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Hierarchically assembled theranostic nanostructures for siRNA delivery and imaging applications.

ABSTRACT: Dual functional hierarchically assembled nanostructures, with two unique functions of carrying therapeutic cargo electrostatically and maintaining radiolabeled imaging agents covalently within separate component building blocks, have been developed via the supramolecular assembly of several spherical cationic shell cross-linked nanoparticles clustered around a central anionic shell cross-linked cylinder. The shells of the cationic nanoparticles and the hydrophobic core domain of the anionic central cylindrical nanostructure of the assemblies were utilized to complex negatively charged nucleic acids (siRNA) and to undergo radiolabeling, respectively, for potential theranostic applications. The assemblies exhibited exceptional cell transfection and radiolabeling efficiencies, providing an overall advantage over the individual components, which could each facilitate only one or the other of the functions.

SUBMITTER: Shrestha R

PROVIDER: S-EPMC3485678 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Hierarchically assembled theranostic nanostructures for siRNA delivery and imaging applications.

Shrestha Ritu R Elsabahy Mahmoud M Luehmann Hannah H Samarajeewa Sandani S Florez-Malaver Stephanie S Lee Nam S NS Welch Michael J MJ Liu Yongjian Y Wooley Karen L KL

Journal of the American Chemical Society 20121010 42

Dual functional hierarchically assembled nanostructures, with two unique functions of carrying therapeutic cargo electrostatically and maintaining radiolabeled imaging agents covalently within separate component building blocks, have been developed via the supramolecular assembly of several spherical cationic shell cross-linked nanoparticles clustered around a central anionic shell cross-linked cylinder. The shells of the cationic nanoparticles and the hydrophobic core domain of the anionic cent ...[more]

PMID: 23050597

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Project description:Development of multifunctional nanostructures that can be tuned to codeliver multiple drugs and diagnostic agents to diseased tissues is of great importance. Hierarchically assembled theranostic (HAT) nanostructures based on anionic cylindrical shell cross-linked nanoparticles and cationic shell cross-linked knedel-like nanoparticles (cSCKs) have recently been developed by our group to deliver siRNA intracellularly and to undergo radiolabeling. In the current study, paclitaxel, a hydrophobic anticancer drug, and siRNA have been successfully loaded into the cylindrical and spherical components of the hierarchical assemblies, respectively. Cytotoxicity, immunotoxicity, and intracellular delivery mechanism of the HAT nanostructures and their individual components have been investigated. Decoration of nanoparticles with F3-tumor homing peptide was shown to enhance the selective cellular uptake of the spherical particles, whereas the HAT nanoassemblies underwent an interesting disassembly process in contact with either OVCAR-3 or RAW 264.7 cell lines. The HAT nanostructures were found to "stick" to the cell membrane and "trigger" the release of spherical cSCKs templated onto their surfaces intracellularly, while retaining the cylindrical part on the cell surface. Combination of paclitaxel and cell-death siRNA (siRNA that induces cell death) into the HAT nanostructures resulted in greater reduction in cell viability than siRNA complexed with Lipofectamine and the assemblies loaded with the individual drugs. In addition, a shape-dependent immunotoxicity was observed for both spherical and cylindrical nanoparticles with the latter being highly immunotoxic. Supramolecular assembly of the two nanoparticles into the HAT nanostructures significantly reduced the immunotoxicity of both cSCKs and cylinders. HAT nanostructures decorated with targeting moieties, loaded with nucleic acids, hydrophobic drugs, radiolabels, and fluorophores, with control over their toxicity, immunotoxicity, and intracellular delivery might have great potential for biomedical delivery applications.

Project description:The synthesis of self-assembled peptide nanoparticles using a facile one-pot synthesis approach is gaining increasing attention, allowing therapy in combination with diagnosis. Their drawback is limited diagnostic potential, which can be improved after necessary modifications and efficacious functionalization. Herein, a cyclic heptapeptide having the Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence was modified by conjugation of the ε-amino group of the terminal lysine residue with diethylenetriamine pentaacetic acid (DTPA) as a bifunctional chelating agent (BFC) for radiolabeling with a γ-emitting radionuclide (99mTc, half-life 6.01 h; energy 140 keV). Further, the free amino group of the middle lysine residue was successfully conjugated with near-infrared fluorescence (NIRF) dye Cyanine5.5 N-succinimidyl ester (Ex/Em = 670/701 nm) by a co-assembly method to form newly designed novel NIRF dye conjugated self-assembled peptide-DTPA (Cy5.5@SAPD) nanoparticles. The fluorescent nanoparticle formation was confirmed by using a fluorescence spectrophotometer (Ex/Em = 650/701 nm), and the transmission electron microscope (TEM) images showed a size of ∼ 40 nm with a lattice fringe distance of 0.294 nm. Cytotoxicity and confocal laser scanning microscopy (CLSM) studies showed that these nanoparticles possess a high affinity for the αvβ3-integrin receptor overexpressed on brain tumor glioblastoma with an EC50 = 20 μM. Moreover, these nanoparticles were observed to have potential to internalize into U87MG cells more prominently than HEK-293 cancer cells and induce apoptosis. The apoptosis assay showed 79.5% apoptotic cells after 24 h treatment of Cy5.5@SAPD nanoparticles. Additionally, these nanoparticles were also radiolabeled with 99mTc for the single photon emission computed tomography (SPECT) imaging study in tumor-bearing female Balb/c mice. The excellent imaging feature of Cy5.5@SAPD-99mTc nanoparticles as a multimodal (SPECT/NIRF) diagnostic probe, as well as noteworthy therapeutic potential was observed. The results suggested that our newly designed novel dual-targeting dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme.

Project description:Synthetic nucleic acids have shown great potential in the treatment of various diseases. Nevertheless, the selective delivery to a target tissue has proved challenging. The coupling of nucleic acids to targeting peptides, proteins, and antibodies has been explored as an approach for their selective tissue delivery. Nevertheless, the preparation of covalently coupled peptides and proteins that can also undergo intracellular release as well as deliver more than one copy of the nucleic acid has proved challenging. Recently, we have developed a novel method for the rapid noncovalent conjugation of nucleic acids to targeting single chain antibodies (scFv) using chemically self-assembled nanostructures (CSANs). CSANs have been prepared by the self-assembly of two dihydrofolate reductase molecules (DHFR(2)) and a targeting scFv in the presence of bis-methotrexate (bis-MTX). The valency of the nanorings can be tuned from one to eight subunits, depending on the length and composition of the linker between the dihydrofolate reductase molecules. To explore their potential for the therapeutic delivery of nucleic acids as well as the ability to expand the capabilities of CSANs by incorporating smaller cyclic targeting peptides, we prepared DHFR(2) proteins fused through a flexible peptide linker to cyclic-RGD, which targets ?v?3 integrins, and a bis-MTX chemical dimerizer linked to an antisense oligonucleotide (bis-MTX-ASO) that has been shown to silence expression of eukaryotic translation initiation factor 4E (eIF4E). Monomeric and multimeric cRGD-CSANs were then prepared with bis-MTX-ASO and shown to undergo endocytosis in the breast cancer cell line, MDA-MB-231, which overexpresses ?v?3. The bis-MTX-ASO was shown to undergo endosomal escape resulting in the knock down of eIF4E with at least the same efficiency as ASO delivered by oligofectamine. The modularity, flexibility, and common method of conjugation may prove to be a useful general approach for the targeted delivery of ASOs, as well as other nucleic acids to cells.

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Hierarchically assembled theranostic nanostructures for siRNA delivery and imaging applications.

Publications

Hierarchically assembled theranostic nanostructures for siRNA delivery and imaging applications.

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