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PubMed2003

Dynamics of endocytosis and exocytosis of poly(D,L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells.

PURPOSE: The purpose of this work was to characterize the process of endocytosis, exocytosis, and intracellular retention of poly (D,L-lactide-co-glycolide) nanoparticles in vitro using human arterial vascular smooth muscle cells (VSMCs). METHODS: Nanoparticles containing bovine serum albumin (BSA) as a model protein and 6-coumarin as a fluorescent marker were formulated by a double emulsion-solvent evaporation technique. The endocytosis and exocytosis of nanoparticles in VSMCs were studied using confocal microscopy and their intracellular uptake and retention were determined quantitatively using high-performance liquid chromatography. RESULTS: Cellular uptake of nanoparticles (mean particle size 97 +/- 3 nm) was a concentration-, time-, and energy-dependent endocytic process. Confocal microscopy demonstrated that nanoparticles were internalized rapidly, with nanoparticles seen inside the cells as early as within 1 min after incubation. The nanoparticle uptake increased with incubation time in the presence of nanoparticles in the medium; however, once the extracellular nanoparticle concentration gradient was removed, exocytosis of nanoparticles occurred with about 65% of the internalized fraction undergoing exocytosis in 30 min. Exocytosis of nanoparticles was slower than the exocytosis of a fluid phase marker, Lucifer yellow. Furthermore, the exocytosis of nanoparticles was reduced after the treatment of cells with the combination of sodium azide and deoxyglucose, suggesting that exocytosis of nanopartides is an energy-dependent process. The nanoparticle retention increased with increasing nanoparticle dose in the medium but the effect was relatively less significant with the increase in incubation time. Interestingly, the exocytosis of nanoparticles was almost completely inhibited when the medium was depleted of serum. Further studies suggest that the addition of BSA in the serum free medium with or without platelet derived growth factor (PDGF) induced exocytosis of nanoparticles. The above result suggests that the protein in the medium is either adsorbed onto nanoparticles and/or carried along with nanoparticles inside the cells, which probably interacts with the exocytic pathway and leads to greater exocytosis of nanoparticles. CONCLUSIONS: The study demonstrated that endocytosis and exocytosis of nanoparticles are dynamic and energy-dependent processes. Better understanding of the mechanisms of endocytosis and exocytosis, studies determining the effect of nanoparticle formulation and composition that may affect both the processes, and characterization of intracellular distribution of nanoparticles with surface modifications would be useful in exploring nanoparticles for intracellular delivery of therapeutic agents.

Cell Membrane↗

PubMed2003

Physical characterization and macrophage cell uptake of mannan-coated nanoparticles.

Previously, we reported on a cationic nanoparticle-based DNA vaccine delivery system engineered from warm oil-in-water microemulsion precursors. In these present studies, the feasibility of lyophilizing the nanoparticles and their thermal properties were investigated. Also, the binding and uptake of the nanoparticles by a macrophage cell line were studied. The nanoparticles (prior to pDNA coating) were freeze-dried with lactose or sucrose as cryoprotectants. The stability of lyophilized nanoparticles at room temperature was monitored and compared to that of the aqueous nanoparticle suspension. The thermal properties of the nanoparticles were investigated using differential scanning calorimetry (DSC). The nanoparticles, coated or uncoated with mannan as a ligand, were incubated with a mannose receptor positive (MR+) mouse macrophage cell line (J774E), at either 4 degrees C or 37 degrees C to study the binding and uptake of the nanoparticles by the cells. It was found that lactose or sucrose (1-5%, w/v) was required for successful lyophilization of the nanoparticles. After 4 months of storage, the size of lyophilized nanoparticles did not significantly increase while those in aqueous suspension grew by over 900%. Unlike its individual components, emulsifying wax (m.p., approximately 55 degrees C) and hexadecyltrimethyl ammonium bromide, the nanoparticles showed a melting point of approximately 90 degrees C. Moreover, the DSC profile of the nanoparticles was different from that of the physical mixture of emulsifying wax and CTAB. After 1 hour incubation at 37 degrees C, the uptake of mannan-coated nanoparticles was 50% higher than that of the uncoated nanoparticles. At 4 degrees C and after one hour, the binding of the mannan-coated nanoparticles by J774E was over 2-fold higher than that of the uncoated nanoparticles. This increase in J774E binding could be abolished by preincubating the cells with free mannan, suggesting that the binding and uptake were receptor-mediated. In conclusion, the nanoparticles were lyophilizable, and lyophilization was shown to enhance the stability of the nanoparticles. DSC provided evidence that the nanoparticles were not a physical mixture of their individual components. Finally, cell binding and uptake studies demonstrated that the nanoparticles have potential application for cell-specific targeting.

Animals↗

PubMed2005

Effect of colloidal nanocatalysis on the metallic nanoparticle shape: the Suzuki reaction.

Dominantly tetrahedral shaped poly(vinylpyrrolidone)-platinum (PVP-Pt) nanoparticles are shown to catalyze the Suzuki reaction between phenylboronic acid and iodobenzene but are not as active as the spherical palladium nanoparticles studied previously. The dominantly tetrahedral PVP-Pt nanoparticles (55 +/- 4% regular tetrahedral, 22 +/- 2% distorted tetrahedral, and 23 +/- 2% spherical nanoparticles) are synthesized by using the hydrogen reduction method. The transmission electron microscopy (TEM) results show that a transformation of shape from tetrahedral to spherical Pt nanoparticles takes place 3 h into the first cycle of the reaction. After the first cycle, the spherical nanoparticles have a similar size distribution to that of the tetrahedral nanoparticles before the reaction and the observed shape distribution is 18 +/-6% regular tetrahedral, 28 +/- 5% distorted tetrahedral, and 54 +/- 5% spherical nanoparticles. After the second cycle of the Suzuki reaction, the shape distribution is 13 +/- 5% regular tetrahedral, 24 +/- 5% distorted tetrahedral, and 63 +/- 7% spherical nanoparticles. After the second cycle, the transformed spherical nanoparticles continue to grow, and this could be due to the strong capping action of the higher molecular weight PVP (M(w) = 360 000), which makes the nanoparticles more resistant to aggregation and precipitation, unlike the Pd nanoparticles capped with the lower molecular weight PVP (M(w) = 40 000) used previously. The transformation in shape also occurs when the nanoparticles are refluxed in the presence of the solvent, sodium acetate, and iodobenzene and results in spherical nanoparticles with a similar size distribution to that of the tetrahedral nanoparticles before any perturbations. However, in the presence of phenylboronic acid, the regular tetrahedral nanoparticles remain dominant (51 +/- 6%) and maintain their size. These results support our previous studies in which we proposed that phenylboronic acid binds to the nanoparticle surface and thus acts as a capping agent for the particle and reacts with the iodobenzene. Recycling the nanoparticles results in a drastic reduction of the catalytic activity, and this must be due to the transformation of shape from the dominantly tetrahedral to the larger dominantly spherical nanoparticles. This also supports results in the literature that show that spherical platinum nanoparticles do not catalyze this reaction.

Journal Article↗

PubMed2005

Influence of administration route on tumor uptake and biodistribution of etoposide loaded solid lipid nanoparticles in Dalton's lymphoma tumor bearing mice.

The study evaluates the capability of tripalmitin nanoparticles in enhancing the tumor uptake of etoposide, and the influence of administration route on the biodistribution and tumor uptake of etoposide loaded tripalmitin (ETPL) nanoparticles in Dalton's lymphoma tumor bearing mice. ETPL nanoparticles were prepared by melt-emulsification and high pressure homogenization followed by the spray drying of nanodispersion. Characterization of the nanoparticles was done by particle size analysis, zeta potential measurement and scanning electron microscopy. The size of ETPL nanoparticles was 387 nm and possessed negative charge. Etoposide and ETPL nanoparticles were radiolabeled with 99mTc with high labeling efficiency. The labeled complexes showed good in vitro stability in the presence of DTPA/cysteine and serum stability. Etoposide and ETPL nanoparticles were injected by subcutaneous, intravenous or intraperitoneal routes and their biodistribution and tumor uptake were determined. Subcutaneous injection reduced the distribution of ETPL nanoparticles to all the tissues studied whereas after intraperitoneal injection, the distribution of ETPL nanoparticles to tissues was higher than free etoposide. The intravenous injection resulted in lower concentrations of ETPL nanoparticles in the organs of RES compared to free etoposide. ETPL nanoparticles experienced significantly high brain distribution after intraperitoneal injection indicating its potential use in targeting etoposide to brain tumors. After subcutaneous injection, the tissue distribution of ETPL nanoparticles increased with time indicating their accumulation at the injection site for a longer time. The tumor uptake of both etoposide and ETPL nanoparticles was significantly high after subcutaneous injection (P<0.001) compared to the other routes of administration. The tumor concentration of ETPL nanoparticles after subcutaneous injection was 59 folds higher than that obtained after intravenous and 8 folds higher than after intraperitoneal route at 24 h post-injection. The tumor concentration of ETPL nanoparticles increased with time after subcutaneous injection indicating the slower and progressive penetration from the injection site into the tumor. The study signifies the advantage of incorporating etoposide into tripalmitin nanoparticles in controlling its biodistribution and enhancing the tumor uptake by several folds. The study also reveals that, of the three routes investigated, subcutaneous injection is the route of preference for facilitating high tumor uptake and retention and is likely to have greater antitumor effect resulting in tumor regression.

Animals↗

PubMed2002

Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A.

In this study, cyclosporin-A (Cy-A) a highly lipophilic, poorly absorbable drug can be prepared easily and reproducibly as positively and negatively charged nanoparticles with the aim of improving its bioavailability and reducing its inter- and intra-individual variability. The nanoparticles were prepared by emulsification solvent diffusion method, using lecithin and poloxamer 188 as emulsifiers, and chitosan HCl, gelatin-A or sodium glycocholate (SGC) as charge inducing agents. The prepared nanoparticles were evaluated with respect to particle size, zeta potential, drug content and encapsulation efficiency. The bioavailability Cy-A from nanoparticles in comparison with the currently available Cy-A microemulsion (Neoral) were assessed in beagle dogs. The results obtained revealed that, it was possible to prepare Cy-A as nanoparticles with size range of 104-148 nm. Chitosan HCl and gelatin-A nanoparticles exhibited +31.2 and +23.1 mV zeta potential, respectively; while SGC-nanoparticles exhibited -41.6 mV zeta potential. The in vivo results showed that, chitosan-nanoparticles gave the highest C(max) (2762.8 ng/ml) of Cy-A after 2.17 h (T(max)), while SGC-nanoparticles gave the lowest one (1202.4 ng/ml after 4.0 h). Furthermore, AUC(0-24) of Cy-A from chitosan-nanoparticles was markedly increased by about 2.6-fold when compared with SGC-nanoparticles and increased by about 1.8-fold when compared with the reference Neoral microemulsion. However, in case of gelatin-nanoparticles the AUC(0-24) of Cy-A increased by about 1.8 and 1.2-fold when compared with SGC-nanoparticles and the reference Neoral microemulsion, respectively. The relative bioavailability of Cy-A from chitosan-nanoparticles was increased by about 73%, and by about 18% from gelatin nanoparticles, while it was decreased by about 36% from SGC-nanoparticles.

Administration, Oral↗

PubMed1999

Mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal tract.

The mucoadhesion of polystyrene nanoparticles having surface hydrophilic polymeric chains in the gastrointestinal (GI) tract was investigated in rats. Radiolabeled nanoparticles were synthesized by adding hydrophobic 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine in the final process of nanoparticle preparation. The radioiodonated diazirine seemed to be incorporated in the hydrophobic polystyrene core of nanoparticles. The incorporation rate was less than 10%, irrespective of nanoparticle type. The diazirine incorporated in nanoparticles exhibited little leakage from them even though they were mixed with a solution corresponding to GI juice. The change in blood ionized calcium concentration after oral administration of salmon calcitonin (sCT) with nanoparticles showed that the in vivo enhancement of sCT absorption by radiolabeled nanoparticles was the same as that by non-labeled nanoparticles. The GI transit rates of nanoparticles having surface poly(N-isopropylacrylamide), poly(vinylamine) and poly(methacrylic acid) chains, which can improve sCT absorption, were slower than that of nanoparticles covered by poly(N-vinylacetamide), which does not enhance sCT absorption at all. These slow transit rates were probably the result of mucoadhesion of nanoparticles. The strength of mucoadhesion depended on the structure of the hydrophilic polymeric chains on the nanoparticle surface. The mucoadhesion of poly(N-isopropylacrylamide) nanoparticles, which most strongly enhanced sCT absorption, was stronger than that of ionic nanoparticles, and poly(N-vinylacetamide) nanoparticles probably did not adhere to the GI mucosa. These findings demonstrated that there is a good correlation between mucoadhesion and enhancement of sCT absorption.

Analgesics↗

PubMedDate not supplied

Plasmid DNA-entrapped nanoparticles engineered from microemulsion precursors: in vitro and in vivo evaluation.

Nonviral gene therapy has been a rapidly growing field. However, delivery systems that can provide protection for pDNA and potential targeting are still desired. A novel pDNA-nanoparticle delivery system was developed by entrapping hydrophobized pDNA inside nanoparticles engineered from oil-in-water (O/W) microemulsion precursors. Plasmid DNA was hydrophobized by complexing with cationic surfactants DOTAP and DDAB. Warm O/W microemulsions were prepared at 50-55 degrees C with emulsifying wax, Brij 78, Tween 20, and Tween 80. Nanoparticles were engineered by simply cooling the O/W microemulsions containing the hydrophobized pDNA in the oil phase to room temperature while stirring. The nanoparticles were characterized by particle sizing, zeta-potential, and TEM. Nanoparticles were challenged with serum nucleases to assess pDNA stability. In addition, the nanoparticles were coincubated with simulated biological media to assess their stability. In vitro hepatocyte transfection studies were completed with uncoated nanoparticles or nanoparticles coated with pullulan, a hepatocyte targeting ligand. In vivo biodistribution of the nanoparticles containing I-125 labeled pDNA was monitored 30 min after tail-vein injection to Balb/C mice. Depending on the hydrophobizing lipid agent employed, uniform pDNA-entrapped nanoparticles (100-160 nm in diameter) were engineered within minutes from warm O/W microemulsion precursors. The nanoparticles were negatively charged (-6 to -15 mV) and spherical. An anionic exchange column was used to separate unentrapped pDNA from nanoparticles. Gel permeation chromatography of pDNA-entrapped and serum-digested nanoparticles showed that the incorporation efficiency was approximately 30%. Free 'naked' pDNA was completely digested by serum nucleases while the entrapped pDNA remained intact. Moreover, in vitro transfection studies in Hep G2 cells showed that pullulan-coated nanoparticles resulted in enhanced luciferase expression, compared to both pDNA alone and uncoated nanoparticles. Preincubation of the cells with free pullulan inhibited the transfection. Finally, 30 min after tail vein injection to mice, only 16% of the 'naked' pDNA remained in the circulating blood compared to over 40% of the entrapped pDNA. Due to the apparent stability of these pDNA-entrapped nanoparticles in the blood, they may have potential for systemic gene therapy applications requiring cell and/or tissue-specific delivery.

Animals↗

PubMed1998

Arterial uptake of biodegradable nanoparticles: effect of surface modifications.

Restenosis is the reobstruction of an artery following interventional procedures such as balloon angioplasty or stenting. Local pharmacotherapeutic approaches using controlled release systems are under investigation to inhibit the regional pathophysiologic process of restenosis. We have been investigating biodegradable nanoparticles (100 +/- 39 nm in diameter, mean +/- sd) for the local intra-arterial drug delivery. The purpose of this study was to investigate nanoparticle surface modifications (see Table 1) to enhance their arterial uptake. The PLGA (polylactic polyglycolic acid copolymer) nanoparticles were formulated by an oil-in-water emulsion solvent evaporation technique using a 2-aminochromone (U-86983, Upjohn and Pharmacia) (U-86) as a model antiproliferative agent. The various formulations of nanoparticles were evaluated for the arterial wall uptake by using an ex-vivo dog femoral artery model. The selected formulations were then tested in vivo in acute dog femoral artery and pig coronary artery models. The nanoparticles surface modified with a cationic compound, didodecyldimethylammonium bromide (DMAB), demonstrated 7-10-fold greater arterial U-86 levels compared to the unmodified nanoparticles in different ex-vivo and in-vivo studies. The mean U-86 levels were 10.7 +/- 1.7 microg/10 mg (dog) and 6.6 +/- 0.6 microg/10 mg (pig) in the artery segments ( approximately 2 cm) which were infused with the nanoparticles. The pig coronary studies further demonstrated that the infusion of nanoparticles with higher U-86 loading reduced the arterial U-86 levels, whereas increasing the nanoparticle concentration in the infusion solutions increased the arterial U-86 levels. The biodistribution studies in pigs following coronary arterial administration of nanoparticles demonstrated disposition of U-86 in the myocardium and distally in the liver and the lung. The mechanism of enhanced arterial uptake of the DMAB surface modified nanoparticles seems to be due to the alteration in the nanoparticle surface charge. The unmodified nanoparticles had a zeta potential of -27.8 +/- 0.5 mV (mean +/- sem, n = 5), whereas the DMAB modified nanoparticles demonstrated a zeta potential of +22.1 +/- 3.2 mV (mean +/- sem, n = 5). The adsorption of DMAB to the nanoparticle surface followed the Freundlich isotherm with binding capacity k = 28.1 microg/mg and affinity constant p = 2. 33. In conclusion, surface modified nanoparticles have potential applications for intra-arterial drug delivery to localize therapeutic agents in the arterial wall to inhibit restenosis.

Animals↗

PubMed2004

Improvement in the luminescence properties and processability of LaF3/Ln and LaPO4/Ln nanoparticles by surface modification.

The surface of lanthanide(III)-doped LaPO4 nanoparticles was modified by reaction with an alcohol, leading to a covalent bond between the ligand and the particle surface. The surface of lanthanide(III)-doped LaF3 nanoparticles was modified to alter the solubility of the nanoparticles and study the influence of surface effects on the luminescence of lanthanide ions doped in the nanoparticles. The coordinated organic ligands can be modified by a quantitative exchange reaction in solution or by using functionalized ligands during the synthesis. Variation of the ratio of ligand to core reagents had a significant influence on the size of the nanoparticles. Smaller nanoparticles were formed with a higher ligand ratio. The optical properties of these nanoparticles show a strong dependence on nanoparticle size, indicating the influence of quenching probably by CH and OH groups at or near the surface of the nanoparticle cores. The luminescence lifetime of LaF3/Eu nanoparticles varied from 6.5 to 7.4 ms for nanoparticles with an average size of 7.1 to 8.4 nm. A significant reduction of the quenching from the surface of the nanoparticles was obtained by the synthesis of core-shell nanoparticles, in which a shell of LaF3 was grown epitaxially around the doped core nanoparticles. This leads to an increase in the luminescence lifetime of the Eu3+ ion and the observation of emissions from the 5D2 energy level, in addition to emissions from the 5D1 and 5D0 levels. The quantum yield of LaF3/Ce,Tb nanoparticles could be increased from 24 to 54% by the growth of a LaF3 shell around the nanoparticles.

Journal Article↗

PubMed2006

Ecotoxic effect of photocatalytic active nanoparticles (TiO2) on algae and daphnids.

BACKGROUND: Due to their large potential for manifold applications, the use of nanoparticles is of increasing importance. As large amounts of nanoparticles may reach the environment voluntarily or by accident, attention should be paid on the potential impacts on the environment. First studies on potential environmental effects of photocatalytic TiO2 nanoparticles have been performed on the basis of widely accepted, standardized test systems which originally had been developed for the characterization of chemicals. The methods were adapted to the special requirements of testing photocatalytic nanoparticles. METHODS: Suspensions of two different nanoparticles were illuminated to induce their photocatalytic activity. For testing, the growth inhibition test with the green alga Desmodesmus subspicatus and the immobilization test with the daphnid Daphnia magna were selected and performed following the relevant guidelines (algae: ISO 8692, OECD 201, DIN 38412-33; daphnids: ISO 6341, OECD 202, DIN 38412-30). The guidelines were adapted to meet the special requirements for testing photocatalytic nanoparticles. RESULTS: The results indicate that it is principally possible to determine the ecotoxicity of nanoparticles. It was shown that nanoparticles may have ecotoxicological effects which depend on the nature of the particles. Both products tested differ in their toxicity. Product 1 shows a clear concentration-effect curve in the test with algae (EC50: 44 mg/L). It could be proven that the observed toxicity was not caused by accompanying contaminants, since the toxic effect was comparable for the cleaned and the commercially available product. For product 2, no toxic effects were determined (maximum concentration: 50 mg/L). In the tests with daphnids, toxicity was observed for both products, although the concentration effect-curves were less pronounced. The two products differed in their toxicity; moreover, there was a difference in the toxicity of illuminated and non-illuminated products. DISCUSSION: Both products differ in size and crystalline form, so that these parameters are assumed to contribute to the different toxicities. The concentration-effect curves for daphnids, which are less-pronounced than the curves obtained for algae, may be due to the different test organisms and/or the differing test designs. The increased toxicity of pre-illuminated particles in the tests with daphnids demonstrates that the photocatalytic activity of nanoparticles lasts for a period of time. CONCLUSION: The following conclusions can be drawn from the test results: (I) It is principally possible to determine the ecotoxicity of (photocatalytic) nanoparticles. Therefore, they can be assessed using methods comparable to the procedures applied for assessing soluble chemicals. (II) Nanoparticles may exert ecotoxicological effects, which depend on the specific nanoparticle. (III) Comparable to traditional chemicals, the ecotoxicity depends on the test organisms and their physiology. (IV) The photocatalytic activity of nanoparticles lasts for a relevant period of time. Therefore, pre-illumination may be sufficient to detect a photocatalytic activity even by using test organisms which are not suitable for application in the pre-illumination-phase. RECOMMENDATIONS AND PERSPECTIVES: First results are presented which indicate that the topic 'ecotoxicity and environmental effects of nanoparticles' should not be neglected. In testing photocatalytic nanoparticles, there are still many topics that need clarification or improvement, such as the cause for an observed toxicity, the improvement of the test design, the elaboration of a test battery and an assessment strategy. On the basis of optimized test systems, it will be possible to test nanoparticles systematically. If a potential risk by specific photocatalytic particles is known, a risk-benefit analysis can be performed and, if required, risk reducing measures can be taken.

Animals↗

PubMed2004

Pharmacokinetics and biodistribution studies of Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles synthesized by two different techniques.

The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of Doxorubicin (Dox) delivered as solution or through nanoparticles after intravenous (i.v.) and intraperitoneal (i.p.) injection. Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles were synthesized by dispersion polymerization (DP) and emulsion polymerization (EP) techniques. The drug loaded DP and EP nanoparticles were administered by i.v. or i.p. routes and the respective pharmacokinetics and tissue distribution were determined. Both types of nanoparticles significantly enhanced the elimination half-life (T(1/2)), mean residence time (MRT) AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox in blood after i.v. injection. Dox delivered through DP nanoparticles rapidly disappeared from blood and distributed to the organs of reticuloendothelial system (RES). But, the clearance of Dox delivered through EP nanoparticles from blood was slower than this of the DP nanoparticles and Dox solution. After i.p. injection, the Dox loaded into DP nanoparticles quickly appeared in blood and undergone rapid distribution to the organs of RES, while the Dox loaded into EP nanoparticles absorbed slowly into blood and remained in the circulation for longer time. The absorption into blood of Dox delivered through DP and EP nanoparticles after i.p. injection was relatively rapid and higher than Dox solution. The T(1/2), MRT, AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox in blood were significantly higher and the clearance (Cl) was lower than for the Dox solution after i.p. injection. The tissue concentrations of Dox delivered through nanoparticles after i.p. injection were significantly lower than after i.v. injection. The bioavailability (F) of Dox was greatly enhanced by DP (approximately 1.9 fold) and EP nanoparticles (approximately 2.12 fold) compared to Dox solution after i.p. injection. EP nanoparticles significantly enhanced the bioavailability, MRT, T(1/2), AUC(0-8), AUC(0-infinity) and AUMC(0-8) of Dox than DP nanoparticles. This signifies the advantage of EP nanoparticles in increasing the elimination half-life of Dox both after i.v. and i.p. injection and enhanced bioavailability after i.p. injection, which is expected to improve the therapeutic efficacy of Dox and reduce the Dox-associated systemic toxicity. Importantly, both DP and EP nanoparticles greatly reduced the distribution of Dox to heart both after i.v. and i.p. injection, suggesting their potential in reducing Dox-associated cardiotoxicity.

Animals↗

PubMed2005

Cellular interactions and in vitro DNA transfection studies with poly(ethylene glycol)-modified gelatin nanoparticles.

In order to develop a systemically administered safe and effective nonviral gene delivery system, cellular interactions and plasmid DNA transfection with poly(ethylene glycol)-modified (PEGylated) gelatin nanoparticles were examined. The DNA-containing nanoparticles were prepared by a controlled water-ethanol solvent displacement method. The nanoparticles were characterized for particle size, surface charge, and DNA loading, release, and stability. For cellular interaction studies, the control and PEGylated gelatin nanoparticles, complexed either with colloidal gold for transmission electron microscopy or loaded with rhodamine-dextran for fluorescence confocal microscopy, were incubated with NIH-3T3 fibroblast cells. At different time points, the location of the nanoparticles in the cellular environment was investigated. Furthermore, a reporter plasmid expressing the enhanced green fluorescent protein was encapsulated in the control gelatin and PEGylated gelatin nanoparticles for in vitro transfection studies. DNA-containing nanoparticles were prepared in the size range of 100-500 nm, with an average of 200 nm. PEGylated gelatin nanoparticles, with a slight negative surface charge, could stably and efficiently encapsulate plasmid DNA. Both transmission electron microscopy and confocal microscopy images showed that the gelatin and PEGylated gelatin nanoparticles rapidly entered the cell through nonspecific endocytosis followed by vesicular transport in the cytosol. Almost 100% of the administered gelatin and PEGylated gelatin nanoparticles were internalized in NIH-3T3 cells within the first 6 h of incubation. A large fraction of the administered nanoparticles was found to be concentrated in the perinuclear region of the cells after 12 h. Green fluorescent protein expression was observed after 12 h of nanoparticle incubation and remained stable for up to 96 h. Flow cytometry results showed that the DNA transfection efficiency with gelatin and PEGylated gelatin nanoparticles was 43% and 61%, respectively, after 96 h. The results of this study illustrate that PEGylated gelatin nanoparticles were rapidly internalized by the cells through nonspecific endocytosis and remained intact in the cytosol for up to 12 h. In addition, the DNA-encapsulated PEGylated gelatin nanoparticles were found to efficiently transfect cells in culture.

3T3 Cells↗

PubMed2007

In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implications.

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors--(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

Animals↗

PubMed2006

Biomimetic assembly of polypeptide-stabilized CaCO(3) nanoparticles.

In this paper, we report a simple polypeptide-directed strategy for fabricating large spherical assembly of CaCO(3) nanoparticles. Stepwise growth and assembly of a large number of nanoparticles have been observed, from the formation of an amorphous liquidlike CaCO(3)-polypeptide precursor, to the crystallization and stabilization of polypeptide-capped nanoparticles, and eventually, the spherical assembly of nanoparticles. The "soft" poly(aspartate)-capping layer binding on a nanoparticle surface resulted in the unusual soft nature of nanoparticle assembly, providing a reservoir of primary nanoparticles with a moderate mobility, which is the basis of a new strategy for reconstructing nanoparticle assembly into complex nanoparticle architectures. Moreover, the findings of the secondary assembly of nanoparticle microspheres and the morphology transformation of nanoparticle assembly demonstrate a flexible and controllable pathway for manipulating the shapes and structures of nanoparticle assembly. In addition, the combination of the polypeptide with a double hydrophilic block copolymer (DHBC) allows it to possibly further control the shape and complexity of the nanoparticle assembly. A clear perspective is shown here that more complex nanoparticle materials could be created by using "soft" biological proteins or peptides as a mediating template at the organic-inorganic interface.

Biomimetic Materials↗

PubMedDate not supplied

Bioadhesive properties of poly(alkylcyanoacrylate) nanoparticles coated with polysaccharide.

Development of bioadhesive nanoparticles is of great interest to improve drug absorption through the intestinal barrier. Various Polysaccharide-coated poly(alkylcyanoacrylate) nanoparticles were prepared. The bioadhesive properties of the nanoparticles coated with dextran or chitosan in end-on or side-on conformation were evaluated with an ex-vivo adsorption experiment on rat intestine. Results show that diffusion of nanoparticles in mucus layer was governed by the nanoparticle diameter and isotherms of adsorption were influenced by the nature of polysaccharide used. High amount of nanoparticles coated with chitosan can be entrapped in the mucus layer even at low nanoparticle concentration in suspension. When nanoparticle concentration increased, a pseudo-plateau was reached. In the case of dextran-coated nanoparticles, linear increase of adsorption was observed and no saturation phenomenon was highlighted over the range of nanoparticle concentration used in this study. These results suggested that interactions involved in bioadhesion mechanism depended on the nature of polysaccharide. Electrostatic interactions are enhanced between chitosan-coated nanoparticles and glycoproteins of mucus leading to a saturated adsorption phenomenon whereas dextran-coated nanoparticles interacted by non-electrostatic interactions with mucus resulting in a non-saturated phenomenon. Polysaccharides grafted at the nanoparticle surface in the brush conformation appeared more favorable to promote interactions of nanoparticles with glycoproteins of mucus in comparison with the more compact loop conformation of polysaccharide chains.

Adhesiveness↗

PubMed2005

Development and characterization of sub-micron poly(D,L-lactide-co-glycolide) particles loaded with magnetite/maghemite nanoparticles.

PURPOSE: The objective of this study is to develop biodegradable sub-micron poly(lactide-co-glycolide) particles loaded with magnetite/maghemite nanoparticles for intravenous drug targeting. METHOD: Sub-micron magnetite/PLGA particles (also called composite nanoparticles) were prepared by a modified double emulsion method (w/o/w) or by an emulsion-evaporation process (o/w). To optimize the composite nanoparticles formulation, the influence of some experimental parameters, such as types of magnetite/maghemite nanoparticles, volume of magnetite suspension and amount of polymer were investigated. The morphology, size and zeta potential of the magnetite/PLGA nanoparticles were determined. The magnetite entrapment efficiency and magnetite content were assessed by dosing iron in the composite nanoparticles. RESULTS: TEM photomicrographs showed that the composite nanoparticles were almost spherical in shape with a rather monomodal distribution in size. All composite nanoparticle formulations were found to have the mean diameter within the range of 268-327 nm with polydispersity index within the range of 0.02-0.15. Magnetite nanoparticles coated with oleic acid showed more efficient entrapment (60%) as compared to uncoated magnetite nanoparticles (48%). In both cases, when the volume of magnetite suspension increased, the magnetite entrapment efficiency decreased but the magnetite content increased. In addition, the two-fold rise in the amount of polymer did not significantly affect the composite nanoparticle characteristics except the magnetite content. Finally, none modification of the mean diameter of the composite nanoparticles was observed after storage for 3 months at 4 degrees C. CONCLUSIONS: Magnetite/PLGA nanoparticles were prepared and the influence of some process parameters have been assessed. Improvement of the magnetite entrapment efficiency are in progress and the magnetization properties of the composite nanoparticles will subsequently be tested.

Adsorption↗

PubMed2004

Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice.

The purpose of these studies was to compare the cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium (Gd) nanoparticles. Gd is a potential agent for neutron capture therapy (NCT) of tumors. Gd nanoparticles were engineered from oil-in-water microemulsion templates. To obtain folate-coated nanoparticles, a folate ligand [folic acid chemically linked to distearoylphosphatidylethanolamine (DSPE) via a PEG spacer MW 3350] was included in nanoparticle preparations. Similarly, control nanoparticles were coated with DSPE-PEG-MW 3350 (PEG-coated). Nanoparticles were characterized based on size, size distribution, morphology, biocompatibility and tumor cell uptake. In vivo studies were carried out in KB (human nasopharyngeal carcinoma) tumor-bearing athymic mice. Biodistribution and tumor retention studies were carried out at pre-determined time intervals after injection of nanoparticles (10 mg/kg). Gd nanoparticles did not aggregate platelets or activate neutrophils. The retention of nanoparticles in the blood 8, 16 and 24 h post-injection was 60%, 13% and 11% of the injected dose (ID), respectively. A maximum Gd tumor localization of 33+/-7 microg Gd/g was achieved. Both folate-coated and PEG-coated nanoparticles had comparable tumor accumulation. However, the cell uptake and tumor retention of folate-coated nanoparticles was significantly enhanced over PEG-coated nanoparticles. Thus, the benefits of folate ligand coating were to facilitate tumor cell internalization and retention of Gd-nanoparticles in the tumor tissue. The engineered nanoparticles may have potential in tumor-targeted delivery of Gd thereby enhancing the therapeutic success of NCT.

Animals↗

PubMed2003

Fluorescence and electron microscopy probes for cellular and tissue uptake of poly(D,L-lactide-co-glycolide) nanoparticles.

Nanoparticles formulated from poly(D,L-lactide-co-glycolide) (PLGA) and poly(lactide) (PLA) are being extensively investigated for different therapeutic applications such as for sustained drug, vaccine, and gene delivery. For many of these applications, it is necessary to study the intracellular distribution as well as the tissue uptake of nanoparticles to optimize the efficacy of the encapsulated therapeutic agent. Fluorescence and electron microscopic techniques are usually used for the above purposes. Colloidal gold particles and fluorescent polystyrene, which are generally used as model particles for electron and fluorescence microscopy, respectively, may not be suitable alternatives to PLGA/PLA nanoparticles for these studies mainly because of the differences in their physical properties and also because they do not contain any therapeutic agent. The aim of the present study was to develop and characterize PLGA nanoparticle formulations that would be suitable for confocal/fluorescence and transmission electron microscopic (TEM) studies. Towards this objective, PLGA nanoparticles containing 6-coumarin as a fluorescent marker and osmium tetroxide as an electron microscopic marker with bovine serum albumin (BSA) as a model protein were formulated. Different physical properties of marker-loaded nanoparticles such as particle size, zeta potential, residual PVA content and protein-loading were compared with those of unloaded nanoparticles and were found to be not significantly different. Furthermore, marker-loaded nanoparticle formulations were non-toxic to the cells as unloaded nanoparticles. Nanoparticles loaded with 6-coumarin were found to be useful for studying intracellular nanoparticle uptake and distribution using confocal microscopy while osmium tetroxide-loaded nanoparticles were found to be useful for studying nanoparticle uptake and distribution in cells and tissue using TEM. It was concluded that 6-coumarin and osmium tetroxide could serve as useful fluorescence and electron microscopy probes, respectively, for incorporation into nanoparticles to study their cellular and tissue distribution.

Cells, Cultured↗