Showing papers on "Drug carrier published in 1994"
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TL;DR: The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier.
Abstract: In preclinical studies, a doxorubicin liposome formulation containing polyethylene-glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-associated doxorubicin were analyzed in seven patients after injections of equivalent doses of free DOX and Doxil and in an additional group of nine patients after injection of Doxil only. Two dose levels were examined, 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 liter/h for Doxil versus 45 liters/h for free DOX) and a small volume of distribution (4 liters for Doxil versus 254 liters for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clinical investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.
1,371 citations
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TL;DR: Sterically stabilized liposomes, containing entrapped doxorubicin, targeted to squamous cell lung carcinoma by means of specific antibodies attached at the liposome surface are capable of reducing tumour burden to a significant extent and eradicating tumour in a significant percentage of mice.
463 citations
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322 citations
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TL;DR: Stealth liposomes have decreased uptake into the mononuclear phagocyte system (MPS), increased circulation half-lives, increased stability to contents leakage, and dose-independent pharmacokinetics.
304 citations
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TL;DR: It is suggested that either a high methoxy pectin formulation or a low methoxypectin with a carefully controlled amount of calcium should maximise colonie specificity by providing optimal protection of a drug during its transit to the colon and a high susceptibility to enzymic attack.
228 citations
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TL;DR: Newly synthesized amphiphilic polyacrylamide and poly(vinyl pyrrolidone), single terminus-modified with long-chain fatty acyl groups, are able to incorporate into the liposomal membrane, and similar to poly(ethylene glycol) prolong liposomes circulation in vivo and decrease liposome accumulation in the liver.
227 citations
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TL;DR: A novel approach to formulate taxol in aqueous medium for i.v. delivery was described, and the cytotoxic activity of taxol was retained when formulated as a mixed-micellar solution.
Abstract: Taxol is a promising antitumor agent with poor water solubility. Intravenous administration of a current taxol formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation upon aqueous dilution. In this study a novel approach to formulate taxol in aqueous medium for i.v. delivery is described. The drug is solubilized in bile salt (BS)/phospholipid (PC) mixed micelles. The solubilization potential of the mixed micelles increased as the total lipid concentration and the molar ratio of PC/BS increased. Precipitation of the drug upon dilution was avoided by the spontaneous formation of drug-loaded liposomes from mixed micelles. The formulation can be stored in a freeze-dried form as mixed micelles to achieve optimum stability, and liposomes can be prepared by simple dilution just before administration. As judged by a panel of cultured cell lines, the cytotoxic activity of taxol was retained when formulated as a mixed-micellar solution. Further, for the same solubilization potential, the mixed-micellar vehicle appeared to be less toxic than the standard nonaqueous vehicle of taxol containing Cremophor EL.
194 citations
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TL;DR: The study proved that the follicular route play an important role in determining the kinetics of drug transfer from liposomes into the skin and indicates that an optimum particle size for optimal drug delivery exists.
188 citations
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TL;DR: In this paper, the phase behavior and stability characteristics of suspensions of colloidal particles containing water-soluble or surface-adsorbed polymers or block copolymers were investigated.
Abstract: After significant developments in liquid crystal and polymer research, scientists became interested in lyotropic systems containing polymers. These studies investigated, for instance, phase behavior and stability characteristics of suspensions of colloidal particles containing water-soluble or surface-adsorbed polymers or block copolymers. The most frequently studied were micelles, latex prticles, and lipid vesicles (liposomes). Liposomes aggregate and fuse in the presence of hydrophilic polymers but their properties were difficult to explain when block copolymers were adsorbed or surfactants with larger polymeric polar heads were inserted into the liposome membrane, because such systems are inherently ill defined. Liposomes containing diacyl surfactants with covalently linked, longer polymer chains display many new properties with very important consequences for both basic and applied research. They stimulate fundamental studies on phase behavior and polymer conformation, scaling laws, colloidal and surface properties, and cell function: applications deal predominantly with liposomes as drug delivery systems. While in basic research theory is currently more advanced than experiment, in medical applications theoretical understanding lags behind experimental achievements. It was discovered only relatively late that liposomes with an appropriate polymer coating are significantly more stable in a biological milieu, a necessary condition for their utility as drug carriers. In particular in medical applications, this practice has rejuvenated the field of anticancer therapy and targeted drug deliviery. All these advances were made possible by an effective and synergistic overlap of many different disciplines.
181 citations
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TL;DR: More clinical pharmacokinetics studies are urgently needed to permit the validation of appropriate pharmacokinetic models that can be used in the future to assist in the optimisation of clinical protocols, and improved conjugate design.
Abstract: Soluble polymer conjugates have only recently been introduced into clinical practice. They can be subdivided into 2 main categories: polymer-protein conjugates, so far the most widely studied; and polymer-drug conjugates, particularly those containing conventional antitumour agents, that are still at an early stage of development. Polymer conjugation can be used to alter the biodistribution, elimination and rate of metabolism of covalently bound drugs. In the case of protein adducts, polymer conjugation prolongs the protein plasma elimination half-life (5- to 500-fold increases in elimination half-life have been reported), reduces proteolytic degradation and has the added benefit of reducing immunogenicity. Cellular uptake of low molecular weight drugs convalently bound to polymeric carriers is restricted to the endocytic route. Thus, the organ and subcellular distribution of the drug can be modified. Cellular uptake has been used to facilitate drug targeting and decreased toxicity. In this review, the theoretical rationale for polymer conjugation is described, as is the limited clinical pharmacokinetic experience with polymer conjugates. As an alteration of the pharmacokinetic profile of a drug was one of the underlying arguments for creation of polymeric conjugates, more clinical pharmacokinetic studies are urgently needed to permit the validation of appropriate pharmacokinetic models that can be used in the future to assist in the optimisation of clinical protocols, and improved conjugate design.
169 citations
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TL;DR: For example, this article showed that the interaction between various types of bio(muco)adhesive polymers and epithelial cells has direct influence on the permeability of mucosal epithelia.
Abstract: For the efficient delivery of peptides, proteins, and other biopharmaceuticals by nonparenteral routes, in particular via the gastrointestinal, or GI, tract, novel concepts are needed to overcome significant enzymatic and diffusional barriers. In this context, bioadhesion technologies offer some new perspectives. The original idea of oral bioadhesive drug delivery systems was to prolong and/or to intensify the contact between controlled-release dosage forms and the stomach or gut mucosa. However, the results obtained during the past decade using existing pharmaceutical polymers for such purposes were rather disappointing. The encountered difficulties were mainly related to the physiological peculiarities of GI mucus. Nevertheless, research in this area has also shed new light on the potential of mucoadhesive polymers. First, one important class of mucoadhesive polymers, poly(acrylic acid), could be identified as a potent inhibitor of proteolytic enzymes. Second, there is increasing evidence that the interaction between various types of bio(muco)adhesive polymers and epithelial cells has direct influence on the permeability of mucosal epithelia. Rather than being just adhesives, mucoadhesive polymers may therefore be considered as a novel class of multifunctional macromolecules with a number of desirable properties for their use as biologically active drug delivery adjuvants. To overcome the problems related to GI mucus and to allow longer lasting fixation within the GI lumen, bioadhesion probably may be better achieved using specific bioadhesive molecules. Ideally, these bind to surface structures of the epithelial cells themselves rather than to mucus by receptor-ligand-like interactions. Such compounds possibly can be found in the future among plant lectins, novel synthetic polymers, and bacterial or viral adhesion/invasion factors. Apart from the plain fixation of drug carriers within the GI lumen, direct bioadhesive contact to the apical cell membrane possibly can be used to induce active transport processes by membrane-derived vesicles (endo- and transcytosis). The nonspecific interaction between epithelia and some mucoadhesive polymers induces a temporary loosening of the tight intercellular junctions, which is suitable for the rapid absorption of smaller peptide drugs along the paracellular pathway. In contrast, specific endo- and transcytosis may ultimately allow the selectively enhanced transport of very large bioactive molecules (polypeptides, polysaccharides, or polynucleotides) or drug carriers across tight clusters of polarized epi- or endothelial cells, whereas the formidable barrier function of such tissues against all other solutes remains intact.
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TL;DR: In this article, a doxorubicin formulation of polyethyleneglycol-coated liposomes (Doxil) in cancer patients indicate that the drug pharmacokinetic properties are significantly altered, with a prolonged distribution half-life of approximately 2 days.
Abstract: Initial clinical studies with doxorubicin entrapped in the bilayer of phosphatidylglycerol-rich liposomes were hindered by the avid reticuloendothelial system (RES) uptake and by drug leakage from circulating liposomes. In contrast, recent tests of a doxorubicin formulation of polyethyleneglycol-coated liposomes (Doxil) in cancer patients indicate that the drug pharmacokinetic properties are significantly altered, with a prolonged distribution half-life of approximately 2 days. Plasma fractionation studies show that nearly all the drug measured in plasma is in liposome-encapsulated form. The dose of Doxil has been escalated from 25 to 60 mg/m2. Stomatitis is the most significant toxicity, and skin toxicity, in the form of hand-foot syndrome, may complicate the repeated administration of Doxil. A number of objective antitumor responses in a variety of malignancies have been observed, indicating that Doxil is an active antitumor compound. Polyethyleneglycol-coated liposomes show a distinct advantage over previous liposome formulations directed at the RES and appear to be a promising drug delivery system for doxorubicin.
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TL;DR: Nanoparticles are colloidal polymeric particles (size <1000nm) to which drugs are bound by sorption, incorporation, or chemical binding and can be altered by coating with surfactants or with physiological components such as serum complement factors.
Abstract: Nanoparticles are colloidal polymeric particles (size < 1000 nm) to which drugs are bound by sorption, incorporation, or chemical binding. After intravenous injection they normally distribute into the organs of the reticuloendothelial system (liver, spleen, lungs, bone marrow). However, their body distribution can be altered by coating with surfactants or with physiological components such as serum complement factors. The influence of these coatings on the body distribution and possible mechanisms for the alteration of this distribution are discussed. Differently coated nanoparticles can be used for the targeting of bound drugs to tumors, to the brain, and to inflamed areas in the body.
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TL;DR: It is demonstrated that taxol incorporated into liposomes penetrates into the acyl chain domain of the bilayer and alters the physical properties of both artificial and biological membranes.
Abstract: Taxol (paclitaxel) is a diterpenoid anticancer agent undergoing intensive human clinical evaluation. The poor aqueous solubility of taxol necessitates administration in excipients causing a variety of adverse effects, including anaphylactoid hypersensitivity reactions. Recently, taxol has been formulated in better-tolerated drug carriers such as liposomes. We investigated the conformation of taxol and the interaction of taxol with dipalmitoylphosphatidylcholine (DPPC) liposomes using fluorescence, circular dichroism, differential scanning calorimetry, fluorescence polarization, and X-ray diffraction. The conformation of taxol in DPPC membranes was similar to that observed in nonpolar solvents such as chloroform. Taxol was found to partition into the bilayer, perturbing the hydrocarbon chain conformation. The taxol C13 side chain was found to be fluorescent, and it displays an environment-sensitive shift in emission spectrum; taxol fluorescence was used to confirm the insertion of the drug into the bilayer. Taxol induces a broadening of the DPPC phase transition, and the location of the drug in the bilayer depends on drug concentration. Incorporation of taxol affects other physical properties of the bilayer such as the lipid order parameter, and this fluidizing effect was also observed upon incorporation of taxol in biological membranes isolated from basolateral plasma membranes of rat liver. These studies demonstrate that taxol incorporated into liposomes penetrates into the acyl chain domain of the bilayer and alters the physical properties of both artificial and biological membranes.
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TL;DR: This review shows examples and discusses the mechanism of RES avoidance by these modifiers of liposomes, with special focus on the glucuronide as a modifier.
Abstract: Liposomes have been investigated for use as drug carriers, and many previous studies have demonstrated enhanced efficacy of encapsulated drugs and the reduction of the side effects of drugs so entrapped. In many cases liposomal drugs are administered via the bloodstream. The stability in the bloodstream, clearance, and biodistribution are dependent on the composition, size, and charge of the liposomes. Rigid, small-size (100-200 nm) liposomes tend to be retained in the blood without degradation. Since the conventional liposomes are trapped in the reticuloendothelial system (RES), RES targeting by means of liposomes is easily achieved. This tendency of liposomes, however, is the most serious limitation when their target is not the RES. Many attempts have been made to avoid the RES-trapping and to prolong the circulation time of liposomes with monosialoganglioside GM1, polyethyleneglycol, glucuronide derivatives, and so on. When the targets are tumor tissues, these RES-avoiding, long-circulating liposomes passively accumulate in such tissues due to extravasation through the leaky vasculature in the tumor tissues. Therefore, long-circulating liposomes are useful tools, especially for tumor imaging and therapy. In this review, we show examples and discuss the mechanism of RES avoidance by these modifiers of liposomes, with special focus on the glucuronide as a modifier.
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TL;DR: Results indicate that this polymeric system has a potential as a polypeptide drug carrier, especially for oral delivery, according to the ionic strength of the aqueous polymer/drug solution.
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TL;DR: This review highlights the work to date investigating the potential of microemulsions as drug cariers and also reports on preliminary studies performed on the use of vesicles formed from nonionic surfactants.
Abstract: Although surfactants have been widely used as pharmaceutical adjuvants for many years, it is only relatively recently that their phase structures have been seriously considered as drug delivery vehicles per se. This review highlights the work to date investigating the potential of microemulsions as drug carriers and also reports on preliminary studies performed on the use of vesicles formed from nonionic surfactants.
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TL;DR: It is concluded that these liposomes are bioadhesive sustained-release carriers of drugs, as desired, meriting further cellular and in vivo studies.
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TL;DR: The lipid emulsion particles described in this study have a potential use as targetable carriers for site-specific drug delivery and may be suitable for dispersing and stability properties of parenteral drug carriers.
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TL;DR: The toxicity of vincristine sulfate was reduced after niosome encapsulation and anticancer activity improved, which may be due to better delivery of vINCristine at the tumour site.
Abstract: Nonionic surfactant vesicles (niosomes) are promising drug carriers for anticancer drugs. Niosome encapsulated vincristine sulfate prepared by transmembrane pH gradient drug uptake process (remote loading method) was evaluated for toxicity and antitumour activity after administration to tumour bearing mice. The toxicity of vincristine sulfate was reduced after niosome encapsulation and anticancer activity improved, which may be due to better delivery of vincristine at the tumour site.
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TL;DR: The in vitro release ofMTX was investigated in two different media, namely simulated gastric and intestinal fluids and the rate of release of MTX decreased with increase in the particle size of the microspheres, while MTX release was faster in gastric fluid when compared to intestinal fluid.
Abstract: Biodegradable hydrophilic gelatin microspheres containing the anticancer drug methotrexate (MTX) of different mean particle sizes (1-5, 5-10, and 15-20 microns) were prepared by polymer dispersion technique and crosslinked with glutaraldehyde. The microspheres were uniform, smooth, solid and in the form of free-flowing powder. About 80 per cent of MTX was incorporated in gelatin microspheres of different sizes. The in vitro release of MTX was investigated in two different media, namely simulated gastric and intestinal fluids. The release profiles indicated that gelatin microspheres released MTX in a zero-order fashion for 4-6 days in simulated gastric fluid and for 5-8 days in simulated intestinal fluid. The rate of release of MTX decreased with increase in the particle size of the microspheres. MTX release was faster in gastric fluid when compared to intestinal fluid.
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TL;DR: Topotecan's half-life in human plasma (pH 7.6) can be enhanced dramatically by packaging the drug within the aqueous, pH 5-adjusted confines of lipid vesicles composed of diasteroylphosphatidylcholine.
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19 May 1994
TL;DR: In this article, gas-filled liposomes having encapsulated therein a drug are used for therapeutic drug delivery, and methods for employing such microspheres in drug delivery applications are described.
Abstract: Therapeutic drug delivery sytems comprising gas-filled microspheres comprising a therapeutic are described. Methods for employing such microspheres in therapeutic drug delivery applications are also provided. Drug delivery systems comprising gas-filled liposomes having encapsulated therein a drug are preferred. Methods of and apparatus for preparing such liposomes and methods for employing such liposomes in drug delivery applications are also disclosed.
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TL;DR: A novel concept in drug delivery, takes advantage of certain properties of the drug "containers" cyclodextrins and liposomes to combine them into a single system thus circumventing problems associated with both systems, to allow accommodation of insoluble drugs in the aqueous phase of vesicles.
Abstract: A novel concept in drug delivery discussed here, takes advantage of certain properties of the drug "containers" cyclodextrins and liposomes to combine them into a single system thus circumventing problems associated with both systems. The concept, entailing entrapment of water-soluble cyclodextrin-drug inclusion complexes in liposomes, would allow accommodation of insoluble drugs in the aqueous phase of vesicles. This would potentially increase the drug to lipid mass ratio to levels above those attained by conventional drug incorporation into the lipid phase, enlarge the range of insoluble drugs amenable to encapsulation to include, for instance, membrane destabilizing agents, allow targeting of complexes to specific sites and reduce toxicity. In the present work, soluble inclusion complexes of hydroxypropyl-beta-cyclodextrin with dehydroepiandrosterone, retinol and retinoic acid were prepared and entrapped into multilamellar liposomes by the dehydration-rehydration procedure. Complex-containing liposomes were then exposed to blood plasma. Results show that complex entrapment into liposomes depends on the lipid composition used. Nearly all of the cyclodextrin and considerable portions of the drugs were found to remain associated with the carrier in the presence of plasma.
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TL;DR: A new novel delivery system for ophthalmic drugs was developed using an antiglaucoma agent Betaxolol Hydrochloride as a model, which optimized the bioavailability and physical stability and ease of resuspendability of the product.
Abstract: A new novel delivery system for ophthalmic drugs was developed using an antiglaucoma agent Betaxolol Hydrochloride as a model. The new delivery system involved both the binding and release of drug from ion exchange resin particles. Betaxolol was studied in-vitro via a release model analysis. The ocular comfort of Betaxolol was greatly enhanced by reducing the availability of free drug molecules in the precorneal tear film. The amount of resin concentration was selected to obtain optimum binding of the drug. The zeta potential of suspended particles was adjusted to produce flocculated suspension. Drug resin particles were then incorporated into the structured vehicle, containing Carbomer 934P as a polymer, to enhance the physical stability and ease of resuspendability of the product. This delivery system also optimized the bioavailability of Betaxolol, reducing the total drug concentration in half to 0.25% Betaxolol in 0.25% BETOPTIC S Ophthalmic Suspension as compared with 0.5% Betaxolol in BETOP...
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TL;DR: The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye, however, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed.
Abstract: Microparticulates are drug-containing small polymeric particles (erodible, non-erodible or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration of particle suspension in the eye, the particles reside at the delivery site (cul-de-sac, sub conjunctiva or vitreous cavity) and the drug is released from the particles through diffusion, chemical reaction, polymer degradation, or ion-exchange mechanism. Several distinct approaches have been used to formulate drugs in microparticulate dosage form for intraocular and topical application. These include erodible microparticulates, swelling mucoadhesive particulates, pH responsive microparticulates, nanoparticles/latex systems, ion-exchange resins, etc. Injection of bioerodible microparticulates in the vitreous for treating infections of posterior segment and the release of acceptable levels of drug up to two weeks has been demonstrated. Both corneal and non-corneal routes of drug entry in the eye from topical instillations are postulated. The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye. However, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed. Fruitful resolution of technological challenges will result in a superior dosage form for both topical and intraocular ophthalmic application. Recent developments and future challenges of microparticulate ophthalmic drug delivery system are discussed in this review.
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TL;DR: Daunorubicin--nanoerythrosome conjugates had a higher antineoplastic activity than the free drug on CDF1 leukemia tumors and this results indicate that nonoerystrosomes could be potentially used as drug carriers.
Abstract: Liposomes and monoclonal antibodies are used as drug carriers for the optimal delivery of pharmacologic agents. However, they present disadvantages that led us to develop a new model of drug carriers: the nanoerythrosomes. Nanoerythrosomes are vesicles prepared by the extrusion of red blood cell ghosts, the average diameter of these vesicles is 0.1 micron. Daunorubicin was covalently linked to nanoerythrosomes and the cytotoxicity of daunorubicin conjugated to nanoerythrosomes was assessed on P388D1 cell line. The results indicated that the cytotoxicity of conjugated daunorubicin was as high as the free daunorubicin. Daunorubicin--nanoerythrosome conjugates had a higher antineoplastic activity than the free drug on CDF1 leukemia tumors. These results indicate that nonoerythrosomes could be potentially used as drug carriers.
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TL;DR: CI-976 is a poorly water soluble lipid regulator with good solubility in triglycerides and a high octanol:water partition coefficient which suggest significant lymphatic transport following gastroin-testinal absorption, which may not be representative of total systemic bioavailability of drug.
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TL;DR: In this article, a concept and strategy for using a block copolymer micelle as a nanoscopic virus-mimicking carrier of anticancer drugs to treat solid tumors is presented.
Abstract: Block copolymers in a selective solvent (a good solvent for one block but a nonsolvent for the other) form micellar structures through the association of the insoluble segments. Micelles formed through the association of amphiphilic block copolymers have several advantageous features as drug carrier systems due to their considerable thermodynamic stability as well as to the formation of a hydrophobic core separated from the outer aqueous milieu by the palisade of hydrophilic segments. The core acts as the microcontainer of hydrophobic drugs. This paper presents a concept and strategy for using a block copolymer micelle as a nanoscopic virus-mimicking carrier of anticancer drugs to treat solid tumors.
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TL;DR: Both in vitro and in vivo HPMA copolymer-containing side-chains terminated in fucosylamine showed a higher adherence to guinea pig colon when compared to HPMACopolymer without fucOSYlamine moieties, which increased their adherence probably by combination of nonpecific hydrophobic binding with specific recognition.