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WIREs Nanomed Nanobiotechnol
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Calcium phosphate‐based composite nanoparticles in bioimaging and therapeutic delivery applications

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Abstract Bioimaging and therapeutic delivery applications are areas of biomedicine where nanoparticles have had significant impact, but the use of a nanomaterial in these applications can be limited by its physicochemical properties. Calcium phosphate‐based composite nanoparticles are nontoxic and biodegradable, and are therefore considered attractive candidates for bioimaging and therapeutic drug delivery applications. Also, the pH‐dependent solubility profiles of calcium phosphate materials make this class of nanoparticles especially useful for in vitro and in vivo delivery of dyes, oligonucleotides, and drugs. In this article, we discuss how calcium phosphate‐based composite nanoparticles fulfill some of the requirements typically made for nanoparticles in biomedical applications. We also highlight recent studies in bioimaging and therapeutic delivery applications focusing on how these studies have addressed some of the challenges associated with using these nanoparticles in bioimaging and delivery of therapeutics. WIREs Nanomed Nanobiotechnol 2012, 4:96–112. doi: 10.1002/wnan.163 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanomaterials and Implants

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Transmission electron microscopy micrograph of indocyanine green encapsulated by calcium phosphosilicate nanoparticles (CPNPs) (a) with inset (b) showing detailed view of spherical particle morphology. Inset (c) shows a schematic of the nanoparticle architecture (green—encapsulated dye, red—alternate encapsulant, blue—surface functionalization). (Reprinted with permission from Ref 3. Copyright 2008 American Chemical Society)

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The effects of calcium phosphosilicate nanoparticles (CPNPs) with encapsulated decanoyl‐ceramide (Cer10) on cell survival and viability of UACC 903 melanoma cells. UACC 903 cells were exposed to rhodamine WT doped CPNPs without Cer10 (a) and with Cer10 (b). Cytotoxicity of nanoparticles both with and without drug was monitored in a dosage‐dependent manner using an MTS assay [green bar represents Cer10 in dimethyl sulfoxide (DMSO), purple bar represents CPNPs without Cer10, and blue bar represent CPNPs with Cer10]. (Reprinted with permission from Ref 5. Copyright 2008 American Chemical Society)

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Transmission light microscopy (top row) and enhanced green fluorescent protein (EGFP) fluorescence microscopy (bottom row) showing cell morphology and fluorescence after transfection with single shell (c), double shell (d), and triple shell (e) calcium phosphate pcDNA3‐EGFP constructs when compared to commercial agent Polyfect® (a) and standard calcium phosphate precipitation method (b). Increased fluorescence in (e) indicates increased transfection for the triple shell particles when compared to the single and double shell particles in (c) and (d), respectively. (Reprinted with permission from Ref 31. Copyright 2006 Pergamon)

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Fluorescence spectra for five organic dyes encapsulated in calcium phosphosilicate nanoparticles (CPNPs): cascade blue (dark blue), 10‐(3‐sulfopropyl) acridinium betaine (SAB: light blue), fluorescein (green), rhodamine WT (orange), and Cy3 amidite (magenta), with inset image showing vials of fluorescent dye doped CPNPs under a UV lamp. (Reprinted with permission from Ref 4. Copyright 2008 American Chemical Society)

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Targeting of indocyanine green (ICG)‐doped calcium phosphosilicate nanoparticles (CPNPs) to an in vivo orthotopic tumor model of pancreatic cancer (a) with polyethylene glycol (PEG) (i), gastrin 10 (ii), and pentagastrin (iii) on the nanoparticle surface. Pancreases from each mouse were excised and imaged (b) along with the brain from mouse receiving gastrin 10 targeted nanoparticles (ii). (Reprinted with permission from Ref 6. Copyright 2010 American Chemical Society)

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A schematic illustrating the steps of the multi‐shell calcium phosphate nanoparticle precipitation approach employed to shield oligonucleotides for therapeutic delivery. A calcium phosphate nanoparticle is decorated with oligonucleotides (step 1) and a second shell of calcium phosphate is precipitated to shield the oligonucleotides on the surface (step 2). Finally, this shell is decorated with oligonucleotides to facilitate dispersion (step 3). In vitro transfection is studied in cells of choice (step 4). (Reprinted with permission from Ref 32. Copyright 2010 Pergamon)

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Progressive dissolution of hydroxyapatite nanoparticles in macrophage lysosomes. At 24 h, the particles are taken up by the cells and localize in the phagosomes (a) and become compacted (b). The nanoparticles then undergo gradual dissolution, first with some particles still intact (c) and with all particles eventually completely dissolved (d). (Reprinted with permission from Ref 29. Copyright 2009 Pergamon)

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Endocytosis of Cy3 encapsulated in calcium phosphosilicate nanoparticles (CPNPs) versus free dye in bovine aortic endothelial cells. Cells were treated with free dye (a), free dye and Cytochalasin‐D to inhibit fusion of endosomes to lysosomes (b), Cy3 CPNPs (c), and Cy3 CPNPs and Cytochalasin‐D (d). The internal organelles are stained in the case of free dye (a), free dye and Cytochalasin‐D (b), and Cy3 CPNPs (c). Cy3 CPNPs did not stain the organelles when treated with Cytochalasin‐D (d) indicating that the particles remained undissolved. (Reprinted with permission from Ref 4 Copyright 2008 American Chemical Society)

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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Diagnostic Tools > In Vitro Nanoparticle-Based Sensing
Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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