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PubMed2004

[Development of polymeric nanoparticles in the targeting drugs carriers].

This review presents the most outstanding contribution in the field of polymeric nanoparticles used as targeting drugs delivery systems. Nanoparticles barrier is a novel kind of controlled release system for drugs which can effectively deliver the drug to a target site and increase the bioavailability and therapeutic benefit, while minizing the side effects. In this paper the applications of nanoparticles in the active, passive and physical targeting drugs carriers are reviewed.

Albumins↗
PubMed2006

RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system.

This work introduces a novel chitosan-based siRNA nanoparticle delivery system for RNA interference in vitro and in vivo. The formation of interpolyelectrolyte complexes between siRNA duplexes (21-mers) and chitosan polymer into nanoparticles, ranging from 40 to 600 nm, was shown using atomic force microscopy and photon correlation spectroscopy. Rapid uptake (1 h) of Cy5-labeled nanoparticles into NIH 3T3 cells, followed by accumulation over a 24 h period, was visualized using fluorescence microscopy. Nanoparticle-mediated knockdown of endogenous enhanced green fluorescent protein (EGFP) was demonstrated in both H1299 human lung carcinoma cells and murine peritoneal macrophages (77.9% and 89.3% reduction in EGFP fluorescence, respectively). In addition, Western analysis showed approximately 90% reduced expression of BCR/ABL-1 leukemia fusion protein while BCR expression was unaffected in K562 (Ph(+)) cells after transfection using nanoparticles containing siRNA specific to the BCR/ABL-1 junction sequence. Effective in vivo RNA interference was achieved in bronchiole epithelial cells of transgenic EGFP mice after nasal administration of chitosan/siRNA formulations (37% and 43% reduction compared to mismatch and untreated control, respectively). These findings highlight the potential application of this novel chitosan-based system in RNA-mediated therapy of systemic and mucosal disease.

Animals↗
PubMed2006

[Recent advances in liposomes and nanoparticles as drug carriers for drug delivery].

Liposomes and nanoparticles have been used as drug carriers to increase solubility, prolong drug duration in vivo, target drug delivery, reduce toxicity and combat multi-drug resistance. With major advances in the preparation techniques, preparation material, and surface modifiers in recent years, liposomes and nanoparticles delivery systems have achieved success in fields including cancer therapy, overcoming biological barriers, and biological drugs and vaccine carriage.

Drug Carriers↗
PubMed2005

Solid lipid nanoparticles as drug delivery systems.

For a decade, trials have been made to utilize solid lipid nanoparticles (SLNs) as alternative drug delivery systems to colloidal drug delivery systems such as lipid emulsions, liposomes, and polymeric nanoparticles. Various lipid matrices, surfactants, and other excipients used in formulation, preparation methods, sterilization and lyophilization of SLNs are discussed in this article. Entrapment efficiency of drug carrier and its effect on physical parameters, drug release, and release mechanisms of various compositions are reviewed and discussed. Important points in characterization and stability of SLNs are outlined. Various in vitro studies carried out by different research groups are mentioned in addition to in vivo evaluation. Exploitation potential of SLNs to administer by various routes of administration are covered. Passive and active drug targeting using SLNs are presented.

Drug Compounding↗
PubMedDate not supplied

A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 1. Synthesis and characterization.

Nonviral gene delivery systems are amenable to forming colloidal particles with a wide range of physicochemical properties that include size, surface charge, and density and type of ligand presented. However, it is not known how to best design these particles without having a set of physicochemical design constraints that have been optimized for the intended gene delivery application. Here, a nanoparticle-based model delivery system is developed that can mimic the surface properties of nonviral gene delivery particles, and this model system is used to define design constraints that should be applied to next generation gene delivery particles. As a test case, a well-defined nanoparticle-based system is developed to guide the rational design of gene delivery to hepatocytes in the liver. The synthetic scheme utilizes monodisperse polystyrene particles and provides for variation of mean particle size and particle size distribution through variation in reaction conditions. The nanoparticles are PEGylated to provide stability in serum and also incorporate targeting ligands, e.g., galactose, at tunable densities. Four nanoparticles are synthesized from uniformly sized polystyrene beads specifically for the purpose of identifying design constraints to guide next generation gene delivery to the liver. These four nanoparticles are Gal-50 and Gal-140, that are galactosylated 50 and 140 nm nanoparticles, and MeO-50 and MeO-140, that are methoxy-terminated 50 and 140 nm nanoparticles. All four particles have the same surface charge, and Gal-50 and Gal-140 have the same surface galactose density. The availability of galactose ligands to receptor binding is demonstrated here by agglutination with RCA120.

Animals↗
PubMed2006

Studies on the oridonin-loaded poly(D,L-lactic acid) nanoparticles in vitro and in vivo.

The purpose of this paper was to investigate the possibility of developing a polymeric nanoparticle delivery system for ORI to increase its solubility, blood circulation time and tissue targeting. Oridonin-loaded poly(D,L-lactic acid) nanoparticles (ORI-PLA-NP) were prepared by the further modified spontaneous emulsion solvent diffusion (MSESD) method. Studies were carried out to characterize and evaluate the produced ORI-PLA-NP both in vitro and in vivo. The experimental results showed that the mean size of the nanoparticles were 137.3 nm, with 87.2% of the nanoparticles distributed between the range of 107 and 195 nm. The entrapment efficiency and actual drug loading of the nanoparticles were 91.88+/-1.83 and 2.32+/-0.05%, respectively. It was demonstrated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) that ORI existed in the form of amorphous in the nanoparticles. The in vitro release profile of ORI-PLA-NP could be expressed well by the Higuchi equation: Q=8.944t(1/2)+11.246. The results of pharmacokinetics demonstrated that being encapsulated in PLA nanoparticles was remarkably effective for ORI to prolong its blood circulation time. After the i.v. administration of ORI-PLA-NP, we could observe a stable and high concentration of ORI in liver, lung and spleen, while its distribution in heart and kidney decreased.

Animals↗
PubMed2006

Thiomers: preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system.

It was the aim of this study to develop a mucoadhesive nanoparticulate delivery system. Nanoparticles were generated by in situ gellation of the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) with tripolyphosphate (TPP) followed by stabilization via the formation of inter- and intrachain disulfide bonds by oxidation with H(2)O(2) in various concentrations. Afterwards TPP was removed by exhaustive dialysis at pH 1-2. Incorporation of the model compound fluorescein diacetate (FDA) was achieved by incubation of this fluorescence marker, dissolved in acetonitrile, with aqueous particle suspensions for 1h at room temperature. Mucoadhesion studies were performed on porcine intestinal mucosa. Results showed that the preparation method described above leads to nanoparticles of a mean diameter of 268+/-15 nm and a FDA load of 2%. Due to the removal of the anionic crosslinker TPP, the zeta potential of the nanoparticles was raised from 4+/-1 up to 19+/-2 mV without loosing stability of the nanoparticles. The more H(2)O(2) was added to the particles, the more inter- and intrachain disulfide bonds were formed. The more thiol groups were oxidized within the particles, however, the lower was the improvement in mucoadhesive properties. Nevertheless, even when 91% of all thiol groups on the nanoparticles were oxidized, their mucoadhesive properties were still twice as high as the mucoadhesive properties of unmodified nanoparticles. Thiolated chitosan nanoparticles show a two-fold higher zeta potential (I), improved stability (II) and more than doubled mucoadhesive properties (III) than corresponding unmodified chitosan nanoparticles. Therefore, they seem to be advantageous over ionically crosslinked chitosan nanoparticles.

Adhesiveness↗
PubMed2005

Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.

Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.

Alzheimer Disease↗
PubMed2006

Porous nanoparticles in drug delivery systems.

This article concentrates mainly on fabrication of porous nanoparticles, its characterisation and its use for controlled release of drug. It also encompasses the strategies that have been used to translate and fabricate a wide range of particulate carriers e.g., nanospheres, liposomes, micelles, oil-in-water emulsions, with prolonged circulation and/or target specificity. Sol-gel technique is one of the most widely used techniques to fabricate porous nanoparticles within the polymer. Such nanoparticles have also applications in vascular drug delivery and release, site-specific targeting, as well as transfusion medicine. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers. We have also critically reviewed and assessed the fate and activity of biodegradable polymeric drug delivery vehicles because the uniformity in degradation of these polymers is questionable. This article will highlight rational approaches in design and surface engineering of nanoscale vehicles and entities for site-specific drug delivery. Potential pitfalls or side effects associated with nanoparticles are also discussed.

Animals↗
PubMed2002

Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel.

BACKGROUND: Paclitaxel (PXL)-eluting stents in animals cause incomplete healing and, in some instances, a lack of sustained suppression of neointimal growth. The present study tested the efficacy of a novel systemic delivery nanoparticle PXL for reducing in-stent restenosis. METHODS AND RESULTS: A saline-reconstituted formulation of PXL stabilized by albumin nanoparticles (nPXL) was tested in 38 New Zealand White rabbits receiving bilateral iliac artery stents. Doses of nPXL (1.0 to 5.0 mg/kg) were administered as a 10-minute intra-arterial infusion; control animals received vehicle (0.9% normal saline). In a follow-up chronic experiment, nPXL 5.0 mg/kg was given at stenting with or without an intravenous 3.5-mg/kg repeat nPXL dose at 28 days; these studies were terminated at 3 months. At 28 days, mean neointimal thickness was reduced (P< or =0.02) by doses of nPXL > or =2.5 mg/kg with evidence of delayed healing. The efficacy of a single dose of nPXL 5.0 mg/kg, however, was lost by 90 days. In contrast, a second repeat dose of nPXL 3.5 mg/kg given 28 days after stenting resulted in sustained suppression of neointimal thickness at 90 days (P< or =0.009 versus single dose nPXL 5.0 mg/kg and controls) with nearly complete neointimal healing. CONCLUSIONS: Although systemic nPXL reduces neointimal growth at 28 days, a single repeat dose was required for sustained neointimal suppression. Thus, this novel systemic formulation of PXL may allow adjustment of dose at the stent treatment site and prove to be a useful adjunct for the clinical prevention of in-stent restenosis.

Angiogenesis Inhibitors↗
PubMed2005

[Regulation of tissue factor expression in brain microvascular endothelial cells by PLA nanoparticles coating NF-kappaB decoy oligonucleotides].

OBJECTIVE: To investigate a new strategy of polylactic acid (PLA) nanoparticles delivery system coating nuclear factor-kappaB (NF-kappaB) decoy oligonucleotides (ODNs) for inhibiting TF expression in cultured brain microvascular endothelial cells(BMECs). METHODS: PLA nanoparticles coating FITC-labeled NF-kappaB decoy ODNs were formulated by nano-deposition method and the characteristics of nanoparticles were detected. BMECs were isolated and cultured in vitro. The cellular uptake and intracellular localization of nanoparticles in BMECs was detected by flow cytometry and confocal microscopy. Changes in the expressions of TF and nuclear protein P65 were examined by RT-PCR and Western blot in NF-kappaB decoy ODNs transfected BMECs by LPS stimulation. RESULTS: The decoy-nanoparticles obtained were uniform spherical particles with an effective diameter of 162.1 nm and a polydispersity index of 0.118. NF-kappaB decoy ODNs encapsulated in nanoparticles could be released in a controlled manner in phosphate-buffered saline for up to 28 days. It was observed that the cellular uptake of nanoparticles were increased with the time of incubation and the concentration of nanoparticles in the medium. Nanoparticles localized mainly in the BMECs cytoplasm. LPS-induced upregulation of TF transcription was inhibited by NF-kappaB decoy ODNs transfection but not by missense ODNs transfection. Furthermore, changes in the transcription level of TF were paralleled by a reduction of capacity of P65 in nuclear extract of NF-kappaB decoy ODNs transfected cells. CONCLUSIONS: These findings offer a potential therapeutic strategy in the control of TF expression in BMECs in vitro.

Animals↗
PubMed2026

Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced RALB transcriptional suppression.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with metastasis being the primary cause of its high mortality. The chromatin-binding protein, high mobility group nucleosome binding domain 1 (HMGN1), has been implicated in tumour progression, but its specific role and mechanism in HCC metastasis remain unclear. This study investigates the function of HMGN1 and its potential as a therapeutic target. Analysis of patient samples confirms an upregulation of HMGN1 in HCC tissues, correlating with advanced disease and poor prognosis. Functional assays demonstrate that HMGN1 promotes HCC metastasis in vitro and in vivo. Mechanistically, integrated RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that HMGN1 binds to the promoter of RAS-like proto-oncogene B (RALB) gene, recruiting the repressive histone mark H3K9me2 to epigenetically silence its transcription and drive metastasis. Therapeutically, a nanoparticle delivery system for siRNA against HMGN1 effectively silences its expression and inhibits metastasis in orthotopic liver xenograft tumour models. Our findings establish HMGN1 as a key epigenetic driver of HCC metastasis and highlight siRNA-nanoparticle targeting of HMGN1 as a promising precision therapeutic strategy.

Humans↗
PubMed2026

TogoPhosTAC as a delivery-ready platform for targeted protein dephosphorylation.

Phosphorylation-targeting chimeras (PhosTACs) enable targeted protein dephosphorylation by recruiting phosphatases through induced proximity. However, the direct recruitment of phosphatase subunits or holoenzymes with small molecules remains challenging, as suitable ligands are scarce and often compromise enzymatic activity or cellular function. Here, we present togoPhosTAC, a hybrid modality that integrates a small-molecule PhosTAC, an engineered FKBP12F36V-phosphatase, and a lipid nanoparticle delivery system. This strategy allows delivery of preassembled PhosTAC-FKBP12F36V-phosphatase complexes or PhosTAC-phosphatase mRNA, enabling rapid and efficient intracellular dephosphorylation. We demonstrate that togoPhosTAC can selectively dephosphorylate EGFR, &#x3b1;-synuclein, and tau in biological contexts, providing a versatile strategy that circumvents the need for genetically engineered phosphatases. We also find togoPhosTAC further enhances tau dephosphorylation as well as its disaggregation in cellulo. Importantly, intrahippocampal or intranasal delivery of togoPhosTAC in PS19 tau transgenic male mice leads to a marked reduction in pathological tau phosphorylation across multiple sites (Ser202, Thr205, Thr231, Ser396, and Ser404), decreases pathological tau burden in related brain regions, and improves Alzheimer's disease-related behavioral deficits. Together, these findings establish a versatile and generalizable approach for precise protein dephosphorylation in disease-relevant systems, overcoming key limitations in phosphatase-recruiting drug discovery.

Animals↗
PubMed2006

Effective targeting of liposomes to liver and hepatocytes in vivo by incorporation of a Plasmodium amino acid sequence.

PURPOSE: Several species of the protozoan Plasmodium effectively target mammalian liver during the initial phase of host invasion. The purpose of this study was to demonstrate that a Plasmodium targeting amino acid sequence can be engineered into therapeutic nanoparticle delivery systems. METHODS: A 19-amino peptide from the circumsporozoite protein of Plasmodium berghei was prepared containing the conserved region I as well as a consensus heparan sulfate proteoglycan binding sequence. This peptide was attached to the distal end of a lipid-polyethylene glycol bioconjugate. The bioconjugate was incorporated into phosphatidylcholine liposomes containing fluorescently labeled lipids to follow blood clearance and organ distribution in vivo. RESULTS: When administered intravenously into mice, the peptide-containing liposomes were rapidly cleared from the circulation and were recovered almost entirely in the liver. Fluorescence and electron microscopy demonstrated that the liposomes were accumulated both by nonparenchymal cells and hepatocytes, with the majority of the liposomal material associated with hepatocytes. Accumulation of liposomes in the liver was several hundredfold higher compared to heart, lung, and kidney, and more than 10-fold higher compared to spleen. In liver slice experiments, liposome binding was specific to sites sensitive to heparinase. CONCLUSIONS: Incorporation of amino acid sequences that recognize glycosaminoglycans is an effective strategy for the development of targeted drug delivery systems.

Animals↗
PubMed1999

Detection and determination of surface levels of poloxamer and PVA surfactant on biodegradable nanospheres using SSIMS and XPS.

The surface chemical characterisation of sub-200 nm poly(DL-lactide co-glycolide) nanospheres has been carried out using the complementary analytical techniques of static secondary ion mass spectrometry (SSIMS) and X-ray photoelectron spectroscopy (XPS). The nanospheres, which are of interest for site-specific drug delivery, were prepared using an emulsification-solvent evaporation technique with poly(vinyl alcohol), Poloxamer 407 and Poloxamine 908 respectively as stabilisers. The presence of surfactant molecules on the surface of cleaned biodegradable colloids was confirmed and identified on a qualitative molecular level (SSIMS) and from a quantitative elemental and functional group analysis (XPS) perspective. SSIMS and XPS data were also used in combination with electron microscopy to monitor the effectiveness of cleaning procedures in removing poorly bound surfactant molecules from the surface of nanospheres. The findings are discussed with respect to the development of nanoparticle delivery systems, particularly the composition of the surface for extending blood circulation times and achieving site-specific deposition.

Adsorption↗
PubMed2003

Insulin containing polyethylenimine-dextran sulfate nanoparticles.

An aqueous nanoparticle delivery system has been developed which employs the oppositely charged polymers polyethylenimine (PEI) and dextran sulfate (DS) with zinc as a stabilizer. It is found that the pH of PEI solutions, the weight ratio of the two polymers, and zinc sulfate concentrations all play significant roles in controlling particle size. Spherical particles of 250 nm mean diameter were produced under optimal conditions which have a zeta potential of approximately +30 mV. Up to 90% drug entrapment efficiency was observed when insulin was used as a model protein drug. No degradation products were detected during in vitro dissolution or in potency studies. Circular dichroism (CD) spectra showed no significant conformational changes compared to free insulin under optimized formulation conditions. Rapid release characteristics were observed in in vitro dissolution studies. Biological activity in steptozotocin-induced diabetic rats, however, exhibited a prolonged hypoglycemic effect. This system offers the following advantages: (1) ease of manufacturing under mild preparation conditions; (2) employment of completely aqueous processing conditions; (3) use of biocompatible polymers which can be prepared aseptically; (4) ability to control particle size; (5) a high level of drug entrapment and (6) an ability to preserve protein secondary structure and biological activity.

Animals↗
PubMed2003

Evaluation of gliadins nanoparticles as drug delivery systems: a study of three different drugs.

In this paper, biopolymer nanoparticles are studied, which unlike many synthetic carriers used for controlled release, are biocompatible and biodegradable systems. Gliadins nanoparticles are obtained by a desolvatation method, also known as drawning-out precipitation. These particles have been shown to be interesting as drug release systems for all-trans-retinoic acid. The aim of this paper was to study the influence of the polarity of different drugs on nanoparticle characteristics such as size and drug loading efficiency. Three drugs of three different polarities were studied: the hydrophobic Vitamin E (VE), the slightly polar mixture of linalool and of linalyl acetate (LLA) and the cationic amphiphilic benzalkonium chloride (BZC). This comparative work shows that the amount of the entrapped VE and LLA is higher than that of the cationic BZC, confirming a strong interaction between gliadins and apolar compounds, due to the apolarity of the proteins. This interaction results in a low diffusion coefficient and a partition coefficient in favour of gliadins, resulting in a low permeability coefficient. The drug release kinetics of two substances, LLA and BZC, are observed, in showing a burst effect, then a diffusion process, which can be modelled assuming that the particles are homogeneous spheres.

Acyclic Monoterpenes↗
PubMedDate not supplied

Biodegradable nanoparticles as a delivery system for cyclosporine: preparation and characterization.

Cyclosporine (CyA) was incorporated into polycaprolactone nanoparticles (PCL-NP) in order to increase its oral bioavailability and to control drug distribution, thereby potentially reducing its toxicity. Prior to in vivo studies, the carrier was optimized and characterized by using different techniques. Light scattering (LS) and transmission and scanning electron microscopy (TEM and SEM) indicated the NP were spherical in shape with a mean size of approximately 100 nm. The influence of the solvent evaporation conditions and the polymer and drug amounts on CyA incorporation was established in order to optimize drug loading. When acetone and excess water were removed at constant temperature, no aggregation phenomena were observed. A value of 180 mg PCL was the minimum polymer amount necessary to encapsulate 95% of the drug initially added to the preparation. Under these conditions, HPLC analysis revealed that approximately 130 microg CyA per mg PCL were incorporated for a total CyA concentration of 2.5 mg/ml, being part of the drug adsorbed onto the particle surface. No structural changes or instability of the components during NP preparation were detected by gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). However, GPC studies showed a competition between poloxamer and CyA for adsorption onto the carrier. In addition, DSC results suggested that at least part of the drug associated to NP remained in its crystal form. Therefore, CyA-loaded NP were easily manufactured and characterized and allow for the administration of therapeutic drug doses to experimental animals.

Animals↗