Antonella Antonelli - Academia.edu (original) (raw)

Papers by Antonella Antonelli

Frontiers in Physiology, Feb 18, 2021

In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such conditi... more In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such condition affects stem and progenitor cell proliferation and differentiation and, at cellular level regulates hematopoietic growth factors, chemokines and adhesion molecules expression. In turn, these molecules affect the proliferation and maturation of other cellular components of the niche. Due to the complexity of the system we started the in vitro investigations of the IL-6, IL-8, TNFα cytokines expression and the vascular endothelial growth factor (VEGF), considered key mediators of the hematopoietic niche, in human macrophages and macrophage cell line. Since in the niche the oxygen availability is mediated by red blood cells (RBCs), we have influenced the anoxic cell cultures by the administration of oxygenated or deoxygenated RBCs (deoxy RBCs). The results reported in this brief paper show that the presence of RBCs up-regulates IL-8 mRNA while IL-6 and VEGF mRNA expression appears down-regulated. This does not occur when deoxy RBCs are used. Moreover, it appears that the administration of RBCs leads to an increase of TNFα expression levels in MonoMac 6 (MM6). Interestingly, the modulation of these factors likely occurs in a hypoxia-inducible factor-1α (HIF-1α) independent manner. Considering the role of oxygen in the hematopoietic niche further studies should explore these preliminary observations in more details.

Nano Research, Jan 3, 2017

In medicine, discrimination between pathologies and normal areas is of great importance, and in m... more In medicine, discrimination between pathologies and normal areas is of great importance, and in most cases, such discrimination is made possible by novel imaging technologies. Numerous modalities have been developed to visualize tissue vascularization in cardiovascular diseases or during angiogenic and vasculogenic processes. Here, we report the recent advances in vasculature imaging, providing an overview of the current non-invasive approaches in biomedical diagnostics and potential future strategies for prognostic assessment of vessel diseases, such as aneurysms and coronary artery occlusion leading to myocardial infarction. There are several contrast agents (CAs) available to improve the visibility of specific tissues at the early stage of diseases, allowing for rapid treatment. However, CAs are also hampered by numerous limitations, including rapid diffusion from blood vessels into the interstitial space, toxicity, and low sensitivity. Extravasation from blood vessels leads to a rapid loss of the image. If the contrast medium can fully be confined to the vascular space, high-resolution structural and functional vascular imaging could be obtained. Many scientists have contributed new materials and/or new carrier systems. For example, the use of red blood cells (RBCs) as CA-delivery systems appears to provide a scalable alternative to current procedures that allows adequate vascular imaging. Recognition and removal of CAs from the circulation can be prevented and/or delayed by using RBCs as biomimetic CA-carriers, and this technology should be clinically validated.

International Journal of Molecular Sciences

During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo ... more During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)—that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)—would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation in...

Biomaterials Science, 2023

Please note that technical editing may introduce minor changes to the text and/or graphics, which... more Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal's standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.

Molecules

The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents... more The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2′-deoxy-guanosine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable sp...

L'invention concerne des erythrocytes exposes a une dialyse avec un tampon hypotonique, qui a... more L'invention concerne des erythrocytes exposes a une dialyse avec un tampon hypotonique, qui absorbent de facon stable des nanoparticules d'oxyde de fer superparamagnetiques et qui peuvent etre utilises en tant qu'agents de contraste pour une IRM. De tels erythrocytes peuvent egalement etre utilises comme vehicules d'administration de medicament.

International Journal of Molecular Sciences

Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitu... more Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very low, and this condition affects stem and progenitor cell proliferation and differentiation and other important functions of this region. Here, we have investigated in vitro the response of endothelial cells to a marked decrease in O2 partial pressure to understand how the basal gene expression of some relevant biological factors (i.e., chemokines and interleukins) that are fundamental for the intercellular communication could change in anoxic conditions. Interestingly, mRNA levels of CXCL3, CXCL5, and IL-34 genes are upregulated after anoxia exposure but become downmodulated by sirtuin 6 (SIRT6) overexpression. Indeed, the expression levels of some other genes (such as L...

International Journal of Molecular Sciences

Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition... more Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic β cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydat...

Biochemical Society Transactions, 2000

2015 5th International Workshop on Magnetic Particle Imaging (IWMPI), 2015

The creation of new magnetic nanoparticles require consideration for careful engineering of size,... more The creation of new magnetic nanoparticles require consideration for careful engineering of size, shape, and coating surface in order to produce new MPI-optimized particles that could be used for the RBC loading procedure. An improved MPI signal can be obtained if a better starting material is used. Although ferucarbotran-loaded RBCs showed a lower MPS spectral response compared to bulk suspension they could be used as new potential MPI tracer; in fact the reduced signal could be counterbalanced by superior in vivo stability of SPIO-loaded RBCs compared to free nanoparticles. The advantage of SPIO-loaded RBCs is that they are stable constructs able to survive for a number of days without being eliminated and with a lifespan comparable to that of untreated RBCs. SPIO-loaded RBCs are biomimetic constructs suited to increase the in vivo circulation of SPIO contrast agents; as longer blood half-time tracer materials they could improve diagnostic imaging procedures, such as angiography analysis of patients with cardiovascular diseases and therapeutic interventions with long-term monitoring, since up to now the time window for data acquisition is limited to the first pass due to very short lifespan of iron oxide nanoparticles.

Clinical Applications of Magnetic Nanoparticles, 2018

Frontiers in Physiology, 2021

In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such conditi... more In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such condition affects stem and progenitor cell proliferation and differentiation and, at cellular level regulates hematopoietic growth factors, chemokines and adhesion molecules expression. In turn, these molecules affect the proliferation and maturation of other cellular components of the niche. Due to the complexity of the system we started the in vitro investigations of the IL-6, IL-8, TNFα cytokines expression and the vascular endothelial growth factor (VEGF), considered key mediators of the hematopoietic niche, in human macrophages and macrophage cell line. Since in the niche the oxygen availability is mediated by red blood cells (RBCs), we have influenced the anoxic cell cultures by the administration of oxygenated or deoxygenated RBCs (deoxy RBCs). The results reported in this brief paper show that the presence of RBCs up-regulates IL-8 mRNA while IL-6 and VEGF mRNA expression appears down-r...

Journal of Magnetism and Magnetic Materials, 2021

Abstract Superparamagnetic iron oxide (SPIO) nanoparticles are available since many years and som... more Abstract Superparamagnetic iron oxide (SPIO) nanoparticles are available since many years and some already approved for human use. More recently, new applications are emerging and the field is moving from the use of SPIO as simply contrast agents, to more complex structures optimized in terms of core, size, shape and coating for different imaging modalities (i.e. MRI vs MPI), and different theranostic applications. Prof. Krishnan M. Kannan has greatly contributed to our understanding of the role of each of these parameters in shaping SPIO best function. Some of these developments are discussed in this short review just as examples. More recently, new cell-based SPIO constructs have also been optimized, moving the field from engineering the nanoparticles to the generation of hybrids cell-nanoparticles construct. These developments have requested additional SPIO optimizations to maintain nanoparticles biocompatibility and properties and, at the same time, prevent cell damage and maintain cell functionality. Related examples form our lab are also discussed.

ACS Applied Materials & Interfaces, 2019

The active and passive electrophysiological properties of blood and tissue have been utilized in ... more The active and passive electrophysiological properties of blood and tissue have been utilized in a vast array of clinical techniques to noninvasively characterize anatomy and physiology and to diagnose a wide variety of pathologies. However, the accuracy and spatial resolution of such techniques are limited by several factors, including an ill-posed inverse problem, which determines biological parameters and signal sources from surface potentials. Here, we propose a method to noninvasively modulate tissue conductivity by aligning superparamagnetic iron oxide-loaded erythrocytes with an oscillating magnetic field. A prototype device is presented, which incorporates a three-dimensional set of Helmholtz coil pairs and fluid-channel-embedded electrode arrays. Alignment of loaded cells (~11 mM iron) within a field of 12 mT is demonstrated, and this directed reorientation is shown to alter the conductivity of blood by ~5 and ~0.5% for stationary and flowing blood, respectively, within fields as weak as 6-12 mT. Focal

Nano Research, 2017

In medicine, discrimination between pathologies and normal areas is of great importance, and in m... more In medicine, discrimination between pathologies and normal areas is of great importance, and in most cases, such discrimination is made possible by novel imaging technologies. Numerous modalities have been developed to visualize tissue vascularization in cardiovascular diseases or during angiogenic and vasculogenic processes. Here, we report the recent advances in vasculature imaging, providing an overview of the current non-invasive approaches in biomedical diagnostics and potential future strategies for prognostic assessment of vessel diseases, such as aneurysms and coronary artery occlusion leading to myocardial infarction. There are several contrast agents (CAs) available to improve the visibility of specific tissues at the early stage of diseases, allowing for rapid treatment. However, CAs are also hampered by numerous limitations, including rapid diffusion from blood vessels into the interstitial space, toxicity, and low sensitivity. Extravasation from blood vessels leads to a rapid loss of the image. If the contrast medium can fully be confined to the vascular space, high-resolution structural and functional vascular imaging could be obtained. Many scientists have contributed new materials and/or new carrier systems. For example, the use of red blood cells (RBCs) as CA-delivery systems appears to provide a scalable alternative to current procedures that allows adequate vascular imaging. Recognition and removal of CAs from the circulation can be prevented and/or delayed by using RBCs as biomimetic CA-carriers, and this technology should be clinically validated.

PLoS ONE, 2013

Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanopart... more Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanoparticles have been developed as magnetic resonance imaging (MRI) contrast agents. Iron oxide nanoparticles, that become superparamagnetic if the core particle diameter is ~ 30nm or less, present R1 and R2 relaxivities which are much higher than those of conventional paramagnetic gadolinium chelates. Generally, these magnetic particles are coated with biocompatible polymers that prevent the agglomeration of the colloidal suspension and improve their blood distribution profile. In spite of their potential as MRI blood contrast agents, the biomedical application of iron oxide nanoparticles is still limited because of their intravascular half-life of only few hours; such nanoparticles are rapidly cleared from the bloodstream by macrophages of the reticulo-endothelial system (RES). To increase the life span of these MRI contrast agents in the bloodstream we proposed the encapsulation of SPIO nanoparticles in red blood cells (RBCs) through the transient opening of cell membrane pores. We have recently reported results obtained by applying our loading procedure to several SPIO nanoparticles with different chemical physical characteristics such as size and coating agent. In the current investigation we showed that the life span of iron-based contrast agents in the mice bloodstream was prolonged to 12 days after the intravenous injection of murine SPIO-loaded RBCs. Furthermore, we developed an animal model that implicates the pretreatment of animals with clodronate to induce a transient suppression of tissue macrophages, followed by the injection of human SPIO-loaded RBCs which make it possible to encapsulate nanoparticle concentrations (5.3-16.7mM Fe) higher than murine SPIO-loaded RBCs (1.4-3.55mM Fe). The data showed that, when human RBCs are used as more capable SPIO nanoparticle containers combined with a depletion of tissue macrophages, Fe concentration in animal blood is 2-3 times higher than iron concentration obtained by the use of murine SPIO-loaded RBCs.

Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine... more Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine concentrations (0.1 µM) become resistant to the drug thanks to an altered deoxycytidine kinase. In this paper we show that deoxycytidine kinase mRNA is significantly reduced in drug-resistant U937 cells (U937-R) although the deoxycytidine kinase promoter is normal. A number of nucleotide deletions, insertions and substitutions was found in the coding region of deoxycytidine kinase gene. Several identified mutations result in truncated forms of the enzyme or in the introduction of stop codons: in one case a complete lack of exon 4 was found. Thus, the deoxycytidine kinase gene accumulates mutations at a very high rate, as already reported for other cytidine analogues (i.e. Ara C) suggesting that the design of new antiviral or anticancer drugs of the cytidine family should take into account the potential development of cell resistance as a critical factor in drug failure. (Mol Cell Biochem 231: 173-177, 2002)

Advanced Drug Delivery Reviews, 2016

Pharmacokinetics, biodistribution, and biological activity are key parameters that determine the ... more Pharmacokinetics, biodistribution, and biological activity are key parameters that determine the success or failure of therapeutics. Many developments intended to improve their in vivo performance, aim at modulating concentration, biodistribution, and targeting to tissues, cells or subcellular compartments. Erythrocyte-based drug delivery systems are especially efficient in maintaining active drugs in circulation, in releasing them for several weeks or in targeting drugs to selected cells. Erythrocytes can also be easily processed to entrap the desired pharmaceutical ingredients before re-infusion into the same or matched donors. These carriers are totally biocompatible, have a large capacity and could accommodate traditional chemical entities (glucocorticoids, immunossuppresants, etc.), biologics (proteins) and/or contrasting agents (dyes, nanoparticles). Carrier erythrocytes have been evaluated in thousands of infusions in humans proving treatment safety and efficacy, hence gaining interest in the management of complex pathologies (particularly in chronic treatments and when sideeffects become serious issues) and in new diagnostic approaches.

Frontiers in Physiology, Feb 18, 2021

In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such conditi... more In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such condition affects stem and progenitor cell proliferation and differentiation and, at cellular level regulates hematopoietic growth factors, chemokines and adhesion molecules expression. In turn, these molecules affect the proliferation and maturation of other cellular components of the niche. Due to the complexity of the system we started the in vitro investigations of the IL-6, IL-8, TNFα cytokines expression and the vascular endothelial growth factor (VEGF), considered key mediators of the hematopoietic niche, in human macrophages and macrophage cell line. Since in the niche the oxygen availability is mediated by red blood cells (RBCs), we have influenced the anoxic cell cultures by the administration of oxygenated or deoxygenated RBCs (deoxy RBCs). The results reported in this brief paper show that the presence of RBCs up-regulates IL-8 mRNA while IL-6 and VEGF mRNA expression appears down-regulated. This does not occur when deoxy RBCs are used. Moreover, it appears that the administration of RBCs leads to an increase of TNFα expression levels in MonoMac 6 (MM6). Interestingly, the modulation of these factors likely occurs in a hypoxia-inducible factor-1α (HIF-1α) independent manner. Considering the role of oxygen in the hematopoietic niche further studies should explore these preliminary observations in more details.

Nano Research, Jan 3, 2017

In medicine, discrimination between pathologies and normal areas is of great importance, and in m... more In medicine, discrimination between pathologies and normal areas is of great importance, and in most cases, such discrimination is made possible by novel imaging technologies. Numerous modalities have been developed to visualize tissue vascularization in cardiovascular diseases or during angiogenic and vasculogenic processes. Here, we report the recent advances in vasculature imaging, providing an overview of the current non-invasive approaches in biomedical diagnostics and potential future strategies for prognostic assessment of vessel diseases, such as aneurysms and coronary artery occlusion leading to myocardial infarction. There are several contrast agents (CAs) available to improve the visibility of specific tissues at the early stage of diseases, allowing for rapid treatment. However, CAs are also hampered by numerous limitations, including rapid diffusion from blood vessels into the interstitial space, toxicity, and low sensitivity. Extravasation from blood vessels leads to a rapid loss of the image. If the contrast medium can fully be confined to the vascular space, high-resolution structural and functional vascular imaging could be obtained. Many scientists have contributed new materials and/or new carrier systems. For example, the use of red blood cells (RBCs) as CA-delivery systems appears to provide a scalable alternative to current procedures that allows adequate vascular imaging. Recognition and removal of CAs from the circulation can be prevented and/or delayed by using RBCs as biomimetic CA-carriers, and this technology should be clinically validated.

International Journal of Molecular Sciences

During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo ... more During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)—that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)—would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation in...

Biomaterials Science, 2023

Please note that technical editing may introduce minor changes to the text and/or graphics, which... more Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal's standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.

Molecules

The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents... more The therapeutic advantages of some platinum complexes as major anticancer chemotherapeutic agents and of nucleoside analogue-based compounds as essential antiviral/antitumor drugs are widely recognized. Red blood cells (RBCs) offer a potential new strategy for the targeted release of therapeutic agents due to their biocompatibility, which can protect loaded drugs from inactivation in the blood, thus improving biodistribution. In this study, we evaluated the feasibility of loading model nucleobase-containing Pt(II) complexes into human RBCs that were highly stabilized by four N-donors and susceptible to further modification for possible antitumor/antiviral applications. Specifically, platinum-based nucleoside derivatives [PtII(dien)(N7-Guo)]2+, [PtII(dien)(N7-dGuo)]2+, and [PtII(dien)(N7-dGTP)] (dien = diethylenetriamine; Guo = guanosine; dGuo = 2′-deoxy-guanosine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate) were investigated. These Pt(II) complexes were demonstrated to be stable sp...

L'invention concerne des erythrocytes exposes a une dialyse avec un tampon hypotonique, qui a... more L'invention concerne des erythrocytes exposes a une dialyse avec un tampon hypotonique, qui absorbent de facon stable des nanoparticules d'oxyde de fer superparamagnetiques et qui peuvent etre utilises en tant qu'agents de contraste pour une IRM. De tels erythrocytes peuvent egalement etre utilises comme vehicules d'administration de medicament.

International Journal of Molecular Sciences

Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitu... more Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very low, and this condition affects stem and progenitor cell proliferation and differentiation and other important functions of this region. Here, we have investigated in vitro the response of endothelial cells to a marked decrease in O2 partial pressure to understand how the basal gene expression of some relevant biological factors (i.e., chemokines and interleukins) that are fundamental for the intercellular communication could change in anoxic conditions. Interestingly, mRNA levels of CXCL3, CXCL5, and IL-34 genes are upregulated after anoxia exposure but become downmodulated by sirtuin 6 (SIRT6) overexpression. Indeed, the expression levels of some other genes (such as L...

International Journal of Molecular Sciences

Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition... more Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic β cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydat...

Biochemical Society Transactions, 2000

2015 5th International Workshop on Magnetic Particle Imaging (IWMPI), 2015

The creation of new magnetic nanoparticles require consideration for careful engineering of size,... more The creation of new magnetic nanoparticles require consideration for careful engineering of size, shape, and coating surface in order to produce new MPI-optimized particles that could be used for the RBC loading procedure. An improved MPI signal can be obtained if a better starting material is used. Although ferucarbotran-loaded RBCs showed a lower MPS spectral response compared to bulk suspension they could be used as new potential MPI tracer; in fact the reduced signal could be counterbalanced by superior in vivo stability of SPIO-loaded RBCs compared to free nanoparticles. The advantage of SPIO-loaded RBCs is that they are stable constructs able to survive for a number of days without being eliminated and with a lifespan comparable to that of untreated RBCs. SPIO-loaded RBCs are biomimetic constructs suited to increase the in vivo circulation of SPIO contrast agents; as longer blood half-time tracer materials they could improve diagnostic imaging procedures, such as angiography analysis of patients with cardiovascular diseases and therapeutic interventions with long-term monitoring, since up to now the time window for data acquisition is limited to the first pass due to very short lifespan of iron oxide nanoparticles.

Clinical Applications of Magnetic Nanoparticles, 2018

Frontiers in Physiology, 2021

In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such conditi... more In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such condition affects stem and progenitor cell proliferation and differentiation and, at cellular level regulates hematopoietic growth factors, chemokines and adhesion molecules expression. In turn, these molecules affect the proliferation and maturation of other cellular components of the niche. Due to the complexity of the system we started the in vitro investigations of the IL-6, IL-8, TNFα cytokines expression and the vascular endothelial growth factor (VEGF), considered key mediators of the hematopoietic niche, in human macrophages and macrophage cell line. Since in the niche the oxygen availability is mediated by red blood cells (RBCs), we have influenced the anoxic cell cultures by the administration of oxygenated or deoxygenated RBCs (deoxy RBCs). The results reported in this brief paper show that the presence of RBCs up-regulates IL-8 mRNA while IL-6 and VEGF mRNA expression appears down-r...

Journal of Magnetism and Magnetic Materials, 2021

Abstract Superparamagnetic iron oxide (SPIO) nanoparticles are available since many years and som... more Abstract Superparamagnetic iron oxide (SPIO) nanoparticles are available since many years and some already approved for human use. More recently, new applications are emerging and the field is moving from the use of SPIO as simply contrast agents, to more complex structures optimized in terms of core, size, shape and coating for different imaging modalities (i.e. MRI vs MPI), and different theranostic applications. Prof. Krishnan M. Kannan has greatly contributed to our understanding of the role of each of these parameters in shaping SPIO best function. Some of these developments are discussed in this short review just as examples. More recently, new cell-based SPIO constructs have also been optimized, moving the field from engineering the nanoparticles to the generation of hybrids cell-nanoparticles construct. These developments have requested additional SPIO optimizations to maintain nanoparticles biocompatibility and properties and, at the same time, prevent cell damage and maintain cell functionality. Related examples form our lab are also discussed.

ACS Applied Materials & Interfaces, 2019

The active and passive electrophysiological properties of blood and tissue have been utilized in ... more The active and passive electrophysiological properties of blood and tissue have been utilized in a vast array of clinical techniques to noninvasively characterize anatomy and physiology and to diagnose a wide variety of pathologies. However, the accuracy and spatial resolution of such techniques are limited by several factors, including an ill-posed inverse problem, which determines biological parameters and signal sources from surface potentials. Here, we propose a method to noninvasively modulate tissue conductivity by aligning superparamagnetic iron oxide-loaded erythrocytes with an oscillating magnetic field. A prototype device is presented, which incorporates a three-dimensional set of Helmholtz coil pairs and fluid-channel-embedded electrode arrays. Alignment of loaded cells (~11 mM iron) within a field of 12 mT is demonstrated, and this directed reorientation is shown to alter the conductivity of blood by ~5 and ~0.5% for stationary and flowing blood, respectively, within fields as weak as 6-12 mT. Focal

Nano Research, 2017

In medicine, discrimination between pathologies and normal areas is of great importance, and in m... more In medicine, discrimination between pathologies and normal areas is of great importance, and in most cases, such discrimination is made possible by novel imaging technologies. Numerous modalities have been developed to visualize tissue vascularization in cardiovascular diseases or during angiogenic and vasculogenic processes. Here, we report the recent advances in vasculature imaging, providing an overview of the current non-invasive approaches in biomedical diagnostics and potential future strategies for prognostic assessment of vessel diseases, such as aneurysms and coronary artery occlusion leading to myocardial infarction. There are several contrast agents (CAs) available to improve the visibility of specific tissues at the early stage of diseases, allowing for rapid treatment. However, CAs are also hampered by numerous limitations, including rapid diffusion from blood vessels into the interstitial space, toxicity, and low sensitivity. Extravasation from blood vessels leads to a rapid loss of the image. If the contrast medium can fully be confined to the vascular space, high-resolution structural and functional vascular imaging could be obtained. Many scientists have contributed new materials and/or new carrier systems. For example, the use of red blood cells (RBCs) as CA-delivery systems appears to provide a scalable alternative to current procedures that allows adequate vascular imaging. Recognition and removal of CAs from the circulation can be prevented and/or delayed by using RBCs as biomimetic CA-carriers, and this technology should be clinically validated.

PLoS ONE, 2013

Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanopart... more Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanoparticles have been developed as magnetic resonance imaging (MRI) contrast agents. Iron oxide nanoparticles, that become superparamagnetic if the core particle diameter is ~ 30nm or less, present R1 and R2 relaxivities which are much higher than those of conventional paramagnetic gadolinium chelates. Generally, these magnetic particles are coated with biocompatible polymers that prevent the agglomeration of the colloidal suspension and improve their blood distribution profile. In spite of their potential as MRI blood contrast agents, the biomedical application of iron oxide nanoparticles is still limited because of their intravascular half-life of only few hours; such nanoparticles are rapidly cleared from the bloodstream by macrophages of the reticulo-endothelial system (RES). To increase the life span of these MRI contrast agents in the bloodstream we proposed the encapsulation of SPIO nanoparticles in red blood cells (RBCs) through the transient opening of cell membrane pores. We have recently reported results obtained by applying our loading procedure to several SPIO nanoparticles with different chemical physical characteristics such as size and coating agent. In the current investigation we showed that the life span of iron-based contrast agents in the mice bloodstream was prolonged to 12 days after the intravenous injection of murine SPIO-loaded RBCs. Furthermore, we developed an animal model that implicates the pretreatment of animals with clodronate to induce a transient suppression of tissue macrophages, followed by the injection of human SPIO-loaded RBCs which make it possible to encapsulate nanoparticle concentrations (5.3-16.7mM Fe) higher than murine SPIO-loaded RBCs (1.4-3.55mM Fe). The data showed that, when human RBCs are used as more capable SPIO nanoparticle containers combined with a depletion of tissue macrophages, Fe concentration in animal blood is 2-3 times higher than iron concentration obtained by the use of murine SPIO-loaded RBCs.

Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine... more Human monoblastoid cells (U937) grown in the presence of therapeutically relevant dideoxycytidine concentrations (0.1 µM) become resistant to the drug thanks to an altered deoxycytidine kinase. In this paper we show that deoxycytidine kinase mRNA is significantly reduced in drug-resistant U937 cells (U937-R) although the deoxycytidine kinase promoter is normal. A number of nucleotide deletions, insertions and substitutions was found in the coding region of deoxycytidine kinase gene. Several identified mutations result in truncated forms of the enzyme or in the introduction of stop codons: in one case a complete lack of exon 4 was found. Thus, the deoxycytidine kinase gene accumulates mutations at a very high rate, as already reported for other cytidine analogues (i.e. Ara C) suggesting that the design of new antiviral or anticancer drugs of the cytidine family should take into account the potential development of cell resistance as a critical factor in drug failure. (Mol Cell Biochem 231: 173-177, 2002)

Advanced Drug Delivery Reviews, 2016

Pharmacokinetics, biodistribution, and biological activity are key parameters that determine the ... more Pharmacokinetics, biodistribution, and biological activity are key parameters that determine the success or failure of therapeutics. Many developments intended to improve their in vivo performance, aim at modulating concentration, biodistribution, and targeting to tissues, cells or subcellular compartments. Erythrocyte-based drug delivery systems are especially efficient in maintaining active drugs in circulation, in releasing them for several weeks or in targeting drugs to selected cells. Erythrocytes can also be easily processed to entrap the desired pharmaceutical ingredients before re-infusion into the same or matched donors. These carriers are totally biocompatible, have a large capacity and could accommodate traditional chemical entities (glucocorticoids, immunossuppresants, etc.), biologics (proteins) and/or contrasting agents (dyes, nanoparticles). Carrier erythrocytes have been evaluated in thousands of infusions in humans proving treatment safety and efficacy, hence gaining interest in the management of complex pathologies (particularly in chronic treatments and when sideeffects become serious issues) and in new diagnostic approaches.