- Moscow, Russia
Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental... more
Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartmental models such as the physiologically-based nanocarrier biopharmaceutics model promise improved sensitivity and resolution for the underlying causes of inequivalence. In the present investigation, both techniques were applied to two nanomaterial-based formulations for intravenous injection, namely, albumin-stabilized rifabutin nanoparticles and rifabutin-loaded PLGA nanoparticles. The antibiotic rifabutin holds great potential for the treatment of severe and acute infections of patients co-infected with human immunodeficiency virus and tuberculosis. The formulations differ significantly in their formulation and material attributes, resulting in an altered biodistribution pattern as con...
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Research Interests: PLGA and Rilpivirine
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Predicting the ability of nanoparticles (NP) to access the tumor is key to the success of chemotherapy using nanotherapeutics. In the present study, the ability of the dual NP-based theranostic system to accumulate in the tumor was... more
Predicting the ability of nanoparticles (NP) to access the tumor is key to the success of chemotherapy using nanotherapeutics. In the present study, the ability of the dual NP-based theranostic system to accumulate in the tumor was evaluated in vivo using intravital microscopy (IVM) and MRI. The system consisted of model therapeutic doxorubicin-loaded poly(lactide-co-glycolide) NP (Dox-PLGA NP) and novel hybrid Ce3/4+-doped maghemite NP encapsulated within the HSA matrix (hMNP) as a supermagnetic MRI contrasting agent. Both NP types had similar sizes of ~100 nm and negative surface potentials. The level of the hMNP and PLGA NP co-distribution in the same regions of interest (ROI, ~2500 µm2) was assessed by IVM in mice bearing the 4T1-mScarlet murine mammary carcinoma at different intervals between the NP injections. In all cases, both NP types penetrated into the same tumoral/peritumoral regions by neutrophil-assisted extravasation through vascular micro- and macroleakages. The maxi...
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Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine... more
Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD₅₀ 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.
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During the drug development process, many pharmacologically active compounds are discarded because of poor water solubility, but nanoparticle-based formulations are increasingly proposed as a solution for this problem. We therefore... more
During the drug development process, many pharmacologically active compounds are discarded because of poor water solubility, but nanoparticle-based formulations are increasingly proposed as a solution for this problem. We therefore studied the distribution of nanoparticulate carriers and the delivery of their poorly water-soluble cargo to a structure of the central nervous system, the retina, under naive and pathological conditions. The lipophilic fluorescent dye coumarin 6 (Cou6) was encapsulated into poly(lactic-co-glycolic acid) PLGA nanoparticles (NPs). After intravenous administration in rats, we analyzed the distribution of cargo Cou6 and of the NP carrier covalently labeled with Cy5.5 in healthy animals and animals with optic nerve crush (ONC). In vivo real-time retina imaging revealed that Cou6 was rapidly released from PLGA NPs and penetrated the inner blood-retina barrier (BRB) within 15 min and PLGA NPs were gradually eliminated from the retinal blood circulation. Ex vivo...
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Doxorubicin (Dox) loaded in poly(butyl cyanoacrylate) nanoparticles (PBCA NP) coated with polysorbate 80 or poloxamer 188 produced a high antitumour effect against orthotopic 101/8 glioblas toma in rats. In the present study, the protein... more
Doxorubicin (Dox) loaded in poly(butyl cyanoacrylate) nanoparticles (PBCA NP) coated with polysorbate 80 or poloxamer 188 produced a high antitumour effect against orthotopic 101/8 glioblas toma in rats. In the present study, the protein adsorption pattern of polysorbate 80or poloxamer 188-coated DOX-loaded PBCA NP after incubation in rat plasma was investig ated. It was shown that the protein adsorption patterns o f both types of NP were similar, exhibiting a high adsorpt ion of apolipoprotein ApoA-I (ApoA-I). It is, therefore, hypothesized that the efficacy of these formulation s may be related to the interaction of ApoA-I on the particl e surface with the scavenger receptor SR-BI expressed at the BBB. Accordingly, these results suggest a correlation be twe n the adsorption of ApoA-I on the nanoparticle surface an d the resulting delivery of drugs to the brain by these p articles.
Research Interests: Chemistry and Doxorubicin
The present analytical survey explores different aspects of hydrolytic degradation of drug dosage forms (DF) based on polylactides, homopolymers of lactic acid (PLA) and copolymers of lactic and glycolic acids (PLGA). The study includes... more
The present analytical survey explores different aspects of hydrolytic degradation of drug dosage forms (DF) based on polylactides, homopolymers of lactic acid (PLA) and copolymers of lactic and glycolic acids (PLGA). The study includes various scientific data from multiple sources describing the effect of the PLGA nanocarrier hydrolytic degradation rate on the profile of drug release from the DFs intended for intravenous and intramuscular administration, including micro- and nanoparticles, and implants. The following aspects are explored in the review: design of experiments aimed at studying the hydrolytic degradation kinetics of PLGA carriers; commonly employed analytical methods; interpretation of the mechanism of PLGA-based DF hydrolytic degradation; factors that influence the hydrolytic degradation rate of PLGA drug carriers as part of DFs; interrelation between the processes of polymer carrier hydrolytic degradation and drug substance release from the PLGA-based DFs.
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The present study is dedicated to investigation of pharmacokinetics of the colloidal delivery system based on polybutylcyanoacrylate nanoparticles for the II generation photosensitizer Photosense. Free or nanoparticle-bound Photosense was... more
The present study is dedicated to investigation of pharmacokinetics of the colloidal delivery system based on polybutylcyanoacrylate nanoparticles for the II generation photosensitizer Photosense. Free or nanoparticle-bound Photosense was injected intravenously in healthy rats in the dose 15 mg/kg. It was shown that pharmacokinetic curve of the free drug was characterized by peak concentration while plasma concentrations of nanoparticulate Photosense were relatively steady. Elimination of nanoparticulate Photosense was more rapid comparing to the free drug. It is noteworthy that nanoparticles did not enhance liver uptake of the drug. Lung level of nanoparticulate drug was found to be lower and spleen uptake was enhanced. More important is the fact that nanoparticles provided two-fold decrease of Photosense skin concentration which is potentially important for decrease of drug-related skin phototoxicity. The above data provide evidence that optimization of Photosense pharmacokinetic ...
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A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in-vitro drug release represents an important critical quality attribute involved in... more
A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in-vitro drug release represents an important critical quality attribute involved in pharmacokinetics. Establishing in vitro-in vivo relationships for nanomedicines requires a careful analysis of the clinical data with respect to the unique differences between drugs and nanomedicines. Also, the biorelevant assay must reflect the release mechanism of the carrier. Four drug delivery systems of doxorubicin were evaluated for their in vitro release behavior under biorelevant conditions using the dispersion releaser. The pharmacokinetics observed during the first-in-men clinical trials were analyzed using a custom-made physiologically-based nanocarrier biopharmaceutics model. The drug product Lipodox® and the clinical candidate NanoCore-7.4 were evaluated to validate the model. Afterward, the in vivo performance of the preclinical candidates NanoCore-6.4 and doxorubicin-loaded nano-cellular vesicle technology systems (nCVTs-Dox) were predicted. In vitro and in vivo release were in good correlation as indicated by the coefficients of determination of 0.98648 (NanoCore-7.4) and 0.94107 (Lipodox®). The predictions required an estimation of the carrier half-life in blood circulation leading to considerable uncertainty. Still, the simulations narrow down the possible scenarios in the clinical evaluation of nanomedicines and provide a valuable addition to animal studies.
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Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the... more
Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine 123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these dyes to the polymer and lipophilic structures and which we also confirmed by computational modeling (log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsula...
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Targeted delivery of doxorubicin still poses a challenge with regards to the quantities reaching the target site as well as the specificity of the uptake. In the present approach, two colloidal nanocarrier systems, NanoCore-6.4 and... more
Targeted delivery of doxorubicin still poses a challenge with regards to the quantities reaching the target site as well as the specificity of the uptake. In the present approach, two colloidal nanocarrier systems, NanoCore-6.4 and NanoCore-7.4, loaded with doxorubicin and characterized by different drug release behaviors were evaluated in vitro and in vivo. The nanoparticles utilize a specific surface design to modulate the lipid corona by attracting blood-borne apolipoproteins involved in the endogenous transport of chylomicrons across the blood–brain barrier. When applying this strategy, the fine balance between drug release and carrier accumulation is responsible for targeted delivery. Drug release experiments in an aqueous medium resulted in a difference in drug release of approximately 20%, while a 10% difference was found in human serum. This difference affected the partitioning of doxorubicin in human blood and was reflected by the outcome of the pharmacokinetic study in rat...
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Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution. To better understand the... more
Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the
biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution.
To better understand the interactions of dyes and nanoparticles and their biological environment,
we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine
123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous
and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media
containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these
dyes to the polymer and lipophilic structures and which we also confirmed by computationalmodeling
(log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo
neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated
Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the
vessels. This observation is a good example of the possiblemisinterpretation of imaging results because
the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood–retina
barrier, whereas in fact no signal fromthe corematerial was found beyond the blood vessels.
biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles’ biodistribution.
To better understand the interactions of dyes and nanoparticles and their biological environment,
we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine
123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous
and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media
containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these
dyes to the polymer and lipophilic structures and which we also confirmed by computationalmodeling
(log PDPPC/PLGA: DiI—2.3, Cou6—0.7). The importance of these factors was demonstrated by in vivo
neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated
Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the
vessels. This observation is a good example of the possiblemisinterpretation of imaging results because
the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood–retina
barrier, whereas in fact no signal fromthe corematerial was found beyond the blood vessels.
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e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier... more
e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m2) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentratio...
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Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED... more
Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188-coated PLGA nanoparticles enabled a 30-fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.
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The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect... more
The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect against the very aggressive intracranial 101.8 glioblastoma in rats that closely resembles human grade IV glioblastomas. The basis for the transport of these particles across the blood-brain barrier appears to be adsorption of blood apolipoproteins (ApoE or ApoA-I) on the nanoparticle surface caused by the poloxamer 188-coating, followed by receptor-mediated transcytosis of the nanoparticles. The objective of the present study is the elucidation of the mechanism by which the poloxamer 188-coated nanoparticles then enter the brain tumor cells. Their intracellular fate, therefore, was investigated using the U87 human glioma cell line. The main mechanism of the PLGA nanoparticle internalization by U87 cells was clathrin-mediated endocytosis. Within 1h free...
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The lysosomal storage disorder (LSD) metachromatic leukodystrophy (MLD) is caused by a deficiency of the soluble, lysosomal hydrolase arylsulfatase A (ASA). The disease is characterized by accumulation of 3-O-sulfogalactosylceramide... more
The lysosomal storage disorder (LSD) metachromatic leukodystrophy (MLD) is caused by a deficiency of the soluble, lysosomal hydrolase arylsulfatase A (ASA). The disease is characterized by accumulation of 3-O-sulfogalactosylceramide (sulfatide), progressive demyelination of the nervous system and premature death. Enzyme replacement therapy (ERT), based on regular intravenous injections of recombinant functional enzyme, is in clinical use for several LSDs. For MLD and other LSDs with central nervous system (CNS) involvement, however, ERT is limited by the blood-brain barrier (BBB) restricting transport of therapeutic enzymes from the blood to the brain. In the present study, the potential of different types of surfactant-coated biodegradable nanoparticles to increase brain delivery of ASA was evaluated. Three different strategies to bind ASA to nanoparticle surfaces were compared: (1) adsorption, (2) high-affinity binding via the streptavidin-biotin system, and (3) covalent binding. ...
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ABSTRACT
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Nanoparticles made of poly(butyl cyanoacrylate) (PBCA) or poly(lactic-co-glycolic acid) (PLGA) coated with polysorbate 80 or poloxamer 188 enable the transport of cytostatics such as doxorubicin across the blood-brain barrier (BBB).... more
Nanoparticles made of poly(butyl cyanoacrylate) (PBCA) or poly(lactic-co-glycolic acid) (PLGA) coated with polysorbate 80 or poloxamer 188 enable the transport of cytostatics such as doxorubicin across the blood-brain barrier (BBB). Following intravenous injection to rats bearing intracranially the very aggressive glioblastoma 101/8 these particles loaded with doxorubicin significantly increased the survival times and led to a complete tumor remission in 20-40% of the animals. Moreover, these particles considerably reduced the dose-limiting cardiotoxicity and also the testicular toxicity of this drug. The drug transport across the BBB by nanoparticles appears to be due to a receptor-mediated interaction with the brain capillary endothelial cells, which is facilitated by certain plasma apolipoproteins adsorbed by nanoparticles in the blood.
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ABSTRACT Previous investigations have shown that doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 (Tween® 80) is able to cross the blood-brain barrier upon intravenous administration and is effective... more
ABSTRACT Previous investigations have shown that doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 (Tween® 80) is able to cross the blood-brain barrier upon intravenous administration and is effective against intracranially implanted 101/8 glioblastoma multiforme in rats at the treatment regimen of 3 × 1.5 mg/kg (as doxorubicin) on days 2, 5, 8 post tumour implantation. The objective of the present study was to investigate the possibility to further prolong the survival of rats with 101/8 glioblastoma by extending the treatment regimen. Doxorubicin-loaded poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 were injected using two different therapeutic regimens. Two groups received four injections at the dose of 1.5 mg/kg (as doxorubicin) on days 2, 5, 8, and 16 post tumour implantation and two other groups received an additional injection on day 20 (5 × 1.5 mg/kg). Histological and immunohistochemical analyses were carried out 24 and 30 days after tumour inoculation to assess the effect of the different therapy regimens in comparison to an untreated control group. The results demonstrate that the extended chemotherapy provided an enhanced survival. Comparison of the treatment outcomes revealed that the five-injection regimen produced a more distinctive antitumor effect manifested as a decreased tumour area and proliferation index as well as a decreased necrotic area and a smaller vascular network. Tumour regression was achieved in approximately 40% of the treated animals. These results demonstrate the promising therapeutic potential of doxorubicin-loaded nanoparticles for systemic chemotherapy of human glioblastoma multiforme.
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Arylsulfatase A (ASA) deficiency is the cause of metachromatic leucodystrophy (MLD), a lysosomal storage disease associated with severe neurological disorders. Poly(butyl cyanoacrylate) (PBCA) nanoparticles overcoated with polysorbate 80... more
Arylsulfatase A (ASA) deficiency is the cause of metachromatic leucodystrophy (MLD), a lysosomal storage disease associated with severe neurological disorders. Poly(butyl cyanoacrylate) (PBCA) nanoparticles overcoated with polysorbate 80 enabled the delivery of several drugs across the blood-brain barrier to the brain suggesting that these nanoparticles also may transport ASA across this barrier. The objective of this research, therefore, was to evaluate the feasibility of loading ASA onto PBCA nanoparticles. A stable ASA-loaded PBCA nanoparticle formulation was developed that could be easily freeze-dried and stored over a period of more than 8 weeks. The maximum loading capacity for this enzyme was -59 microg per 1 mg of PBCA. In the presence of 3% sucrose as a lyoprotector the activity of freeze-dried ASA was found to be 100% recoverable.
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Lysosomal storage disorders like mucopolysaccharidosis (MPS) VI are rare diseases with a lack of well-suited treatments. Even though an enzyme replacement therapy (ERT) of recombinant arylsulfatase B (ASB) is available for MPS VI, the... more
Lysosomal storage disorders like mucopolysaccharidosis (MPS) VI are rare diseases with a lack of well-suited treatments. Even though an enzyme replacement therapy (ERT) of recombinant arylsulfatase B (ASB) is available for MPS VI, the administration cannot positively affect the neurologic manifestations such as spinal cord compression. Since nanoparticles (NP) have shown to be effective drug carriers, the feasibility of arylsulfatase B adsorption onto poly(butyl cyanoacrylate) (PBCA) nanoparticles was investigated in this study. In order to advance the ERT of ASB, the adsorption of the latter on the surface of PBCA NP as well as in vitro release in serum was investigated. With alteration of parameters like temperature, incubation time, pH, and enzyme amount, the adsorption process revealed to be stable with a maximum capacity of 67 microg/mg NP at a pH of 6.3. In vitro release experiments demonstrated that the adsorption is stable for at least 60 minutes in human blood serum, indica...
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Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In... more
Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive de...
Research Interests: Biomedical Engineering, Magnetic Resonance Imaging, Nanoparticles, Transgenic Mice, Humans, and 15 moreControlled release, Liver, Mice, Animals, Hepatocellular Carcinoma, Particle Size, Excipients, Cell Survival, Contrast Media, Polyethylene Glycols, Serum albumin, Tissue distribution, Rhodamine, Liver neoplasms, and Pharmacology and pharmaceutical sciences
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In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated. HSA-NPs were... more
In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated. HSA-NPs were conjugated with Gd-DTPA (Gd-HSA-NPs) and coupled with transferrin (Gd-HSA-NP-Tf). Mice underwent MRI before or after injection of Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-Tf. All the studied contrast agents provided a contrast enhancement (CE) in the blood, heart muscle, and liver. Compared to Gd-DTPA, CE with HSA-NP was achieved at lower Gd doses. Gd-HSA-NP-Tf yielded significantly higher CE than Gd-HSA-NP in the skeletal muscle, blood, cardiac muscle, and liver (p < 0.05). Gd-HSA-NP-Tf achieved a significantly higher CE than Gd-HSA-NP and Gd-DTPA in the blood, cardiac muscle, and liver (p < 0.05). In the brain, only Gd-HSA-NP-Tf was found to cause a significant CE (p < 0.05). The Gd-HSA nanoparticles have potential as MRI contrast agents. In particular, Gd-HSA-NP-Tf has a potential as a specific contrast agent for the brain, while the blood-brain barrier is still intact, as well as in the heart, liver, and skeletal muscle.
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Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear... more
Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear to be a suitable carrier due to their safety and feasibility of functionalization. In the present study HSA nanoparticles were conjugated with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) using carbodiimide chemistry. The nanoparticles had a uniform spherical shape and a diameter of 235±19nm. For better optical visualization in vitro and in vivo, the HSA-Gd nanoparticles were additionally labeled with rhodamine 123. As shown by confocal microscopy and flow cytometry analysis, the fluorescent nanoparticles were readily taken up by Huh-7 hepatocellular carcinoma cells. After 24h incubation in blood serum, less than 5% of the Gd(III) was released from the particles, which suggests that this nanoparticulate system may be stable in vivo and, therefore, may serve as potentially safe T1 MRI contrast agent for MRI of hepatocellular carcinoma.
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This is the first report evaluating the nanoparticle delivery system for three antituberculosis drugs: isoniazid, rifampin, and streptomycin. The typical particle size is 250 nm. We studied accumulation of these drugs in human monocytes... more
This is the first report evaluating the nanoparticle delivery system for three antituberculosis drugs: isoniazid, rifampin, and streptomycin. The typical particle size is 250 nm. We studied accumulation of these drugs in human monocytes as well as their antimicrobial activity against Mycobacterium tuberculosis residing in human monocyte-derived macrophages. Nanoparticle encapsulation increased the intracellular accumulation (cell-association) of all three tested drugs,
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The objective of this study was to investigate the therapeutic effects of doxorubicin bound to polysorbate-coated nanoparticles that had previously been shown to significantly enhance survival in the orthotopic rat 101/8 glioblastoma... more
The objective of this study was to investigate the therapeutic effects of doxorubicin bound to polysorbate-coated nanoparticles that had previously been shown to significantly enhance survival in the orthotopic rat 101/8 glioblastoma model. Tumor-bearing animals were subjected to chemotherapy using doxorubicin in solution (Dox-sol) or doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (Dox-np) injected intravenously on Days 2, 5 and 8 post tumor implantation. The antitumor effect was assessed on Days 10, 14 and 18 post tumor implantation. Tumors showed signs of malignancy including invasion of brain tissue, brisk mitotic activity, microvascular proliferation, necrosis and increased proliferation resembling human glioblastoma. Dox-np produced a considerably more pronounced antitumor effect exhibited as a reduced tumor size, lower proliferation, and a decreased necrotic area compared to Dox-sol and to untreated control groups. A drastic effect of Dox-np on vascularization indicated an antiangiogenic mode of action.