Erhan Altinoglu - Academia.edu (original) (raw)

Papers by Erhan Altinoglu

... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and ... more ... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and Engineering by Erhan İ. Altınoğlu 2010 Erhan İ. Altınoğlu Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ...

Cell Chemical Biology

Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive ther... more Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.

Organic Process Research & Development

Organic Process Research & Development

Particle analysis of K3[Fe(CN)6] (<10µm) .

Proquest Dissertations and Theses Thesis the Pennsylvania State University 2010 Publication Number Aat 3436116 Isbn 9781124352480 Source Dissertation Abstracts International Volume 72 01 Section B Page 179 P, 2010

... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and ... more ... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and Engineering by Erhan İ. Altınoğlu 2010 Erhan İ. Altınoğlu Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ...

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2010

Near infrared imaging has presented itself as a powerful diagnostic technique with potential to s... more Near infrared imaging has presented itself as a powerful diagnostic technique with potential to serve as a minimally invasive, nonionizing method for sensitive, deep tissue diagnostic imaging. This potential is further realized with the use of nanoparticle (NP)-based near infrared (NIR) contrast agents that are not prone to the rapid photobleaching and instability of their organic counterparts. This review discusses applications that have successfully demonstrated the utility of nanoparticles for NIR imaging, including NIR-emitting semiconductor quantum dots (QDs), resonant gold nanoshells, and dye-encapsulating nanoparticles. NIR QDs demonstrate superior optical performance with exceptional fluorescence brightness stability. However, the heavy metal composition and high propensity for toxicity hinder future application in clinical environments. NIR resonant gold nanoshells also exhibit brilliant signal intensities and likewise have none of the photo-or chemical-instabilities characteristic of organic contrast agents. However, concerns regarding ineffectual clearance and long-term accumulation in nontarget organs are a major issue for this technology. Finally, NIR dyeencapsulating nanoparticles synthesized from calcium phosphate (CP) also demonstrate improved optical performances by shielding the component dye from undesirable environmental influences, thereby enhancing quantum yields, emission brightness, and fluorescent lifetime. Calcium phosphate nanoparticle (CPNP) contrast agents are neither toxic, nor have issues with long-term sequestering, as they are readily dissolved in low pH environments and ultimately absorbed into the system. Though perhaps not as optically superior as QDs or nanoshells, these are a completely nontoxic, bioresorbable option for NP-based NIR imaging that still effectively improves the optical performance of conventional organic agents.

Nano Letters, 2008

Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potentia... more Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potential as a nontoxic, bioresorbable vehicle for drug delivery to cells and tumors. The objectives of this study were to develop a calcium phosphate nanoparticle encapsulation system for organic dyes and therapeutic drugs so that advanced fluoresence methods could be used to assess the efficiency of drug delivery and possible mechanisms of nanoparticle bioabsorption. Highly concentrated CPNPs encapsulating a variety of organic fluorophores were successfully synthesized. Well-dispersed CPNPs encapsulating Cy3 amidite exhibited nearly a 5-fold increase in fluorescence quantum yield when compared to the free dye in PBS. FCS diffusion data and cell staining were used to show pH-dependent dissolution of the particles and cellular uptake, respectively. Furthermore, an experimental hydrophobic cell growth inhibitor, ceramide, was successfully delivered in vitro to human vascular smooth muscle cells via encapsulation in CPNPs. These studies demonstrate that CPNPs are effective carriers of dyes and drugs for bioimaging and, potentially, for therapeutic intervention. Encasement of fluorescent dyes and other organic molecules in nanoparticulate systems is of significant importance in the fields of drug delivery and biological imaging. 1-7 Approaches to capture organic molecules in nanoparticles is an area of intense research addressing many schemes ranging from polymeric systems 8,9 and liposomes 10 to inorganic oxides. 2,4,5,7,11-13 However, many of these systems have significant shortcomings that limit their usefulness as bioimaging agents or as drug delivery vehicles. For example, it has been shown in polymeric nanoparticles for cellular uptake that endocytosis may be immediately followed by exocytosis once the concentration gradient of particles outside the cell is removed. 8

Nano Letters, 2008

Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the f... more Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the following attributes: nanoscale-size, targetability and stability under physiological conditions. Often, these nanoscale drug delivery vehicles are limited due to agglomeration, poor solubility or cytotoxicity. Thus, we have designed a methodology to encapsulate hydrophobic antineoplastic chemotherapeutics within a 20-30 nm diameter, pH-responsive, non-agglomerating, non-toxic calcium phosphate nanoparticle matrix. In the present study, we report on calcium phosphate nanocomposite particles (CPNP) that encapsulate both fluorophores and chemotherapeutics, are colloidally stable in physiological solution for extended time at 37°C and can efficaciously deliver hydrophobic antineoplastic agents, such as ceramide, in several cell model systems. Keywords Calcium phosphate; nanoparticles; ceramide; in vitro chemotherapy; cancer Nanoparticles with fluorescent properties have been prepared by several synthetic approaches, 1-7 some of which exploit the benefits of self-assembly, particularly reverse micelles, to prepare a wide range of nanocolloids. 8-18 For example, reverse micelle techniques have been used to produce nearly monodisperse fluorescent semiconductor quantum dots with various shapes and sizes as well as to capture organic fluorophores within silica inorganic matrices. 2-6, 19, 20 While suitable for drug delivery in vitro where immune responses do not exist, semiconductor or silica nanocomposite particles with surface decoration are not particularly efficacious for drug delivery in humans. 1, 6, 21 Biodegradation of the decorated therapeutics prior to delivery can be severe. To overcome these limitations and realize the full potential of nanocomposite drug and fluorophore delivery systems, we have developed non-agglomerating nano-sized calcium phosphatebased composite particles. Reasonably high, but benign, concentrations of calcium and phosphate (1 to 5mM) occur in all vertebrates and are naturally non-toxic as well as bioresorbable. 22-24 Calcium phosphate has been widely used to provide transfection of DNA and deliver drugs via surface decoration of calcium phosphate microparticles. 2, 5, 13, 14, 16, 25 The present study reports the colloidal properties of stable, non-aggregating, 20 nm nanocomposite calcium phosphate particles embedded with fluoroprobes and a small

Journal of Physics: Condensed Matter, 2010

We present results of a fluorescent quantum efficiency (Φ(F)) study on the encapsulation of the n... more We present results of a fluorescent quantum efficiency (Φ(F)) study on the encapsulation of the near-infrared dye indocyanine green (ICG) in bioresorbable calcium phosphate nanoparticles (CPNPs). The Φ(F) (described as the ratio of photons emitted to photons absorbed) provides a quantitative means of describing the fluorescence of an arbitrary molecule. However, standard quantum efficiency measurement techniques provide only the Φ(F) of the smallest fluorescing unit-in the case of a nanoparticle suspension, the nanoparticle itself. This presents a problem in accurately describing the Φ(F) of fluorophores embedded in an inorganic nanoparticle. Combining the incidence of scattering with an evaluation of the differences in local electric field and photochemical environment, we have developed a method to determine the Φ(F) of the constituent fluorescent molecules embedded in such a nanoparticle, which provides a more meaningful comparison with the unencapsulated fluorophore. While applicable to generic systems, we present results obtained by our method for the ICG-CPNP in a phosphate buffered 0.15 M saline solution (PBS, pH 7.4)--specifically, Φ(F, free dye) = 0.027 ± 0.001, Φ(F, particle) = 0.053 ± 0.003, and for the individual encapsulated molecules, Φ(F, molecule) = 0.066 ± 0.004. The method developed also provides insight into the influences of encapsulation and key parameters to engineer resonant enhancement effects from the emission of the encapsulated fluorophores corresponding to an eigenmode of the embedding particle for tailored optical properties.

Biophysical Journal, 2009

ABSTRACT We present results of a fluorescent quantum efficiency (phi) study on the encapsulation ... more ABSTRACT We present results of a fluorescent quantum efficiency (phi) study on the encapsulation of the near infrared dye indocyanine green (ICG) in calcium phosphate (CP) nanoparticles (dia˜50 nm). The quantum efficiency (phi, described as the ratio of photons emitted to photons absorbed) provides a quantitative means of describing the fluorescence of an arbitrary molecule. However, standard quantum efficiency measurement techniques provide only phi of the smallest fluorescing unit -- in the case of a nanoparticle suspension, the nanoparticle itself. This presents a problem in accurately describing the quantum efficiency of fluorophores embedded in a nanoparticle. We have developed a method to determine the quantum efficiency of the constituent fluorescent molecules embedded in such a nanoparticle, which provides a more meaningful comparison with the unencapsulated fluorophore. While applicable to generic systems, we present results obtained by our method for the ICG/CP nanoparticles in phosphate buffer solution, revealing a dramatic improvement in per-molecule phi driven by encapsulation.

ACS Nano, 2008

Early detection is a crucial element for the timely diagnosis and successful treatment of all hum... more Early detection is a crucial element for the timely diagnosis and successful treatment of all human cancers but is limited by the sensitivity of current imaging methodologies. We have synthesized and studied bioresorbable calcium phosphate nanoparticles (CPNPs) in which molecules of the near-infrared (NIR) emitting fluorophore, indocyanine green (ICG), are embedded. The ICG-CPNPs demonstrate exceptional colloidal and optical characteristics. Suspensions consisting of 16 nm average diameter particles are colloidally stable in physiological solutions (phosphate buffered 0.15 M saline (PBS), pH 7.4) with carboxylate or polyethylene glycol (PEG) surface functionality. ICG-doped CPNPs exhibit significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore, consistent with the multiple molecules encapsulated per particle. The quantum efficiency per molecule of the ICG-CPNPs is 200% greater at 0.049 +/- 0.003 over the free fluorophore in PBS. Photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. PEGylated ICG-CPNPs accumulate in solid, 5 mm diameter xenograft breast adenocarcinoma tumors via enhanced retention and permeability (EPR) within 24 h after systemic tail vein injection in a nude mouse model. Ex situ tissue imaging further verifies the facility of the ICG-CPNPs for deep-tissue imaging with NIR signals detectable from depths up to 3 cm in porcine muscle tissue. Our ex vivo and in vivo experiments verify the promise of the NIR CPNPs for diagnostic imaging in the early detection of solid tumors.

... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and ... more ... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and Engineering by Erhan İ. Altınoğlu 2010 Erhan İ. Altınoğlu Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ...

Cell Chemical Biology

Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive ther... more Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.

Organic Process Research & Development

Organic Process Research & Development

Particle analysis of K3[Fe(CN)6] (<10µm) .

Proquest Dissertations and Theses Thesis the Pennsylvania State University 2010 Publication Number Aat 3436116 Isbn 9781124352480 Source Dissertation Abstracts International Volume 72 01 Section B Page 179 P, 2010

... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and ... more ... INFRARED DIAGNOSTIC IMAGING AND PHOTODYNAMIC THERAPY A Dissertation in Materials Science and Engineering by Erhan İ. Altınoğlu 2010 Erhan İ. Altınoğlu Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ...

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2010

Near infrared imaging has presented itself as a powerful diagnostic technique with potential to s... more Near infrared imaging has presented itself as a powerful diagnostic technique with potential to serve as a minimally invasive, nonionizing method for sensitive, deep tissue diagnostic imaging. This potential is further realized with the use of nanoparticle (NP)-based near infrared (NIR) contrast agents that are not prone to the rapid photobleaching and instability of their organic counterparts. This review discusses applications that have successfully demonstrated the utility of nanoparticles for NIR imaging, including NIR-emitting semiconductor quantum dots (QDs), resonant gold nanoshells, and dye-encapsulating nanoparticles. NIR QDs demonstrate superior optical performance with exceptional fluorescence brightness stability. However, the heavy metal composition and high propensity for toxicity hinder future application in clinical environments. NIR resonant gold nanoshells also exhibit brilliant signal intensities and likewise have none of the photo-or chemical-instabilities characteristic of organic contrast agents. However, concerns regarding ineffectual clearance and long-term accumulation in nontarget organs are a major issue for this technology. Finally, NIR dyeencapsulating nanoparticles synthesized from calcium phosphate (CP) also demonstrate improved optical performances by shielding the component dye from undesirable environmental influences, thereby enhancing quantum yields, emission brightness, and fluorescent lifetime. Calcium phosphate nanoparticle (CPNP) contrast agents are neither toxic, nor have issues with long-term sequestering, as they are readily dissolved in low pH environments and ultimately absorbed into the system. Though perhaps not as optically superior as QDs or nanoshells, these are a completely nontoxic, bioresorbable option for NP-based NIR imaging that still effectively improves the optical performance of conventional organic agents.

Nano Letters, 2008

Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potentia... more Encapsulation of imaging agents and drugs in calcium phosphate nanoparticles (CPNPs) has potential as a nontoxic, bioresorbable vehicle for drug delivery to cells and tumors. The objectives of this study were to develop a calcium phosphate nanoparticle encapsulation system for organic dyes and therapeutic drugs so that advanced fluoresence methods could be used to assess the efficiency of drug delivery and possible mechanisms of nanoparticle bioabsorption. Highly concentrated CPNPs encapsulating a variety of organic fluorophores were successfully synthesized. Well-dispersed CPNPs encapsulating Cy3 amidite exhibited nearly a 5-fold increase in fluorescence quantum yield when compared to the free dye in PBS. FCS diffusion data and cell staining were used to show pH-dependent dissolution of the particles and cellular uptake, respectively. Furthermore, an experimental hydrophobic cell growth inhibitor, ceramide, was successfully delivered in vitro to human vascular smooth muscle cells via encapsulation in CPNPs. These studies demonstrate that CPNPs are effective carriers of dyes and drugs for bioimaging and, potentially, for therapeutic intervention. Encasement of fluorescent dyes and other organic molecules in nanoparticulate systems is of significant importance in the fields of drug delivery and biological imaging. 1-7 Approaches to capture organic molecules in nanoparticles is an area of intense research addressing many schemes ranging from polymeric systems 8,9 and liposomes 10 to inorganic oxides. 2,4,5,7,11-13 However, many of these systems have significant shortcomings that limit their usefulness as bioimaging agents or as drug delivery vehicles. For example, it has been shown in polymeric nanoparticles for cellular uptake that endocytosis may be immediately followed by exocytosis once the concentration gradient of particles outside the cell is removed. 8

Nano Letters, 2008

Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the f... more Paradigm-shifting modalities to more efficiently deliver drugs to cancerous lesions require the following attributes: nanoscale-size, targetability and stability under physiological conditions. Often, these nanoscale drug delivery vehicles are limited due to agglomeration, poor solubility or cytotoxicity. Thus, we have designed a methodology to encapsulate hydrophobic antineoplastic chemotherapeutics within a 20-30 nm diameter, pH-responsive, non-agglomerating, non-toxic calcium phosphate nanoparticle matrix. In the present study, we report on calcium phosphate nanocomposite particles (CPNP) that encapsulate both fluorophores and chemotherapeutics, are colloidally stable in physiological solution for extended time at 37°C and can efficaciously deliver hydrophobic antineoplastic agents, such as ceramide, in several cell model systems. Keywords Calcium phosphate; nanoparticles; ceramide; in vitro chemotherapy; cancer Nanoparticles with fluorescent properties have been prepared by several synthetic approaches, 1-7 some of which exploit the benefits of self-assembly, particularly reverse micelles, to prepare a wide range of nanocolloids. 8-18 For example, reverse micelle techniques have been used to produce nearly monodisperse fluorescent semiconductor quantum dots with various shapes and sizes as well as to capture organic fluorophores within silica inorganic matrices. 2-6, 19, 20 While suitable for drug delivery in vitro where immune responses do not exist, semiconductor or silica nanocomposite particles with surface decoration are not particularly efficacious for drug delivery in humans. 1, 6, 21 Biodegradation of the decorated therapeutics prior to delivery can be severe. To overcome these limitations and realize the full potential of nanocomposite drug and fluorophore delivery systems, we have developed non-agglomerating nano-sized calcium phosphatebased composite particles. Reasonably high, but benign, concentrations of calcium and phosphate (1 to 5mM) occur in all vertebrates and are naturally non-toxic as well as bioresorbable. 22-24 Calcium phosphate has been widely used to provide transfection of DNA and deliver drugs via surface decoration of calcium phosphate microparticles. 2, 5, 13, 14, 16, 25 The present study reports the colloidal properties of stable, non-aggregating, 20 nm nanocomposite calcium phosphate particles embedded with fluoroprobes and a small

Journal of Physics: Condensed Matter, 2010

We present results of a fluorescent quantum efficiency (Φ(F)) study on the encapsulation of the n... more We present results of a fluorescent quantum efficiency (Φ(F)) study on the encapsulation of the near-infrared dye indocyanine green (ICG) in bioresorbable calcium phosphate nanoparticles (CPNPs). The Φ(F) (described as the ratio of photons emitted to photons absorbed) provides a quantitative means of describing the fluorescence of an arbitrary molecule. However, standard quantum efficiency measurement techniques provide only the Φ(F) of the smallest fluorescing unit-in the case of a nanoparticle suspension, the nanoparticle itself. This presents a problem in accurately describing the Φ(F) of fluorophores embedded in an inorganic nanoparticle. Combining the incidence of scattering with an evaluation of the differences in local electric field and photochemical environment, we have developed a method to determine the Φ(F) of the constituent fluorescent molecules embedded in such a nanoparticle, which provides a more meaningful comparison with the unencapsulated fluorophore. While applicable to generic systems, we present results obtained by our method for the ICG-CPNP in a phosphate buffered 0.15 M saline solution (PBS, pH 7.4)--specifically, Φ(F, free dye) = 0.027 ± 0.001, Φ(F, particle) = 0.053 ± 0.003, and for the individual encapsulated molecules, Φ(F, molecule) = 0.066 ± 0.004. The method developed also provides insight into the influences of encapsulation and key parameters to engineer resonant enhancement effects from the emission of the encapsulated fluorophores corresponding to an eigenmode of the embedding particle for tailored optical properties.

Biophysical Journal, 2009

ABSTRACT We present results of a fluorescent quantum efficiency (phi) study on the encapsulation ... more ABSTRACT We present results of a fluorescent quantum efficiency (phi) study on the encapsulation of the near infrared dye indocyanine green (ICG) in calcium phosphate (CP) nanoparticles (dia˜50 nm). The quantum efficiency (phi, described as the ratio of photons emitted to photons absorbed) provides a quantitative means of describing the fluorescence of an arbitrary molecule. However, standard quantum efficiency measurement techniques provide only phi of the smallest fluorescing unit -- in the case of a nanoparticle suspension, the nanoparticle itself. This presents a problem in accurately describing the quantum efficiency of fluorophores embedded in a nanoparticle. We have developed a method to determine the quantum efficiency of the constituent fluorescent molecules embedded in such a nanoparticle, which provides a more meaningful comparison with the unencapsulated fluorophore. While applicable to generic systems, we present results obtained by our method for the ICG/CP nanoparticles in phosphate buffer solution, revealing a dramatic improvement in per-molecule phi driven by encapsulation.

ACS Nano, 2008

Early detection is a crucial element for the timely diagnosis and successful treatment of all hum... more Early detection is a crucial element for the timely diagnosis and successful treatment of all human cancers but is limited by the sensitivity of current imaging methodologies. We have synthesized and studied bioresorbable calcium phosphate nanoparticles (CPNPs) in which molecules of the near-infrared (NIR) emitting fluorophore, indocyanine green (ICG), are embedded. The ICG-CPNPs demonstrate exceptional colloidal and optical characteristics. Suspensions consisting of 16 nm average diameter particles are colloidally stable in physiological solutions (phosphate buffered 0.15 M saline (PBS), pH 7.4) with carboxylate or polyethylene glycol (PEG) surface functionality. ICG-doped CPNPs exhibit significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore, consistent with the multiple molecules encapsulated per particle. The quantum efficiency per molecule of the ICG-CPNPs is 200% greater at 0.049 +/- 0.003 over the free fluorophore in PBS. Photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. PEGylated ICG-CPNPs accumulate in solid, 5 mm diameter xenograft breast adenocarcinoma tumors via enhanced retention and permeability (EPR) within 24 h after systemic tail vein injection in a nude mouse model. Ex situ tissue imaging further verifies the facility of the ICG-CPNPs for deep-tissue imaging with NIR signals detectable from depths up to 3 cm in porcine muscle tissue. Our ex vivo and in vivo experiments verify the promise of the NIR CPNPs for diagnostic imaging in the early detection of solid tumors.