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1.  Biodegradable Cationic Polymeric Nanocapsules for Overcoming Multidrug Resistance and Enabling Drug-Gene Co-Delivery to Cancer Cells 
Nanoscale  2014;6(3):1567-1572.
Having unique architectural features, cationic polymeric nanocapasules (NCs) with well-defined covalently-stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in significant chemotherapeutic effect and/or IL-8 gene silencing.
doi:10.1039/c3nr04804g
PMCID: PMC4522154  PMID: 24326457
2.  Size-Tunable and Monodisperse Tm3+/Gd3+-Doped Hexagonal NaYbF4 Nanoparticles with Engineered Efficient Near Infrared-to-Near Infrared Upconversion for In Vivo Imaging 
ACS Applied Materials & Interfaces  2014;6(16):13884-13893.
Hexagonal NaYbF4:Tm3+ upconversion nanoparticles hold promise for use in high contrast near-infrared-to-near-infrared (NIR-to-NIR) in vitro and in vivo bioimaging. However, significant hurdles remain in their preparation and control of their morphology and size, as well as in enhancement of their upconversion efficiency. Here, we describe a systematic approach to produce highly controlled hexagonal NaYbF4:Tm3+ nanoparticles with superior upconversion. We found that doping appropriate concentrations of trivalent gadolinium (Gd3+) can convert NaYbF4:Tm3+ 0.5% nanoparticles with cubic phase and irregular shape into highly monodisperse NaYbF4:Tm3+ 0.5% nanoplates or nanospheres in a pure hexagonal-phase and of tunable size. The intensity and the lifetime of the upconverted NIR luminescence at 800 nm exhibit a direct dependence on the size distribution of the resulting nanoparticles, being ascribed to the varied surface-to-volume ratios determined by the different nanoparticle size. Epitaxial growth of a thin NaYF4 shell layer of ∼2 nm on the ∼22 nm core of hexagonal NaYbF4:Gd3+ 30%/Tm3+ 0.5% nanoparticles resulted in a dramatic 350 fold NIR upconversion efficiency enhancement, because of effective suppression of surface-related quenching mechanisms. In vivo NIR-to-NIR upconversion imaging was demonstrated using a dispersion of phospholipid-polyethylene glycol (DSPE-PEG)-coated core/shell nanoparticles in phosphate buffered saline.
doi:10.1021/am503288d
PMCID: PMC4149327  PMID: 25027118
near-infrared; upconversion nanocrystals; core−shell; bioimaging
3.  High Contrast In vitro and In vivo Photoluminescence Bioimaging Using Near Infrared to Near Infrared Up-Conversion in Tm3+ and Yb3+ Doped Fluoride Nanophosphors 
Nano letters  2008;8(11):3834-3838.
A new approach for photoluminescence imaging in vitro and in vivo has been shown, utilizing near infrared to near infrared (NIR-to-NIR) up-conversion in nanophosphors. This NIR-to-NIR up-conversion process provides deeper light penetration into biological specimen and results in high contrast optical imaging due to absence of an autofluorescence background and decreased light scattering. Aqueous dispersible fluoride (NaYF4) nanocrystals (20–30 nm size) co-doped with the rare earth ions, Tm3+ and Yb3+, were synthesized and characterized by TEM, XRD and photoluminescence (PL) spectroscopy. In vitro cellular uptake was shown by the PL microscopy visualizing the characteristic emission of Tm3+ at ~ 800 nm excited with 975 nm. No apparent cytotoxicity was observed. Subsequent animal imaging studies were performed using Balb-c mice injected intravenously with up-converting nanophosphors, demonstrating the high contrast PL imaging in vivo.
doi:10.1021/nl802223f
PMCID: PMC3523349  PMID: 18928324
Nanophosphors; Energy Up-conversion; Near Infrared In vitro and In vivo imaging
4.  Gene Silencing of Human Neuronal Cells for Drug Addiction Therapy using Anisotropic Nanocrystals 
Theranostics  2012;2(7):695-704.
Theranostic platform integrating diagnostic imaging and therapeutic function into a single system has become a new direction of nanoparticle research. In the process of treatment, therapeutic efficacy is monitored. The use of theranostic nanoparticle can add an additional "layer" to keep track on the therapeutic agent such as the pharmacokinetics and biodistribution. In this report, we have developed quantum rod (QR) based formulations for the delivery of small interfering RNAs (siRNAs) to human neuronal cells. PEGlyated QRs with different surface functional groups (amine and maleimide) were designed for selectively down-regulating the dopaminergic signaling pathway which is associated with the drug abuse behavior. We have demonstrated that the DARPP-32 siRNAs were successfully delivered to dopaminergic neuronal (DAN) cells which led to drastic knockdown of specific gene expression by both the electrostatic and covalent bond conjugation regimes. The PEGlyated surface offered high biocompatibilities and negligible cytotoxicities to the QR formulations that may facilitate the in vivo applications of these nanoparticles.
doi:10.7150/thno.3459
PMCID: PMC3418925  PMID: 22896771
Quantum Rod; Gene Delivery; Addiction Gene Therapy; Phospholipid; PEG; siRNA.
6.  Gold Nanorod-siRNA Induces Efficient In Vivo Gene Silencing in the Rat Hippocampus 
Nanomedicine (London, England)  2011;6(4):617-630.
Gold nanorods (GNRs), cellular imaging nanoprobes, have been used for drug delivery therapy to immunologically privileged regions in the brain. We demonstrate that nanoplexes formed by electrostatic binding between negatively charged RNA and positively charged GNRs, silence the expression of the target housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) within the CA1 hippocampal region of the rat brain, without showing cytotoxicity. Fluorescence imaging with siRNACy3GAPDH and dark field imaging using plasmonic enhanced scattering from GNRs were used to monitor the distribution of the nanoplexes within different neuronal cell types present in the targeted hippocampal region. Our results show robust nanoplex uptake and slow release of the fluorescent gene silencer with significant impact on suppression of GAPDH gene expression (70% gene silencing, >10 days post-injection). The observed gene knockdown using nanoplexes in targeted regions of the brain opens a new era of drug treatment for neurological disorders.
doi:10.2217/nnm.11.20
PMCID: PMC3132138  PMID: 21718174
gold nanorods; hippocampus; rat; siRNA; transfection; neurological disorders; dark field; brain
7.  Single Cell Assay for Molecular Diagnostics and Medicine: Monitoring Intracellular Concentrations of Macromolecules by Two-photon Fluorescence Lifetime Imaging 
Theranostics  2015;5(9):919-930.
Molecular organization of a cell is dynamically transformed along the course of cellular physiological processes, pathologic developments or derived from interactions with drugs. The capability to measure and monitor concentrations of macromolecules in a single cell would greatly enhance studies of cellular processes in heterogeneous populations. In this communication, we introduce and experimentally validate a bio-analytical single-cell assay, wherein the overall concentration of macromolecules is estimated in specific subcellular domains, such as structure-function compartments of the cell nucleus as well as in nucleoplasm. We describe quantitative mapping of local biomolecular concentrations, either intrinsic relating to the functional and physiological state of a cell, or altered by a therapeutic drug action, using two-photon excited fluorescence lifetime imaging (FLIM). The proposed assay utilizes a correlation between the fluorescence lifetime of fluorophore and the refractive index of its microenvironment varying due to changes in the concentrations of macromolecules, mainly proteins. Two-photon excitation in Near-Infra Red biological transparency window reduced the photo-toxicity in live cells, as compared with a conventional single-photon approach. Using this new assay, we estimated average concentrations of proteins in the compartments of nuclear speckles and in the nucleoplasm at ~150 mg/ml, and in the nucleolus at ~284 mg/ml. Furthermore, we show a profound influence of pharmaceutical inhibitors of RNA synthesis on intracellular protein density. The approach proposed here will significantly advance theranostics, and studies of drug-cell interactions at the single-cell level, aiding development of personal molecular medicine.
doi:10.7150/thno.11863
PMCID: PMC4493531  PMID: 26155309
Fluorescence lifetime imaging (FLIM); two-photon excited fluorescence; macromolecular crowding; protein concentration; nuclear organization; nucleoplasm; nucleolus; nuclear speckles.
8.  Influence of non-reactive solvent on optical performance, photopolymerization kinetics and morphology of nanoporous polymer gratings 
European polymer journal  2010;46(5):937-943.
A study of nanoporous polymer gratings, with controllable nanostructured porosity, as a function of grating performance, photopolymerization kinetics and morphology is presented. Modifying the standard holographic polymer dispersed liquid crystal (H-PDLC) system, by including a non-reactive solvent, results in a layered, nanoporous morphology and produces reflective optical elements with excellent optical performance of broadband reflection. The addition of the non-reactive solvent in the pre-polymer mixture results in a morphology typified by void/polymer layer-by-layer structures if sufficient optical energy is used during the holographic writing process. The duration and intensity of optical exposure necessary to form well-aligned nanoporous structures can only be obtained in the modified system by (a) illumination under longer time of holographic interference patterning (30 min) or (b) illumination under very short time of holographic interference patterning (30 s) and followed by post-curing using homogeneous optical exposure for 60 min. Comparatively, a typical H-PDLC is formed in less than 1 min. To further understand the differences in the formation of these two analogous materials, the temporal dynamics of the photoinitiation and polymerization (propagation) kinetics were examined. It is shown herein that the writing exposure gives a cross-linked polymer network that is denser in the bright regions. With 60% (or even 45%) acrylate conversion, almost no free monomer would be left after the writing. Continued exposure serves primarily to add cross-links. This has the tendency to collapse the network, especially the less dense portions, which in effect get glued down to the more dense parts. To the extent that the solvent increases the mobility of the polymer network, this process will be aided. Equally important, the size of the periodic nanopores can be varied from 10 to 50 nm by controlling either the LC concentration in the pre-polymer mixture or by controlling the time of the homogeneous post-cure.
doi:10.1016/j.eurpolymj.2010.01.022
PMCID: PMC4276335  PMID: 25544779
Nanoporous polymer; Holographic polymer dispersed liquid crystal; Photopolymerization kinetics; Phase separation
9.  Fluorogenic, Two-Photon Triggered Photoclick Chemistry in Live Mammalian Cells 
Journal of the American Chemical Society  2013;135(45):10.1021/ja407867a.
The tetrazole-based photoclick chemistry has provided a powerful tool to image proteins in live cells. To extend photoclick chemistry to living organisms with improved spatiotemporal control, here we report the design of naphthalene-based tetrazoles that can be efficiently activated by two-photon excitation with a 700 nm femtosecond pulsed laser. A water-soluble, cell-permeable naphthalene-based tetrazole was identified that reacts with acrylamide with the effective two-photon cross section for the cycloaddition reaction determined to be 3.8 GM. Furthermore, the use of this naphthalene-tetrazole for real-time, spatially controlled imaging of microtubules in live mammalian cells via the fluorogenic, two-photon triggered photoclick chemistry was demonstrated.
doi:10.1021/ja407867a
PMCID: PMC3866799  PMID: 24168622
10.  A New Method for Delivering a Hydrophobic Drug for Photodynamic Therapy Using Pure Nanocrystal Form of the Drug 
Molecular pharmaceutics  2007;4(2):289-297.
A carrier free method for delivery of a hydrophobic drug in its pure form, using nanocrystals (nano sized crystals) is proposed. To demonstrate this technique, nanocrystals of a hydrophobic photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide (HPPH), have been synthesized using re-precipitation method. The resulting drug nanocrystals were monodispersed and stable in aqueous dispersion, without the necessity of an additional stabilizer (surfactant). As shown by confocal microscopy, these pure drug nanocrystals were taken-up by the cancer cells with high avidity. Though the fluorescence and photodynamic activity of the drug were substantially quenched in the form of nanocrystals in aqueous suspension, both these characteristics were recovered under in vitro and in vivo conditions. This recovery of drug activity and fluorescence is possibly due to the interaction of nanocrystals with serum albumin, resulting in conversion of the drug nanocrystals into the molecular form. This was confirmed by demonstrating similar recovery in presence of Fetal Bovine Serum (FBS) or Bovine Serum Albumin (BSA). Under similar treatment conditions, the HPPH in nanocrystal form or in 1% Tween 80/water formulation showed comparable in vitro and in vivo efficacy.
doi:10.1021/mp060117f
PMCID: PMC2667689  PMID: 17266331
nanocrystals; re-precipitation method; photosensitizers; photodynamic therapy; singlet oxygen; drug delivery
11.  Pd-Porphyrin-Crosslinked Implantable Hydrogels with Oxygen-Responsive Phosphorescence 
Advanced healthcare materials  2013;3(6):891-896.
Development of long-term implantable luminescent biosensors for subcutaneous oxygen has proved challenging due to difficulties in immobilizing a biocompatible matrix that prevents sensor aggregation yet maintains sufficient concentration for transdermal optical detection. Here, we demonstrate that Pd-porphyrins can be used as PEG crosslinkers to generate a polyamide hydrogel with extreme porphyrin density (~5 mM). Dye aggregation was avoided due to the spatially constraining 3-D mesh formed by the porphyrins themselves. The hydrogel exhibited oxygen-responsive phosphorescence and could be stably implanted subcutaneously in mice for weeks without degradation, bleaching or host rejection. To further facilitate oxygen detection using steady state techniques, we developed an oxygen non-responsive companion hydrogel by blending copper and free base porphyrins to yield intensity-matched luminescence for ratiometric detection.
doi:10.1002/adhm.201300483
PMCID: PMC4143977  PMID: 24259519
hydrogels; porphyrins; imaging; oxygen sensing; phosphorescence; implants
12.  Well-Defined Degradable Cationic Polylactide as Nanocarrier for the Delivery of siRNA to Silence Angiogenesis in Prostate Cancer 
Advanced healthcare materials  2012;1(6):751-761.
Well-defined tertiary amine-functionalized cationic polylactides (CPLAs) are synthesized by thiol-ene click functionalization of an allyl-functionalized polylactide, and utilized here for the delivery of interleukin-8 (IL-8) siRNA via CPLA-IL-8 siRNA nanoplexes. The CPLAs possess remarkable hydrolytic degradability, and their cytotoxicity is relatively low. The CPLA-IL-8 siRNA nanoplexes can be readily taken up by prostate cancer cells, resulting in significant IL-8 gene silencing. It is found that the degradability and cytotoxicity of CPLAs, as well as the transfection efficiency of the CPLA-IL-8 siRNA nanoplexes, positively correlate with the amine mol% of CPLAs.
doi:10.1002/adhm.201200094
PMCID: PMC3634581  PMID: 23184827
cationic polymer; degradable polymer; prostate cancer; gene delivery; RNAi
13.  (α-NaYbF4:Tm3+)/CaF2 Core/Shell Nanoparticles with Efficient Near-Infrared to Near-Infrared Upconversion for High-Contrast Deep Tissue Bioimaging 
ACS nano  2012;6(9):8280-8287.
We describe the development of novel and biocompatible core/shell (α-NaYbF4:Tm3+)/CaF2 nanoparticles which exhibit highly efficient NIRin-NIRout upconversion (UC) for high contrast and deep bioimaging. When excited at ~980 nm, these nanoparticles emit photoluminescence (PL) peaked at ~800 nm. The quantum yield of this UC PL under low power density excitation (~0.3 W/cm2) is 0.6±0.1%. This high UC PL efficiency is realized by suppressing surface quenching effects via hetero-epitaxial growth of a biocompatible CaF2 shell which results in a 35-fold increase in the intensity of UC PL from the core. Small animal whole-body UC PL imaging with exceptional contrast (signal-to-background ratio of 310) is shown using BALB/c mice intravenously injected with aqueously dispersed nanoparticles (700 pmol/kg). High-contrast UC PL imaging of deep tissues is also demonstrated, using a nanoparticle-loaded synthetic fibrous mesh wrapped around rat femoral bone, and a cuvette with nanoparticle aqueous dispersion - covered with a 3.2-cm thick animal tissue (pork).
doi:10.1021/nn302972r
PMCID: PMC3523358  PMID: 22928629
near infrared; photoluminescence bioimaging; upconversion nanocrystals; lanthanide; core/shell
14.  Increasing TNF Levels Solely in the Rat Hippocampus Produces Persistent Pain-like Symptoms 
Pain  2012;153(9):1871-1882.
The manifestation of chronic, neuropathic pain includes elevated levels of the cytokine tumor necrosis factor-alpha (TNF). Previously, we have shown that the hippocampus, an area of the brain most notable for its role in learning and memory formation, plays a fundamental role in pain sensation. Using an animal model of peripheral neuropathic pain, we have demonstrated that intracerebroventricular (icv) infusion of a TNF antibody adjacent to the hippocampus completely alleviated pain. Furthermore, icv infusion of rTNF adjacent to the hippocampus induced pain behavior in naïve animals similar to that expressed during a model of neuropathic pain. These data support our premise that enhanced production of hippocampal-TNF is integral in pain sensation. In the present study, TNF gene expression was induced exclusively in the hippocampus eliciting increased local bioactive TNF levels, and animals were assessed for pain behaviors. Male, Sprague-Dawley rats received stereotaxic injection of gold nanorod (GNR)-complexed cDNA (control or TNF) plasmids (nanoplasmidexes), and pain responses (i.e., thermal hyperalgesia and mechanical allodynia) were measured. Animals receiving hippocampal microinjection of TNF nanoplasmidexes developed thermal hyperalgesia bilaterally. Sensitivity to mechanical stimulation also developed bilaterally in the rat hind paws. In support of these behavioral findings, immunoreactive staining for TNF, bioactive levels of TNF, and levels of TNF mRNA as per PCR analysis were assessed in several brain regions and found to be increased only in the hippocampus. These findings indicate that the specific elevation of TNF in the hippocampus is not a consequence of pain, but in fact induces these behaviors/symptoms.
doi:10.1016/j.pain.2012.05.028
PMCID: PMC3417838  PMID: 22770843
15.  Organically Modified Silica Nanoparticles with Intraparticle Heavy-Atom Effect on the Encapsulated Photosensitizer for Enhanced Efficacy of Photodynamic Therapy 
We report a novel nanoassembly formulation for photodynamic therapy, which is composed of covalently iodine-concentrated organically modified silica (ORMOSIL) nanoparticles (diameter <30 nm) and a hydrophobic photosensitizer embedded therein. Comparative studies with iodinated and non-iodinated nanoparticles have demonstrated that the intraparticle external heavy-atom effect on the encapsulated photosensitizer molecules significantly enhances the efficiency of 1O2 generation, and thereby, the in vitro PDT efficacy.
doi:10.1021/jp900573s
PMCID: PMC3686300  PMID: 23795227
16.  Near infrared phosphorescent polymeric nanomicelles: efficient optical probes for tumor imaging and detection 
ACS applied materials & interfaces  2009;1(7):1474-1481.
We report a formulation of near infrared (NIR) phosphorescent polymeric nanomicelles and their use for in vivo high contrast optical imaging, targeting and detection of tumors in small animals. NIR phosphorescent molecules of Pt(II)-tetraphenyltetranaphthoporphyrin [Pt(TPNP)] were found to maintain their NIR phosphorescence properties when encapsulated into phospholipid nanomicelles. The prepared phosphorescent micelles are of ~100 nm size and are highly stable in aqueous suspensions. A large spectral separation between Pt(TPNP) absorption, peaked at ~700 nm, and its phosphorescence emission, with peak at ~ 900 nm, allows a dramatic decrease in the level of background autofluorescence and scattered excitation light in the NIR spectral range, where the signal from phosphorescent probe is observed. In vivo animal imaging with subcutaneously xenograted tumor-bearing mice has resulted in high contrast optical images, indicating highly specific accumulation of the phosphorescent micelles into tumors. Using optical imaging with NIR phosphorescent nanomicelles, detection of smaller, visually undetectable tumors has also been demonstrated.
doi:10.1021/am9001293
PMCID: PMC3681954  PMID: 20355951
Optical imaging; Near Infra Red (NIR); Phosphorescence; nanomicelles
17.  Core/Shell NaGdF4:Nd3+/NaGdF4 Nanocrystals with Efficient Near-Infrared to Near-Infrared Downconversion Photoluminescence for Bioimaging Applications 
ACS nano  2012;6(4):2969-2977.
We have synthesized core/shell NaGdF4:Nd3+/NaGdF4 nanocrystals with an average size of 15 nm and exceptionally high photoluminescence (PL) quantum yield. When excited at 740 nm, the nanocrystals manifest spectrally distinguished, near infrared to near infrared (NIR-to-NIR) downconversion PL peaked at ~900, ~1050, and ~1300 nm. The absolute quantum yield of NIR-to-NIR PL reached 40% for core-shell nanoparticles dispersed in hexane. Time-resolved PL measurements revealed that this high quantum yield was achieved through suppression of nonradiative recombination originating from surface states and cross relaxations between dopants. NaGdF4:Nd3+/NaGdF4 nanocrystals, synthesized in organic media, were further converted to be water-dispersible by eliminating the capping ligand of oleic acid. NIR-to-NIR PL bioimaging was demonstrated both in vitro and in vivo through visualization of the NIR-to-NIR PL at ~900 nm under incoherent lamp light excitation. The fact that both excitation and the PL of these nanocrystals are in the biological window of optical transparency, combined with their high quantum efficiency, spectral sharpness and photostability, makes these nanocrystals extremely promising as optical biomaging probes.
doi:10.1021/nn2042362
PMCID: PMC3430515  PMID: 22401578
near-infrared; photoluminescence; nanocrystals; lanthanide; bioimaging
18.  Morphine and galectin-1 modulate HIV-1 infection of human monocytes-derived macrophages 
Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they not only play a role in the development of this disease but also impact the overall course of disease progression. Galectin-1 is a member of a family of β-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Since the drug abuse epidemic and the HIV-1 epidemic are closely interrelated we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocytes-derived macrophages (MDM). Here, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDM. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDM. We utilized a nanotechnology approach that uses gold nanorod-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1 and the nanoplexes reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex.
doi:10.4049/jimmunol.1102276
PMCID: PMC3324598  PMID: 22430735
19.  Facile Synthesis and Potential Bioimaging Applications of Hybrid Upconverting and Plasmonic NaGdF4: Yb3+, Er3+/Silica/Gold Nanoparticles 
Theranostics  2013;3(4):275-281.
We present a simple method for preparing water dispersible NaGdF4: Yb3+, Er3+/silica/gold nanoparticles. The emission intensity and color of the upconverting cores are modulated by the plasmonic absorbance and field enhancement from the gold nanoparticles. The applicability of hybrid NPs for multi-modal bioimaging probes is illustrated by in vitro confocal microscopy of living cancer cells.
doi:10.7150/thno.4983
PMCID: PMC3630528  PMID: 23606914
Upconversion; Gold; Nanoparticles; Photoluminescence; Bioimaging.
20.  Bioengineering Silicon Quantum Dot Theranostics using a Network Analysis of Metabolomic and Proteomic Data in Cardiac Ischemia 
Theranostics  2013;3(9):719-728.
Metabolomic profiling is ideally suited for the analysis of cardiac metabolism in healthy and diseased states. Here, we show that systematic discovery of biomarkers of ischemic preconditioning using metabolomics can be translated to potential nanotheranostics. Thirty-three patients underwent percutaneous coronary intervention (PCI) after myocardial infarction. Blood was sampled from catheters in the coronary sinus, aorta and femoral vein before coronary occlusion and 20 minutes after one minute of coronary occlusion. Plasma was analysed using GC-MS metabolomics and iTRAQ LC-MS/MS proteomics. Proteins and metabolites were mapped into the Metacore network database (GeneGo, MI, USA) to establish functional relevance. Expression of 13 proteins was significantly different (p<0.05) as a result of PCI. Included amongst these was CD44, a cell surface marker of reperfusion injury. Thirty-eight metabolites were identified using a targeted approach. Using PCA, 42% of their variance was accounted for by 21 metabolites. Multiple metabolic pathways and potential biomarkers of cardiac ischemia, reperfusion and preconditioning were identified. CD44, a marker of reperfusion injury, and myristic acid, a potential preconditioning agent, were incorporated into a nanotheranostic that may be useful for cardiovascular applications. Integrating biomarker discovery techniques into rationally designed nanoconstructs may lead to improvements in disease-specific diagnosis and treatment.
doi:10.7150/thno.5010
PMCID: PMC3767118  PMID: 24019856
metabolomics; silicon quantum dots; theranostics; cardiac ischemia; myocardial infarction.
21.  Anti-HIV-1 nanotherapeutics: promises and challenges for the future 
The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis for human immunodeficiency virus (HIV)-infected patients, however the adverse side effects associated with prolonged HAART therapy use continue. Although systemic viral load can be undetectable, the virus remains sequestered in anatomically privileged sites within the body. Nanotechnology-based delivery systems are being developed to target the virus within different tissue compartments and are being evaluated for their safety and efficacy. The current review outlines the various nanomaterials that are becoming increasingly used in biomedical applications by virtue of their robustness, safety, multimodality, and multifunctionality. Nanotechnology can revolutionize the field of HIV medicine by not only improving diagnosis, but also by improving delivery of antiretrovirals to targeted regions in the body and by significantly enhancing the efficacy of the currently available antiretroviral medications.
doi:10.2147/IJN.S25871
PMCID: PMC3468275  PMID: 23055735
nanotherapeutics; HAART; HIV; nano; nanomedicine; drug delivery
22.  Nanoparticle Based Galectin-1 Gene Silencing, Implications in Methamphetamine Regulation of HIV-1 Infection in Monocyte Derived Macrophages 
Galectin-1, an adhesion molecule, is expressed in macrophages and implicated in human immunodeficiency virus (HIV-1) viral adsorption. In this study, we investigated the effects of methamphetamine on galectin-1 production in human monocyte derived macrophages (MDM) and the role of galectin-1 in methamphetamine potentiation of HIV-1 infection. Herein we show that levels of galectin-1 gene and protein expression are significantly increased by meth-amphetamine. Furthermore, concomitant incubation of MDM with galectin-1 and methamphetamine facilitates HIV-1 infection compared to galectin-1 alone or methamphetamine alone. We utilized a nanotechnology approach that uses gold nanorod (GNR)-galectin-1 siRNA complexes (nanoplexes) to inhibit gene expression for galectin-1. Nanoplexes significantly silenced gene expression for galectin-1 and reversed the effects of methamphetamine on galectin-1 gene expression. Moreover, the effects of methamphetamine on HIV-1 infection were attenuated in the presence of the nanoplex in MDM.
doi:10.1007/s11481-012-9379-7
PMCID: PMC3419803  PMID: 22689223
Macrophage; HIV-1; Galectin-1; Goldnanorod; siRNA
23.  Intense Visible and Near-Infrared Upconversion Photoluminescence in Colloidal LiYF4:Er3+ Nanocrystals under Excitation at 1490 nm 
ACS nano  2011;5(6):4981-4986.
We report intense upconversion photoluminescence (PL) in colloidal LiYF4:Er3+ nanocrystals under excitation with telecom-wavelength at 1490 nm. The intensities of two- and three-photon anti-Stokes upconversion PL bands are higher than or comparable to that of the Stokes emission under excitation with low power density in the range of 5–120 W/cm2. The quantum yield of the upconversion PL was measured to be as high as ~1.2±0.1%, which is almost 4 times higher than the highest upconversion PL quantum yield reported up to date for lanthanide-doped nanocrystals in 100 nm sized hexagonal NaYF4:Yb3+20%, Er3+2% using excitation at ~980 nm. Power dependence study revealed that the intensities of all PL bands have linear dependence on the excitation power density, which was explained by saturation effects in the intermediate energy states.
doi:10.1021/nn201083j
PMCID: PMC3430509  PMID: 21557587
near-infrared; upconversion photoluminescence; nanocrystals; lanthanide; telecommunications
24.  Doxorubicin conjugated quantum dots to target alveolar macrophages/inflammation 
Nanomedicine  2010;7(1):88-96.
The ability to provide targeted therapeutic delivery in the lung would be a major advancement in pharmacological treatments for many pulmonary diseases. Critical issues for such successful delivery would require the ability to target specific cell types, minimize toxicity (i.e. inflammatory response) and to deliver therapeutic levels of drugs. We report here on the ability of nanoconjugates of CdSe/CdS/ZnS Quantum Dots (QDs) and doxorubicin (Dox) to target alveolar macrophages cells (aMØ), which play a critical role in the pathogenesis of inflammatory lung injuries. Confocal imaging showed the release of Dox from the QD-Dox nanoconjugate, as was evident by its accumulation in the cell nucleus and induction of apoptosis, suggesting that the drug retains its bioactivity after coupling to the nanoparticle. Inflammatory injury parameters (albumin leakage, proinflammatory cytokines and neutrophil infiltration) were recorded after in vivo admistration of QD-Dox and Dox observing no significant effect after QD-Dox treatment compared with Dox. These results demonstrate that nanoparticle platforms can provide targeted macrophage-selective therapy for the treatment of pulmonary disease.
doi:10.1016/j.nano.2010.09.001
PMCID: PMC3363005  PMID: 20887813
Quantum dots; alveolar macrophages; drug delivery; cytokines; inflammation
25.  Organically Modified Silica Nanoparticles Are Biocompatible and Can Be Targeted to Neurons In Vivo 
PLoS ONE  2012;7(1):e29424.
The application of nanotechnology in biological research is beginning to have a major impact leading to the development of new types of tools for human health. One focus of nanobiotechnology is the development of nanoparticle-based formulations for use in drug or gene delivery systems. However most of the nano probes currently in use have varying levels of toxicity in cells or whole organisms and therefore are not suitable for in vivo application or long-term use. Here we test the potential of a novel silica based nanoparticle (organically modified silica, ORMOSIL) in living neurons within a whole organism. We show that feeding ORMOSIL nanoparticles to Drosophila has no effect on viability. ORMOSIL nanoparticles penetrate into living brains, neuronal cell bodies and axonal projections. In the neuronal cell body, nanoparticles are present in the cytoplasm, but not in the nucleus. Strikingly, incorporation of ORMOSIL nanoparticles into the brain did not induce aberrant neuronal death or interfered with normal neuronal processes. Our results in Drosophila indicate that these novel silica based nanoparticles are biocompatible and not toxic to whole organisms, and has potential for the development of long-term applications.
doi:10.1371/journal.pone.0029424
PMCID: PMC3250438  PMID: 22238611

Results 1-25 (43)