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Synthesis and properties of modified siRNA having …

Pyridyl disulfide linkers include cleavable disulfide bonds, which facilitates a quantitative evaluation of the reaction efficiency. Jon . calculated the concentration of surface-bound peptide molecules on the nanoparticles by quantifying the released pyridine-2-thione []. In an effort to develop integrin-targeted iron oxide nanoparticles as theranostic agents, amine-modified iron oxide nanoparticles were synthesized, and SPDP was added to convert the primary amine groups on the nanoparticles to sulfhydryl-reactive pyridyldisulfide groups. Conjugation between the thiol group-containing cyclic RGD peptides and the SPDP-activated nanoparticles produced pyridine-2-thione, which was immediately collected by spin filtering (at 100 K). The immobilized cRGD molecules were quantified based on the ultraviolet (UV) absorbance at 343 nm of the collected pyridine-2-thione filtrate, indicating that the average number of conjugated cRGD peptides on each nanoparticle was 0.39 wt%. This linker is useful for enhancing the intracellular gene silencing properties of siRNA. Bhatia . studied the gene-silencing efficacy of siRNA-conjugated QDs using cleavable (sulfo-LC-SPDP) or noncleavable (sulfo-SMCC) cross-linkers []. They immobilized thiol-modified siRNA specific for EGFP to amine-functionalized QDs via sulfo-LC-SPDP or sulfo-SMCC linkers and quantified the EGFP fluorescence intensity. The siRNA attached QDs via the sulfo-LC-SPDP linker provided greater silencing efficiency than those attached via the sulfo-SMCC linker. The cleavable disulfide cross-linker released siRNA from the nanoparticles into the intracellular reducing environment, which affected the interactions between the siRNA and the RNA induced silencing complex (RISC), which is necessary for gene knockdown.

Synthesis of New Tetrazole and Triazole Substituted Pyroglutamic Acid and Proline Derivatives.
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The efficient and functional group tolerant CuAAC reaction is useful for introducing complex structure into RNA, particularly modifications that would require extensive use of protecting groups or are incompatible with reagents used during automated RNA synthesis, such as carbohydrates, peptides and lipids. These modifications hold promise for altering the tissue delivery and cellular uptake properties of siRNAs, important hurdles to the advancement of RNAi-based therapeutics. Indeed, Alnylam Pharmaceuticals investigators recently described a small library of siRNAs modified with the CuAAC reaction to introduce long lipophilic chains including the linoleyl group (15,), cholesterol, oligoamine and a carbohydrate (). While no novel cellular uptake properties were described for the conjugated siRNAs, initial tests of activity indicated that siRNAs prepared with modified passenger strands effectively silenced a reporter gene with minimal loss of activity.

Triazole-linked analogues of DNA and RNA ..

S., Synthesis of bile acid dimers linked with 1,2,3-triazole ring at C-3, C-11, and C-24 positions.
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A broad spectrum of chemical approaches has been used to conjugate targeting moieties, therapeutic molecules, or contrast agents to nanoparticle surfaces. These methods can be categorized as conventional bioconjugation strategies (direct conjugation, linker chemistry, physical interactions), click chemistry, or hybridization methods (Table ). The primary goal of targeted ligand conjugation is to bind a targeting moiety without losing its functionality after attachment to the nanoparticle. For example, binding of an antibody to a nanoparticle without consideration for the recognition site can shield the functional regions and reduce the targeting properties. Conjugated therapeutic agents, such as drugs and siRNA, must be designed to release from a nanoparticle system after cellular uptake to show therapeutic effects. In the following sections, the unique advantages and drawbacks of each strategy will be discussed, and several examples of the strategy, including decoration of iron oxide nanoparticle surfaces with the above-listed targeting moieties will be highlighted.

In general, nanoparticles tend to aggregate through hydrophobic interactions or attractive van der Waals forces in an effort to minimize the surface energy. In the blood stream, such aggregates can trigger opsonization, the process by which a particle becomes covered with opsonin proteins, thereby making it more visible to the mononuclear phagocytic system (MPS), such as RES. The phagocytic mechanisms render nanoparticles ineffective as theranostic devices by removing them from the bloodstream []. Therefore, evading uptake by RES and increasing the blood circulation half-life are major challenges for developing theranostic nanoparticles in clinical applications []. Several methods of camouflaging nanoparticles have been developed to yield 'stealth' nanoparticles, which are invisible to MPS. These approaches interfere with the binding of opsonin proteins to the nanoparticle surfaces in support of a long circulation half-life, thereby increasing the chance that the nanoparticles can effectively target tumor sites. In order to impart stealth properties to the nanoparticles, one of the most promising molecules is the FDA-approved PEG. Natural or synthetic polymers, small organic molecules, and core-shell structures have also been utilized for nanoparticle surface coatings. However, a high surface coverage can decrease binding to and uptake by target cancer cells. This section describes the use of several coating molecules as shielding materials. The optimal surface densities of the coating materials and the targeted ligands will be discussed.

Synthesis and biological properties of triazole-linked ..

T., Expedient Synthesis of Triazole-Linked Glycosyl Amino Acids and Peptides.
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Medarova . synthesized a breast tumor-targeted nanodrug designed to specifically shuttle siRNA to human breast cancer while simultaneously allowing for the noninvasive monitoring of the siRNA delivery process []. The nanodrug consisted of SPIONs for MRI monitoring, Cy5.5 fluorescence dye for near-infrared (IR) optical imaging, and siRNA to target the tumor-specific antiapoptotic gene . Magnetic iron oxide nanoparticles are extensively used as multimodal imaging probes in combination with optical fluorescence dyes to obtain the benefits of optical imaging, such as rapid screening and high sensitivity. Because tumor-associated underglycosylated mucin-1 (uMUC-1) antigen is overexpressed in >90% of breast cancers and in >50% of all cancers in humans [], researchers have decorated nanodrugs with uMUC-1-targeting EPPT synthetic peptides for selective tumor targeting. As shown in Figure A, amine-functionalized superparamagnetic iron oxide nanoparticles with a cross-linked dextran coating (MN) have been prepared, and a Cy5.5 dye was conjugated to the surface of nanoparticles to produce MN-Cy5.5. Subsequently, thiol-modified, FITC-labeled EPPT peptides and siRNA were coupled to MN-Cy5.5 via a heterofunctional cross-linker, -succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The resulting therapeutic and diagnostic nanodrug (MN-EPPT-siBIRC5) exhibited superparamagnetic and fluorescence properties. After intravenous injection of the nanodrugs into mice with BT-20 breast tumors, the tumors were clearly imaged, as verified simultaneously by T2 MRI and near-IR optical imaging (Figure B). Systemic administration of the nanodrug once a week over 2 weeks induced considerable levels of necrosis and apoptosis in the tumors as a result of the siBIRC5-mediated inhibition of the antiapoptotic survivin protooncogene, translating into a significant decrease in tumor growth rate (Figure C). This tumor-targeted, imaging-capable nanodrug highlights the potential of MRI-guided tumor treatment, which can be used to quantify changes in the tumor volume over the treatment schedule as well as to guide selection of an optimal treatment time course.

The first example of the use of click chemistry to modify RNA came when Jao and Salic metabolically labeled cellular RNA with 5-ethynyluridine (7,), which could subsequently be detected via reaction with an azide-bearing fluorophore (). Using this approach, the authors were able to image sites of transcription in cultured cells as well as in tissues from whole animals. This method provides a sensitive and efficient alternative to monitoring cellular transcription via 5-bromouridine incorporation and, indeed, can now be carried out with a commercially available kit (Click-iT® Nascent RNA Capture Kit, Invitrogen). This pioneering work on click chemistry with RNA was done with cellular RNA in fixed cells using CuSO4 and ascorbic acid for catalysis of the cycloaddition reaction. Unfortunately, these conditions can lead to substantial degradation of RNA and are not suitable as a synthetic protocol for triazole-modified strands. Nevertheless, earlier studies on click reactions with modified DNA suggested that the presence of a copper-binding ligand would reduce degradation observed in the presence of copper salts (). With this information in hand, we and others have since published protocols for high yielding CuAAC reactions useful for preparing triazole-modified RNA for a variety of applications (–, –, –).

A., Jr., Synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by copper-catalyzed cycloaddition-coupling of azides and terminal alkynes.
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Synthesis and biological properties of triazole-linked locked ..

(A) Schematic diagram showing bioconjugation of HAuNS-siRNA and photothermal-induced siRNA release. (B) Schematic diagram showing the synthesis of F-PEG-HAuNS-siRNA and the proposed intracellular events following near-IR irradiation. (C) Effect of p65 siRNA photothermal transfection combined with irinotecan delivered to nude mice bearing HeLa cancer xenografts. (D) Micro-PET/CT imaging of nude mice bearing HeLa cervical cancer xenografts in right rear leg 6 h after intravenous injection of F-PEG-HAuNS-siRNA(DOTA-64Cu) or PEG-HAuNS-siRNA(DOTA-64Cu). Arrowheads indicate the tumors. Reproduced with permission from ref. [].

Click Chemistry -- Publications

A Convenient Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition/Coupling of Alkynes, Phenylboronic Acids, and Sodium Azide Catalyzed by Cu(I)/Cu(II).

Surface modification, functionalization and …

Li . designed folate receptor-targeted hollow gold nanospheres carrying siRNA recognizing NF-B, a transcription factor related to the expression of genes involved in tumor development [,]. In this case, the photothermal effects of gold nanospheres were utilized to regulate drug release and as a therapeutic tool. Core/shell-structured hollow gold nanospheres (HAuNS, 40 nm) were initially synthesized, consisting of a thin gold wall with a hollow interior, and the structures displayed strong surface plasmon resonance (SPR) tunability in the near-IR region [-]. Thiol-modified siRNA duplexes directed toward the NF-B p65 subunit were then introduced to the surface of HAuNS. Folates were coupled to the nanoparticles through a thioctic acid-terminated PEG linker to produce F-PEG-HAuNS-siRNA (Figure A and B). Irradiation with a pulsed near-IR laser (800 nm) altered the absorption spectra of the HAuNS-siRNA solutions significantly, indicating a loss in the structural integrity and triggering the dissociation of siRNA from HAuNS, when demonstrated by TEM and fluorescence microscopy images. This mode of action is termed 'photothermal transfection'. Intravenous injection of the nanospheres into HeLa xenografts resulted in the distinct downregulation of the NF-B p65 subunit only for the folate-conjugated nanosphere treatment combined with near-IR laser irradiation, suggesting that selective targeting and endolysosomal escape of the nanoparticles was activated by near-IR irradiation at the tumor site. tests, in which therapy was combined with administration of irinotecan, a chemotherapeutic agent that increases sensitivity to NF-B inhibition, yielded a substantially enhanced apoptotic response (Figure C). micro-positron emission tomography (PET))/computed tomography (CT) imaging also confirmed the folate-mediated tumor-targeted theranostic properties of the nanostructures (Figure D). Although significant uptake of the nanoparticles was observed in the liver, spleen, kidney, and lung, no significant downregulation of p65 in these organs was observed as a result of the tumor-selective near-IR irradiation.

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