Imaging and therapeutic applications of zinc(<scp>ii</scp>)-dipicolylamine molecular probes for anionic biomembranes

Rice, Douglas R.; Clear, Kasey J.; Smith, Bradley D.

doi:10.1039/c6cc03669d

Cited by 62 publications

(62 citation statements)

References 155 publications

(179 reference statements)

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“…Thus, fluorescent ZnDPA probes can be used to image various forms of microbial infection and different types of diseased tissue that have high levels of cell death. 17 …”

Section: Introductionmentioning

confidence: 99%

Preassembled Fluorescent Multivalent Probes for the Imaging of Anionic Membranes

et al. 2017

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A new self-assembly process known as Synthavidin (Synthetic Avidin) technology was used to prepare targeted probes for near-infrared fluorescence imaging of anionic membranes and cell surfaces, a hallmark of many different types of disease. The probes were pre-assembled by threading a tetralactam macrocycle with six appended zinc-dipicolylamine (ZnDPA) targeting units onto a linear scaffold with one or two squaraine docking stations to produce hexavalent or dodecavalent fluorescent probes. A series of liposome titration experiments showed that multivalency promoted stronger membrane binding by the dodecavalent probe. In addition, the dodecavalent probe exhibited turn-on fluorescence due to probe unfolding during fluorescence microscopy at the membrane surface. But the dodecavalent probe also had a higher tendency to self-aggregate after membrane binding leading to probe self-quenching under certain conditions. This self-quenching effect was apparent during fluorescence microscopy experiments that recorded low fluorescence intensity from anionic dead and dying mammalian cells that were saturated with the dodecavalent probe. Conversely, probe self-quenching was not a factor with anionic microbial surfaces where there was intense fluorescence staining by the dodecavalent probe. A successful set of rat tumor imaging experiments confirmed that the pre-assembled probes have sufficient mechanical stability for effective in vivo imaging. The results demonstrate the feasibility of this general class of pre-assembled fluorescent probes for multivalent targeting, but fluorescence imaging performance depends on the specific physical attributes of the biomarker target such as the spatial distance between different copies of the biomarker and the propensity of the probe/biomarker complex to self-aggregate.

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“…Thus, fluorescent ZnDPA probes can be used to image various forms of microbial infection and different types of diseased tissue that have high levels of cell death. 17 …”

Section: Introductionmentioning

confidence: 99%

Preassembled Fluorescent Multivalent Probes for the Imaging of Anionic Membranes

et al. 2017

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“…In step two, the squaraine component of the anchored CSP is threaded with a tetralactam macrocycle that has appended targeting ligands. The study employed two different tetralactam macrocycles, 6C with six carboxylates, which enhance liposome affinity for cationic surfaces, and 6Z with six zinc(II)‐dipicolylamine (ZnDPA) units, which enable selective targeting of anionic membranes and cell surfaces . A major attribute of this surface functionalization method is its efficiency, as it simultaneously endows the liposomes with targeting ligand, protective PEG chains, and deep‐red fluorescence reporter group.…”

Section: Introductionmentioning

confidence: 99%

Non‐Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep‐Red Fluorescence Reporter Groups

Shaw

Liu

Brennan

et al. 2017

Chemistry A European J

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A new self-assembly method is used to rapidly functionalize the surface of liposomes without perturbing the membrane integrity or causing leakage of the aqueous contents. The key molecule is a cholesterol-squaraine-PEG conjugate with three important structural elements: a cholesterol membrane anchor, a fluorescent squaraine docking station that allows rapid and high-affinity macrocycle threading, and a long PEG-2000 chain to provide steric shielding of the decorated liposome. The two-step method involves spontaneous insertion of the conjugate into the outer leaflet of pre-formed liposomes followed by squaraine threading with a tetralactam macrocycle that has appended targeting ligands. A macrocycle with six carboxylates permitted immobilization of intact fluorescent liposomes on the surface of cationic polymer beads, whereas a macrocycle with six zinc(II)-dipicolylamine units enabled selective targeting of anionic membranes, including agglutination of bacteria in the presence of human cells.

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“…The fluorescent probe mSeek and control BODIPY Dye were prepared during previous studies. [26] The ligands apo-1 – apo-5 were prepared by conducting Mannich reactions with the appropriate phenol derivative having different substituents at the 4-position (Scheme 2). [29] Dimeric ligand apo-8 was made by conducting a copper-catalyzed azide-alkyne cycloaddition (CuAAC) using apo-5 .…”

Section: Resultsmentioning

confidence: 99%

“…[26] Recently, we discovered that ZnDPA complexes selectively target and kill the trypanosomatid parasite Leishmania major ( L. major ), a causative agent of cutaneous leishmaniasis. [27] The surface of Leishmania parasites is negatively charged due to high fractions of anionic lipids and a thick coating of the anionic polysaccharide lipophosphoglycan.…”

Section: Introductionmentioning

confidence: 99%

Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes

Rice

Betancourt-Mendiola

Murillo-Solano

et al. 2017

Bioorganic & Medicinal Chemistry

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This study measured the antiplasmodial activity of nine zinc-dipicolylamine (ZnDPA) complexes against three strains of Plasmodium falciparum, the causative parasite of malaria. Growth inhibition assays showed significant activity against all tested strains, with 50% inhibitory concentrations between 5 and 600 nM and almost no toxic effect against host cells including healthy red blood cells. Fluorescence microscopy studies with a green-fluorescent ZnDPA probe showed selective targeting of infected red blood cells. The results suggest that ZnDPA coordination complexes are promising antiplasmodial agents with potential for targeted malaria treatment.

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Imaging and therapeutic applications of zinc(ii)-dipicolylamine molecular probes for anionic biomembranes

Cited by 62 publications

References 155 publications

Preassembled Fluorescent Multivalent Probes for the Imaging of Anionic Membranes

Preassembled Fluorescent Multivalent Probes for the Imaging of Anionic Membranes

Non‐Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep‐Red Fluorescence Reporter Groups

Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes

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