Isohexylcyanoacrylate Dipeptide Gangliosides

Biocompatible and biodegradable colloidal drug delivery systems were obtained by means of in-situ polymerization of alkylcyanoacrylate [874]. In particular, nanocapsules of PECA were prepared by adding the monomer to an organic phase, consisting of Miglyol 812(R) and an organic solvent (ethanol, acetone, or acetonitrile), and subsequently mixing the organic phase with an aqueous phase containing Pluronic F68(R) at different concentrations. The mechanism of formation and the influence of preparation conditions on the quality of nanocapsule formulations were investigated by freeze-fracture electron microscopy and laser light scattering. The mechanism of drug release from PECA nano-capsules was mainly diffusion from the oil core through the intact polymer barrier. Figure 25a gives a diagrammatic representation of a microdelivery particle and Figure 25b shows PECA nanocapsules containing hydroquinone [875].

Macrophages can become cytotoxic toward tumor cells when activated by immunomodulators. Three different muramyl peptides were synthesized: one hydrolyzable lipophilic ester derivative (MTP-Chol) and two nonhydrolyz-able lipophilic ether derivatives (MTP-octadecane and MTP-heptadecafluorooctadecane) [876]. Activation of the RAW 264.7 cell line was studied by measuring nitrite production as an indication of NO-synthase activity. The lipophilic ester derivative, incorporated within nanocapsules, was as active as a free muramyl dipeptide, whereas the lipophilic ether derivatives were unable to activate macrophages. The results indicated that lipophilic muramyl peptides needed to be hydrolyzed to yield a hydrosoluble metabolite in order to activate macrophages.

Poly(ethylcyanoacrylate) nanocapsules suitable for use as drug delivery systems were prepared by in-situ polymerization, addition of the monomer to an organic phase, and subsequent mixing of the latter to an aqueous phase containing a nonionic surfactant. Different preparation conditions were able to influence the final poly(ethylcyanoacrylate) nano-capsule colloidal suspension [877].

The drug-loaded polymeric nanospheres were prepared composed of the methoxy PEG (MePEG) and PCL that showed a narrow size distribution and average diameter of less than 200 nm [878]. The nanosphere having a relatively high drug-loading efficiency of about 42% was obtained when the feed weight ratio of indomethacin to polymer was 1:1.

The association with poly(alkylcyanoacrylate) nano-spheres and nanocapsules of monosialoganglioside GM1 and other chemically modified gangliosides was investigated with the aim of developing a colloidal drug delivery system


Figure 25. (a) Diagrammatic representation of a micro-delivery particle and (b) PECA nanoparticles containing hydroquinone. After [875], R. Arshady, in "Microspheres, Microcapsules and Liposomes," MML Series, Vols. 1 and 2. Citus Books, London, 1999. © 1999, Citus Books.

suitable for use by the oral route [879]. Gangliosides were successfully associated with a biodegradable cyanoacrylic carrier either in the form of nanospheres or as nanocapsules, avoiding any degradation of the ganglioside molecule during the polymerization process. The drug loading was found to be more efficient for nanocapsules.

Antihypertensive effects of a nanocapsular form of dar-odipine, a dihydropyridine calcium entry blocker, were studied [880]. Two problems were addressed, associated with the use of dihydropyridine calcium entry blockers in antihypertensive therapy, namely, potent vasodilation and short half-lives, by incorporating the representative blocker, darodipine, into a nanocapsular vehicle. The effect of various poloxamer coatings on in vitro adhesion of isohexylcyanoacrylate nanospheres to rat ileal segments under liquid flow was investigated [881]. Polyisohexyl-cyanoacrylate nanocapsules containing cyclosporin were prepared by mixing in a 1:2 ratio an oil/ethanol solution of monomer and drug with an aqueous phase [882, 883]. Drug nanoencapsulation rate was controlled by its partition coefficient between the inner (organic) and outer (aqueous) phases. The biodegradable polyisohexylcyanoacrylate nanoparticles were shown to be able to deliver the growth hormone releasing factor as a sustained-release system [884]. Nanocapsules were prepared by interfacial polymerization of isohexylcyanoacrylate and coated with poloxamers to reduce the recognition and uptake by retic-uloendothelial cells of the liver and spleen [885]. Several phthalocyanine derivatives were encapsulated into nano-capsules and their in vitro photocytotoxic activity against V-79 cells was compared to that of free drug. Nano-encapsulation did not reduce the activity of amphiphilic drugs while hydrophilic and lipophilic compounds were affected in diverse ways. Body distribution in mice of intravenously injected radiolabeled cyclosporine associated with polyisohexylcyanoacrylate nanocapsules or nanospheres was studied [886].

The nanoparticle uptake by the rat gastrointestinal mucosa, quantitation, and particle-size dependency were studied [887]. Polystyrene microspheres in the size range 50 nm to 3 / m were fed by gavage to female Sprague Daw-ley rats daily for 10 days at a dose of 1.25 mg/kg. Histo-logical evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen were confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 / m I-125-labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles.

6.3.5. Polys -caprolactone/Poly(ethylene imine)/Poly(ethylene oxide-b-sebacic acid) Polymethylidene/ Dodecanoate/Oligonucleotides

Two dialkylmethylidenemalonate (DAMM) analogs, diallyl-methylidenemalonate (AAMM) and cyclohexylethylmethyli-denemalonate (CEMM), were synthesized and evaluated for their capacity to polymerize to stable nanoparticles and to adsorb primaquine diphosphate [888]. The interaction between polystyrene microspheres and the follicle-associated epithelium of rabbit Peyer's patches was examined [889].

In order to evaluate the concentration of a hydrophilic drug, phenobarbitone, in a suspension of poly-e-caprolactone nanocapsules, a gas chromatographic-mass spectrometric procedure, performed after methylation of the drug, was developed and validated [890]. Treatment with muramyldipeptide (MDP) or a lipophilic derivative (MTP-Chol) included in nanocapsules renders macrophages cytostatic toward tumor cells. At the same time, nitric oxide synthase (EC 1.14.23) activity was induced, as determined by measurement of the two end products of the reaction (nitrite and L-citrulline) [891].

In order to evaluate the concentration of a hydrophilic drug, phenobarbitone, in a suspension of poly-e-caprolactone nanocapsules, a gas chromatographic-mass spectrometric procedure, performed after methylation of the drug, was developed and validated [892]. The preparation of primidone-loaded poly-e-caprolactone nanocapsules according to the interfacial deposition technique was described [893]. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst effect.

Amphiphilic diblock copolymers composed of MePEG and e-caprolactone (e-CL) were prepared for the formation of micelles [894]. The copolymer was formed by the ring-opening mechanism of e-CL in the presence of MePEG containing hydroxyl functional groups at one end of the chain. To estimate their feasibility as vehicles for drugs, MePEG/e-CL block copolymeric micelles were prepared by dialysis against water. Indomethacin was incorporated into the hydrophobic inner core of these micelles as a typical model drug for nonsteroidal anti-inflammatory drugs. From the dynamic light scattering measurements, the size of micelle formed was less than 200 nm, and their size increased with the amount of indomethacin encapsulated into the inner core of MePEG/e-CL block copolymers.

The influence of factors (pH, enzymes, etc.) chosen partially to mimic in vivo conditions on the release of a model drug, indium oxine, from PCL nanocapsules in vitro was determined [895]. A nanocapsule suspension, an emulsion (o/w), and a solution in olive oil were prepared in order to compare the release of a radioactive tracer, indium oxine, as a function of time by an in vitro dialysis method. Nano-capsules were prepared by interfacial deposition of PCL and characterized by particle size distribution (laser light scattering) and determination of the polymer molecular weight by gel permeation chromatography.

Nanocapsules of poly-e-caprolactone and Eudragit S90(R) were prepared by using the spray-drying process using colloidal silicon dioxide as a technological carrier [896]. The morphological analysis of the surface at the powders showed that nanocapsules remained intact, and no change in particle size was detected after the spray-drying process.

Various methods were tested for sample preparation, in order to determine progesterone concentration in nanocapsules consisting of benzyl benzoate in a poly-e-caprolactone shell [897]. The opening of nanocapsules by a dissolution-dilution in acetonitrile was validated.

The efficacy of colloidal particles as drug carriers is closely related to their interaction with proteins and enzymes in different body fluids [898]. A work analyzed the interaction phenomenon between lysozyme, a positively charged enzyme that was highly concentrated in mucosas, and two different drug carriers: nanocapsules made of an oily core coated by the polymer poly-e-caprolactone (PECL) and nanoparticles made solely of poly-e-caprolactone [898]. The interaction of lysozyme with these colloidal drug carriers was highly affected by their surface charge.

Polymethylidene malonate nanoparticles were prepared in phosphate buffer through emulsion polymerization of monomeric units; the kinetics of the reaction was monitored by spectrophotometry at 400 nm. Average nano-particle sizes, molecular weights, and biodegradability of this potential drug carrier were determined under various conditions [899].

One of the major limiting steps for the absorption of peptide drugs from the intestine is proteolytic degradation. To slow this degradation, human calcitonin was trapped in polyacrylamide nanoparticles, and human calcitonin and insulin were encapsulated with polyisobutylcyanoacrylate [900]. Human calcitonin trapped in polyacrylamide nano-particles showed no delayed release characteristics and thus would not provide protection from proteases. Proteolytic degradation of human calcitonin and insulin in polyisobutyl-cyanoacrylate nanocapsules was slower than the free pep-tides in solution.

A rapid, sensitive, and selective HPLC assay was developed for the simultaneous determination of ethyl clofi-brate and its major metabolite, clofibric acid, in plasma of humans and rats [901]. The assay involves extraction of the compounds into chloroform-isoamyl alcohol (99:1, v/v) from plasma acidified with sulfuric acid. The HPLC assay was used to monitor the plasma concentration-time profiles of ethyl clofibrate released from polylactic nanocapsules in both man and rat. Activity of a-chymotrypsin immobilized in poly(N, N-diallyl-N, N-didodecylammonium) bromide nanocapsules was studied [902].

The synthesis and the characterization of a poly(2-methyloxazoline)-block-poly(dimethylsiloxane)-block-poly (2-methyloxazoline) triblock copolymer carrying polymer-izable groups at both chain ends were described [903]. This copolymer forms vesicular structures in dilute aqueous solution, the size of which can be controlled in the range from 50 up to about 500 nm. The methacrylate end groups of the triblock copolymer can be polymerized in the vesicular aggregates using an UV-induced free radical polymerization.

A diblock copolymer, poly(ethylene oxide-b-sebacic acid), was prepared by polycondensation [904]. Its self-assembly in water via a microphase inversion resulted in narrowly distributed stable polymeric nanoparticles with a size around 70 nm. Such formed nanoparticles had a core-shell nanos-tructure, with the insoluble hydrophobic polysebacic acid blocks as the core and the soluble hydrophilic polyethylene oxide blocks as the protective shell. The core was degradable, and its degradation led to the disintegration of the nanoparticle. The degradation was a first-order reaction, and the degradation rate increased with the dispersion temperature.

ABA block copolymers of polylactide and poly(ethylene glycol) as amphiphilic bioabsorbable polymers were synthesized by the ring-opening polymerization of DL-lactide onto PEG 2000 or PEG 6000 and their structures were characterized on the basis of proton NMR. Biodegradable nano-capsules of an aqueous insulin solution were prepared from the block copolymers and polylactide by an improved interfacial coacervation technique [905]. The diameters of the nanocapsules were mainly dependent on the ratio of the two chains in the block polymers. The size of the nano-capsules decreased with an increase in the amount of surfactant used. More insulin solution resulted in an enlargement of the nanocapsules in diameter.

Poly(ethylene imine) was used for the complexation of dodecanoic acid resulting in a poly(ethylene imine) dode-canoate complex with a lamellar nanostructure and a repeat unit of 2.9 nm [906].

Antisense oligonucleotides are molecules that are able to inhibit gene expression being therefore potentially active for the treatment of viral infections or cancer. Antisense oligonucleotides with base sequences complementary to a specific RNA can, after binding to intracellular mRNA, selectively modulate the expression of a gene. However, because of their poor stability in biological medium and their weak intracellular penetration, colloidal drugs carriers such as nanoparticles were developed for the delivery of oligonucleotides [907]. Oligonucleotides associated to nano-particles were shown to be protected against degradation and to penetrate more easily into different types of cells. As a consequence, nanoparticles were shown to improve the efficiency of oligonucleotides for the inhibition of the proliferation of cells expressing the point mutated Ha-ras gene. Nanocapsules were prepared by interfacial polymerization of isobutylcyanoacrylate in a w/o emulsion [908]. A nanotechnology was said to be able to encapsulate oligonu-cleotides, rather than adsorbing them at the surface of a solid support, which had great potential for oligonucleotide delivery.

EWS Fli-1, a fusion gene resulting from a f(11;22) translocation, was found in 90% of both Ewing's sarcoma and primitive neuroectodermal tumor. The polyisobutylcyanoacrylate nanocapsules with an aqueous core were able to encapsulate efficiently high amounts of phosphorothioate oligonu-cleotides directed against EWS Fli-1 chimeric RNA [909].

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