprobes for sensing of reactive oxygen and reactive nitrogen species

Provided is an activatable probe that undergoes intramolecular cyclization and subsequent aggregation in apoptotic tumor cells upon peptidase-initiated, and most advantageously caspase-3, activation. These caspase-sensitive nano-aggregation probes (C-SNAFs) are generally biocompatible, possess NIR spectral properties or may serve as PET or MRI imaging agents, and have a mechanism of target-mediated nanostructure self-assembly amenable to in vivo use. The probes encompass biocompatible condensation chemistry products that comprise D-cysteine and 2-cyano-6-hydroxyquinoline (CHQ) moieties linked to an amino-luciferin scaffold, and which can be activated by a two-step reaction requiring caspase-3/7-mediated cleavage of an aspartate-glutamate-valine-aspartate (L-DEVD) capping peptide and the free intracellular thiol-mediated reduction of the disulfide bond.

Caspase-triggered nano-aggregation probes and methods of use

Provided herein are assays and in vitro methods to determine susceptibility to a drug effective against a pathogenic bacteria, for example, a pathogenic Mycobacteria, that has a beta-lactamase activity. An excitation wavelength is delivered to a biological sample obtained from a subject having an infection from the pathogenic bacteria in the presence of a beta-lactamase substrate. The intensity of a signal, such as a fluorescent, luminescent or colorimetric signal, at an emission wavelength of a product of the beta-lactamase on the subject is correlated to drug susceptibility. Also provided is an assay system for monitoring drug susceptibility of a pathogenic bacteria comprising color-producing substrates for a beta-lactamase of the pathogenic bacteria, an assay device for visibly detecting a product of the beta-lactamase on the substrate thereof and a reader configured to quantify the visibly detected product.

Use of bacterial beta-lactamase for in vitro diagnostics and in vivo imaging, diagnostics and therapeutics

Provided herein are methods for detecting, quantifying, differentiating, diagnosing and imaging pathogenic bacteria or condition associated therewith using substrates for bacterial enzymes. Fluorescent, luminescent or colorimetric signals emitted by substrates or enzyme products in the presence of the bacteria are compared to controls to detect and locate the pathogenic bacteria. Provided is a method for screening therapeutic agents to treat the pathophysiological conditions by measuring a signal emitted from the substrates or products in the presence and absence of the potential therapeutic agent and a diagnostic method for detecting a mycobacterial infection in a subject by contacting biological samples with a substrate and imaging for signals emitted from a mycobacterial beta-lactamase product. Also provided are fluorogenic substrates or substrates comprising a colored dye or a chemical reagent effective to induce a color or pH change.

Embodiments of the present disclosure include hybrid quantum dot/protein nanostructure, hybrid quantum dot/protein nanostructure systems, methods of using hybrid quantum dot/protein nanostructures, and the like.

Hybrid quantum dot/protein nanostructure, methods of making, and methods of use thereof

An enzyme detection method includes forming a caged substrate; releasing an uncaged substrate by cleaving a caging molecule from the caged substrate; and emitting a light emission from a Bioluminescence Resonance Energy Transfer luminescent nanocrystal conjugate reacting with the uncaged substrate.

Growing community of inventors

Sunnyvale, CA, United States of America

Jianghong Rao