Rajesh Shinde - Academia.edu (original) (raw)
Papers by Rajesh Shinde
Particle and Particle Systems Characterization, Feb 1, 1998
The transport properties of particulate process streams and their final product quality, are dire... more The transport properties of particulate process streams and their final product quality, are directly affected by critical parameters of particle size distribution, f(x), and volume, mass, or number density of particles or dispersed phase droplets. A method is proposed for the potential on-line monitoring of particle size distribution and volume fraction in real time, using frequencydomain photon migration measurements (FDPM). Theory, experimental measurements, and results for the determination of particle size distributions for both a polystyrene latex and a titanium dioxide suspension determined using the photon migration technique are presented. The critical issues associated with the application of photon migration to particulate and dispersed phase processes are discussed, including the effects of interparticle interactions on the transport of light.
The Journal of Chemical Physics
ABSTRACT
Pharmacology and Toxicology: Basic and Clinical Aspects, 2006
Proceedings of the National Academy of Sciences, 2007
Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and fo... more Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. Molecular transporters can be used to address these problems. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Here, we describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real time. This process effectively emulates drug-conjugate delivery, drug release, and drug turnover by an intracellular target, providing a facile method to evaluate comparative uptake of new transporters and efficacy and selectivity of linker release as required for fundamental studies and therapeutic applications.
Particle & Particle Systems Characterization, 1998
The transport properties of particulate process streams and their final product quality, are dire... more The transport properties of particulate process streams and their final product quality, are directly affected by critical parameters of particle size distribution, f(x), and volume, mass, or number density of particles or dispersed phase droplets. A method is proposed for the potential on-line monitoring of particle size distribution and volume fraction in real time, using frequencydomain photon migration measurements (FDPM). Theory, experimental measurements, and results for the determination of particle size distributions for both a polystyrene latex and a titanium dioxide suspension determined using the photon migration technique are presented. The critical issues associated with the application of photon migration to particulate and dispersed phase processes are discussed, including the effects of interparticle interactions on the transport of light.
Journal of the American Chemical Society, 2006
The design, synthesis, and evaluation of conjugates of arginine-rich transporters and luciferin a... more The design, synthesis, and evaluation of conjugates of arginine-rich transporters and luciferin are described that release luciferin only after entry into cells that are stably transfected with luciferase. Each molecule of free luciferin that is released after entry generates a photon that can be measured allowing for real-time quantification of uptake and release in cells. The process provides a method to assay uptake and release of free luciferin as a function of variations in the releasable linker and in the transporter.
Journal of Pharmaceutical Sciences, 2009
Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to pr... more Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to produce powders having high purity, controlled morphology, and retained bioactivity. We demonstrate the use of supercritical carbon dioxide as an antisolvent for meeting this need for two model drug systems, quercetin, a sparingly soluble antioxidant, and short interfering RNA (siRNA), which can silence genes. In both cases we achieve retention of bioactivity as well as a narrow particle size distribution in which the particles are free of impurities.
Journal of Pharmaceutical Sciences, 1999
The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder a... more The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder absorbance in pharmaceutical powders is described in the context of other optical techniques. FDPM consists of launching intensity-modulated light into a powder and detecting the phase delay and amplitude modulation of the re-emitted light as a function of the modulation frequency. From analysis of the data using the diffusion approximation to the radiative transport equation, the absorption coefficient can be obtained. Absorption coefficient measurements of riboflavin in lactose mixtures are presented at concentrations of 0.1 to 1% (w/w) at near-infrared wavelengths where solution absorption cross sections are difficult to accurately measure using traditional transmission measurements in nonscattering solutions. FDPM measurements in powders enabled determinations of absorption coefficients that increase linearly with concentration (w/w) according to Beer-Lambert relationship. The extension of FDPM for monitoring absorbance of low-dose and ultralow-dose powder blending operations is presented.
Journal of Colloid and Interface Science, 1999
Time-dependent measurements of light propagation were conducted in aqueous dispersions of 523 nm ... more Time-dependent measurements of light propagation were conducted in aqueous dispersions of 523 nm diameter polystyrene at concentrations between 0.1 and 0.4 solids volume fraction in order to assess how particle correlation is influenced by depletion interactions arising from the addition of soluble polyethyleneoxide (PEO). In the absence of polymer, the transport scattering length can be predicted from Mie scattering theory and the Percus-Yevick (P-Y) model for static structure of a dense hard-sphere colloidal solution. Depletion forces arising from the addition of PEO of varying molecular weights influenced the spatial ordering of the dispersion and caused a further increase in the transport scattering length beyond that predicted by hard-sphere static structure factor but similar to that predicted by the mean sphere approximation (MSA) to the P-Y model described by Ye et al. (1996). Onset of flocculation occurred with increased PEO addition and correlated with PEO molecular weight. Phase separation was noted by no further change in the transport scattering length, except when flocculation was induced by the highest molecular weight PEO. The use of time-dependent measurements of light propagation in dense systems provides an alternative to smallangle light, neutron, and X-ray scattering characterization of interaction potentials in dense, multiply scattering samples and promises further fruitful investigation of colloidal particle interactions in suspensions.
The Journal of Chemical Physics, 1999
ABSTRACT
Journal of Biomedical Optics, 2009
Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulatio... more Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 degrees C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.
Bioconjugate Chemistry, 2006
Delivery of therapeutics and imaging agents to target tissues requires localization and activatio... more Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.
Biochemistry, 2006
In vivo bioluminescence imaging has become a cornerstone technology for preclinical molecular ima... more In vivo bioluminescence imaging has become a cornerstone technology for preclinical molecular imaging. This imaging method is based on light-emitting enzymes, luciferases, which require specific substrates for light production. When linked to a specific biological process in an animal model of human biology or disease, the enzyme-substrate interactions become biological indicators that can be studied noninvasively in living animals. Signal intensity in these animal models depends on the availability of the substrate for the reaction within living cells in intact organs. The biodistribution and clearance rates of the substrates are therefore directly related to optimal imaging times and signal intensities and ultimately determine the sensitivity of detection and predictability of the model. Modifications of D-luciferin, the substrate for the luciferases obtained from beetle, including fireflies, result in novel properties and offer opportunities for improved bioassays. For this purpose, we have synthesized a conjugate, glycine-Daminoluciferin, and investigated its properties relative to those of D-aminoluciferin and D-luciferin. The three substrates exhibited different kinetic properties and different intracellular accumulation profiles due to differences in their molecular structure, which in turn influenced their biodistribution in animals. Glycine-D-aminoluciferin had a longer in vivo circulation time than the other two substrates. The ability to assay luciferase in vitro and in vivo using these substrates, which exhibit different pharmacokinetic and pharmacodynamic properties, will provide flexibility and improve current imaging capabilities.
Applied Optics, 1999
Near-infrared, frequency-domain photon migration measurements of phase shift are used to derive a... more Near-infrared, frequency-domain photon migration measurements of phase shift are used to derive accurate values of isotropic scattering coefficients in concentrated, interacting suspensions of aqueous polystyrene microspheres with volume concentrations ranging from 1% to 45% by solids and mean diameters ranging from 135 to 500 nm. Under conditions of high ionic strength, the isotropic scattering coefficient can be quantitatively predicted by the Percus-Yevick model for hard-sphere interactions and Mie theory. In addition, the attractive interactions between scatterers arising from the addition of soluble poly͑ethylene glycol͒ with molecular weights of 100 and 600 K cause hindered scattering. The increases in static structure and decreases in isotropic scattering coefficient agree with that predicted by Mie theory and the depletion interaction model developed by Asakura and Oosawa ͓J. Chem. Phys. 22, 1255 ͑1954͔͒. These results demonstrate the success of monitoring interaction between particles by use of multiple-scattered light and the necessity of incorporating models for these interactions when predicting scattering of dense, concentrated suspensions.
Journal of Pharmaceutical Sciences, 2010
A key challenge in developing RNAi-based therapeutics is efficient delivery of functional short i... more A key challenge in developing RNAi-based therapeutics is efficient delivery of functional short interfering RNA (siRNA) to target cells. To address this need, we have used a supercritical CO 2 process to incorporate siRNA in biodegradable polymer nanoparticles (NPs) for in vivo sustained release. By this means we have obtained complete encapsulation of the siRNA with minimal initial burst effect from the surface of the NPs. The slow release of a fluorescently labeled siRNA mimic (siGLO Red) was observed for up to 80 days in vivo after intradermal injection into mouse footpads. In vivo gene silencing experiments were also performed, showing reduction of GFP signal in the epidermis of a reporter transgenic mouse model, which demonstrates that the siRNA retained activity following release from the polymer NPs. ß
Particle and Particle Systems Characterization, Feb 1, 1998
The transport properties of particulate process streams and their final product quality, are dire... more The transport properties of particulate process streams and their final product quality, are directly affected by critical parameters of particle size distribution, f(x), and volume, mass, or number density of particles or dispersed phase droplets. A method is proposed for the potential on-line monitoring of particle size distribution and volume fraction in real time, using frequencydomain photon migration measurements (FDPM). Theory, experimental measurements, and results for the determination of particle size distributions for both a polystyrene latex and a titanium dioxide suspension determined using the photon migration technique are presented. The critical issues associated with the application of photon migration to particulate and dispersed phase processes are discussed, including the effects of interparticle interactions on the transport of light.
The Journal of Chemical Physics
ABSTRACT
Pharmacology and Toxicology: Basic and Clinical Aspects, 2006
Proceedings of the National Academy of Sciences, 2007
Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and fo... more Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. Molecular transporters can be used to address these problems. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Here, we describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real time. This process effectively emulates drug-conjugate delivery, drug release, and drug turnover by an intracellular target, providing a facile method to evaluate comparative uptake of new transporters and efficacy and selectivity of linker release as required for fundamental studies and therapeutic applications.
Particle & Particle Systems Characterization, 1998
The transport properties of particulate process streams and their final product quality, are dire... more The transport properties of particulate process streams and their final product quality, are directly affected by critical parameters of particle size distribution, f(x), and volume, mass, or number density of particles or dispersed phase droplets. A method is proposed for the potential on-line monitoring of particle size distribution and volume fraction in real time, using frequencydomain photon migration measurements (FDPM). Theory, experimental measurements, and results for the determination of particle size distributions for both a polystyrene latex and a titanium dioxide suspension determined using the photon migration technique are presented. The critical issues associated with the application of photon migration to particulate and dispersed phase processes are discussed, including the effects of interparticle interactions on the transport of light.
Journal of the American Chemical Society, 2006
The design, synthesis, and evaluation of conjugates of arginine-rich transporters and luciferin a... more The design, synthesis, and evaluation of conjugates of arginine-rich transporters and luciferin are described that release luciferin only after entry into cells that are stably transfected with luciferase. Each molecule of free luciferin that is released after entry generates a photon that can be measured allowing for real-time quantification of uptake and release in cells. The process provides a method to assay uptake and release of free luciferin as a function of variations in the releasable linker and in the transporter.
Journal of Pharmaceutical Sciences, 2009
Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to pr... more Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to produce powders having high purity, controlled morphology, and retained bioactivity. We demonstrate the use of supercritical carbon dioxide as an antisolvent for meeting this need for two model drug systems, quercetin, a sparingly soluble antioxidant, and short interfering RNA (siRNA), which can silence genes. In both cases we achieve retention of bioactivity as well as a narrow particle size distribution in which the particles are free of impurities.
Journal of Pharmaceutical Sciences, 1999
The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder a... more The measurement and analysis of frequency-domain photon migration (FDPM) measurements of powder absorbance in pharmaceutical powders is described in the context of other optical techniques. FDPM consists of launching intensity-modulated light into a powder and detecting the phase delay and amplitude modulation of the re-emitted light as a function of the modulation frequency. From analysis of the data using the diffusion approximation to the radiative transport equation, the absorption coefficient can be obtained. Absorption coefficient measurements of riboflavin in lactose mixtures are presented at concentrations of 0.1 to 1% (w/w) at near-infrared wavelengths where solution absorption cross sections are difficult to accurately measure using traditional transmission measurements in nonscattering solutions. FDPM measurements in powders enabled determinations of absorption coefficients that increase linearly with concentration (w/w) according to Beer-Lambert relationship. The extension of FDPM for monitoring absorbance of low-dose and ultralow-dose powder blending operations is presented.
Journal of Colloid and Interface Science, 1999
Time-dependent measurements of light propagation were conducted in aqueous dispersions of 523 nm ... more Time-dependent measurements of light propagation were conducted in aqueous dispersions of 523 nm diameter polystyrene at concentrations between 0.1 and 0.4 solids volume fraction in order to assess how particle correlation is influenced by depletion interactions arising from the addition of soluble polyethyleneoxide (PEO). In the absence of polymer, the transport scattering length can be predicted from Mie scattering theory and the Percus-Yevick (P-Y) model for static structure of a dense hard-sphere colloidal solution. Depletion forces arising from the addition of PEO of varying molecular weights influenced the spatial ordering of the dispersion and caused a further increase in the transport scattering length beyond that predicted by hard-sphere static structure factor but similar to that predicted by the mean sphere approximation (MSA) to the P-Y model described by Ye et al. (1996). Onset of flocculation occurred with increased PEO addition and correlated with PEO molecular weight. Phase separation was noted by no further change in the transport scattering length, except when flocculation was induced by the highest molecular weight PEO. The use of time-dependent measurements of light propagation in dense systems provides an alternative to smallangle light, neutron, and X-ray scattering characterization of interaction potentials in dense, multiply scattering samples and promises further fruitful investigation of colloidal particle interactions in suspensions.
The Journal of Chemical Physics, 1999
ABSTRACT
Journal of Biomedical Optics, 2009
Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulatio... more Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 degrees C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.
Bioconjugate Chemistry, 2006
Delivery of therapeutics and imaging agents to target tissues requires localization and activatio... more Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.
Biochemistry, 2006
In vivo bioluminescence imaging has become a cornerstone technology for preclinical molecular ima... more In vivo bioluminescence imaging has become a cornerstone technology for preclinical molecular imaging. This imaging method is based on light-emitting enzymes, luciferases, which require specific substrates for light production. When linked to a specific biological process in an animal model of human biology or disease, the enzyme-substrate interactions become biological indicators that can be studied noninvasively in living animals. Signal intensity in these animal models depends on the availability of the substrate for the reaction within living cells in intact organs. The biodistribution and clearance rates of the substrates are therefore directly related to optimal imaging times and signal intensities and ultimately determine the sensitivity of detection and predictability of the model. Modifications of D-luciferin, the substrate for the luciferases obtained from beetle, including fireflies, result in novel properties and offer opportunities for improved bioassays. For this purpose, we have synthesized a conjugate, glycine-Daminoluciferin, and investigated its properties relative to those of D-aminoluciferin and D-luciferin. The three substrates exhibited different kinetic properties and different intracellular accumulation profiles due to differences in their molecular structure, which in turn influenced their biodistribution in animals. Glycine-D-aminoluciferin had a longer in vivo circulation time than the other two substrates. The ability to assay luciferase in vitro and in vivo using these substrates, which exhibit different pharmacokinetic and pharmacodynamic properties, will provide flexibility and improve current imaging capabilities.
Applied Optics, 1999
Near-infrared, frequency-domain photon migration measurements of phase shift are used to derive a... more Near-infrared, frequency-domain photon migration measurements of phase shift are used to derive accurate values of isotropic scattering coefficients in concentrated, interacting suspensions of aqueous polystyrene microspheres with volume concentrations ranging from 1% to 45% by solids and mean diameters ranging from 135 to 500 nm. Under conditions of high ionic strength, the isotropic scattering coefficient can be quantitatively predicted by the Percus-Yevick model for hard-sphere interactions and Mie theory. In addition, the attractive interactions between scatterers arising from the addition of soluble poly͑ethylene glycol͒ with molecular weights of 100 and 600 K cause hindered scattering. The increases in static structure and decreases in isotropic scattering coefficient agree with that predicted by Mie theory and the depletion interaction model developed by Asakura and Oosawa ͓J. Chem. Phys. 22, 1255 ͑1954͔͒. These results demonstrate the success of monitoring interaction between particles by use of multiple-scattered light and the necessity of incorporating models for these interactions when predicting scattering of dense, concentrated suspensions.
Journal of Pharmaceutical Sciences, 2010
A key challenge in developing RNAi-based therapeutics is efficient delivery of functional short i... more A key challenge in developing RNAi-based therapeutics is efficient delivery of functional short interfering RNA (siRNA) to target cells. To address this need, we have used a supercritical CO 2 process to incorporate siRNA in biodegradable polymer nanoparticles (NPs) for in vivo sustained release. By this means we have obtained complete encapsulation of the siRNA with minimal initial burst effect from the surface of the NPs. The slow release of a fluorescently labeled siRNA mimic (siGLO Red) was observed for up to 80 days in vivo after intradermal injection into mouse footpads. In vivo gene silencing experiments were also performed, showing reduction of GFP signal in the epidermis of a reporter transgenic mouse model, which demonstrates that the siRNA retained activity following release from the polymer NPs. ß