Showing papers on "Drug carrier published in 1996"

Brain drug delivery of small molecules using immunoliposomes

Abstract: Immunoliposomes (antibody-directed liposomes) were used in the present study for delivery of the antineoplastic agent daunomycin to the rat brain A coupling procedure was introduced, which allows conjugation of a thiolated antibody to maleimide-grafted 85-nm liposomes sterically stabilized with PEG Antibody was thereby coupled to the terminal end of a PEG-conjugated linker lipid No brain uptake of PEG-conjugated liposomes carrying [3H]daunomycin was observed However, brain targeting of immunoliposomes carrying [3H]daunomycin was mediated by the OX26 monoclonal antibody to the rat transferrin receptor, which is selectively enriched at the brain microvascular endothelium that comprises the blood-brain barrier in vivo Coupling of 30 OX26 antibodies per liposome resulted in optimal brain delivery Saturation of delivery was observed at higher antibody densities Determination of brain levels of immunoliposomes over 24 h revealed that immunoliposomes accumulate in brain tissue Brain targeting of immunoliposomes was not observed in immunoliposomes conjugated with a mouse IgG2a isotype control In addition, coinjection of free OX26 saturated plasma clearance of immunoliposomes Since a single liposome may carry > or = 10,000 drug molecules, the use of PEG-conjugated immunoliposomes increases the drug carrying capacity of the monoclonal antibody by up to 4 logarithmic orders in magnitude In summary, specific OX26-mediated targeting of daunomycin to the rat brain was achieved by the use of an immunoliposome-based drug delivery system

Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery.

Abstract: Agents with MW > 50%) and reproducibly various agents (200 < or = MW < or = 10(6); lipophilic/hydrophilic) into the body. Transfersomes were successfully used in animals and humans, also for the transcutaneous peptide and protein delivery. The theoretical rational for this is described together with the corresponding experimental models and practical examples.

Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes.

Abstract: Purpose. The mucoadhesiveness of polymer-coated liposomes was evaluated to develop a novel drug carrier system for oral administration of poorly absorbed drugs such as peptide drugs. Methods. Multilamellar liposomes consisting of dipalmitoylphosphatidylcholine (DPPC) and dicetyl phosphate (DCP) (DPPC:DCP = 8:2 in molar ratio) were coated with chitosan (CS), polyvinyl alcohol having a long alkyl chain (PVA-R) and poly (acrylic acid) bearing a cholesteryl group. The adhesiveness of the resultant polymer-coated liposomes to the rat intestine was measured in vitro by a particle counting method with a Coulter counter. The CS-coated liposomes containing insulin were administered to normal rats and the blood glucose level was monitored. Results. The existence of polymer layers on the surface of liposomes was confirmed by measuring the zeta potential of liposomes. The CS-coated liposomes showed the highest mucoadhesiveness and the degree of adhesion was dependent on the amount of CS on the surface of the liposomes. The blood glucose level of rats was found to be significantly decreased after administration of the CS-coated liposomes containing insulin. The lowered glucose level was maintained for more than 12h after administration of the liposomal insulin, which suggested mucoadhesion of the CS-coated liposomes in the intestinal tract of the rats.

Doxorubicin Encapsulated in Liposomes Containing Surface-Bound Polyethylene Glycol: Pharmacokinetics, Tumor Localization, and Safety in Patients with AIDS-Related Kaposi's Sarcoma

Abstract: A study of the plasma pharmacokinetics, tumor localization, and safety of a single dose of doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol (PEG-liposomal doxorubicin) was conducted in patients with Kaposi's sarcoma (KS) as a manifestation of acquired immune deficiency syndrome (AIDS). Eighteen patients with AIDS-KS diagnosed by examination of biopsy specimens were randomly assigned to receive either standard doxorubicin or PEG-liposomal doxorubicin. Consecutive participants were entered at three dose levels (10, 20, and 40 mg/m2) in ascending fashion. Clearance of PEG-liposomal doxorubicin was 0.034 L/h/m2 to 0.108 L/h/m2, volume of distribution (Vd) was 2.2 L/m2 to 4.4 L/m2, and half-lives (t1/2) of the initial decline in the plasma concentration-time curve and of the terminal decline were 3.77 hours and 41.3 hours, respectively. Seventy-two hours after administration, doxorubicin levels observed in lesions of patients receiving PEG-liposomal doxorubicin were 5.2 to 11.4 times greater than those found in patients given comparable doses of standard doxorubicin. PEG-liposomal doxorubicin and standard doxorubicin were roughly equipotent in producing toxicity. Encapsulation in liposomes containing surface-bound PEG significantly limits the distribution and elimination of doxorubicin, results in greater accumulation of the drug in KS lesions 72 hours after dosing than does standard doxorubicin, and may improve drug efficacy and therapeutic index in the treatment of AIDS-KS.

Thermosensitive liposomes: extravasation and release of contents in tumor microvascular networks.

Abstract: Purpose: The purpose of this study was to determine whether hyperthermic exposure would accelerate drug release from thermosensitive sterically stabilized liposomes and enhance their extravasation in tumor tissues. Materials and Methods: In vivo fluorescence video microscopy was used to measure the extravasation of liposomes, as well as release of their contents, in a rat skin flap window chamber containing a vascularized mammary adenocarcinoma under defined thermal conditions (34°, 42°, and 45°C). Images of tissue areas containing multiple blood vessels were recorded via a SIT camera immediately before, and for upto 2 h after i.v. injection of two liposome populations with identical lipid composition: one liposome preparation was surface labeled with Rhodamine-PE (Rh-PE) and the other contained either Doxorubicin (Dox) or calcein at self-quenching concentrations. The light intensity of the entire tissue area was measured at 34°C (the physiological temperature of the skin) for 1 h, and at 42° or 45°C for a second hour. These measurements were then used to calculate the fluorescent light intensity arising from each tracer (liposome surface label and the released contents) inside the vessel and in the interstitial region. Results: The calculated intensity of Rh-PE for the thermosensitive liposomes in the interstitial space (which represents the amout of extravasated liposomes) was low during the first hour, while temperature was maintained at 34°C and increased to 47 times its level before heating, when the tumor was heated at 42° or 45° C for 1 h. The calculated intensity of the liposome contents (Dox) in the interstitial space was negligible at 34°C, and increased by 38- and 76-fold, when the tumor was heated at 42° and 45° C for 1 h, respectively. Similar values were obtained when calcein was encapsulated in liposomes instead of Dox. A similar increase in liposome extravasation was seen with nonthermosensitive liposomes, but negligible release of Dox occurred when the window chamber was heated to 45°C for 1 h. Extravasation of liposomes continued after heating was stopped, but content release stopped after removal of heat. Release of Dox from extravasated liposomes was also seen if heating was applied 24 h after liposome administration, but no further enhancement of liposome extravasation occurred in this case. Conclusions: Our data suggest that hyperthermia can be used to selectively enhance both the delivery and the rate of release of drugs from thermosensitive liposomes to targeted tissues.

Drug delivery systems: water soluble taxol 2'-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness.

Abstract: Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(circulation) > t1/2(hydrolysis). When PEG derivatives of molecular weight approximately 40 kDa were employed with paclitaxel, ca. 4% by weight of paclitaxel was carried by the water soluble prodrug form, and equivalent in vivo toxicity and increased life expectancy in the P388-treated mouse was observed. An effective method for prescreening prodrugs was found to be the acute murine lethality, which reflects the equivalency of the solubilized transport form and the native drug.

Carrier effects on biological activity of amphotericin B.

Abstract: Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo.

Abstract: Purpose. To evaluate the effect of the crosslinked poly(acrylate) carbomer 934P (C934P) and its freeze-dried neutralized sodium salt (FNaC934P) as well as chitosan hydrochloride on the intestinal absorption of the peptide drug buserelin.

Nanoparticles and microparticles for drug and vaccine delivery

Abstract: Nanoparticles are polymeric particles in the nanometer size range whereas microparticles are particles in the micrometre size range. Both types of particle are used as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or solid dispersions or onto which these materials may be absorbed or chemically bound. These particles have been shown to enhance the delivery of certain drugs across a number of natural and artificial membranes. In addition, the particles were shown to accumulate in areas of the intestine that appear to be the Peyer's patches. Possibly because of the combination of both effects these particles were able to significantly improve the bioavailability of some drugs after peroral administration in comparison with solutions. Recently nanoparticles coated with polysorbate 80 enabled the passage of small peptides and other drugs across the blood-brain barrier and the exhibition of a pharmacological effect after intravenous injection. Without the use of this type of nanoparticles the drugs did not cross this barrier and yielded no effect.

Microparticulate systems for the delivery of proteins and vaccines

Abstract: Stability of Proteins and Their Delivery from Biodegradable Polymer Microspheres, Steven S. Schwenderman Injectable Biodegradable Microspheres for Vaccine Delivery, Thomas Kissel and Regina Koneberg Preparation of Microparticulates Using Supercritical Fluids, Barbara L. Knutson, Pablo G. Debenedetti, and Jean W. Tom Polyphoshazene Hydrogel Microspheres for Protein Delivery, Alexander K. Andrianov and Lendon G. Payne Lipospheres for Vaccine Delivery, Shimon Ameselem, Carl R. Alving, and Abraham J. Domb The Characterization of Polyanhydride Microspheres, Anette Brunner and Achim Gopferich Nanoparticulate Drug Carrier Technology, Maria J. Alonso Biodistribution of Surface-Modified Liposomes and Particles, Vladimir P. Torchilin and Vladimir S. Trubetskoy Poly(Etylene Glycol)-Coated Biodegradable Nanospheres for Intravenous Drug Administration, Ruxandra Gref, Yoshiharu Minamitake, and Maria Teresa Peracchia, and Robert Langer Polymerized and Microencapsulated Liposomes for Oral Delivery and Vaccination, Jun,ichi Okada Pharmacokinetics of Microparticulate Systems, Pravin R. Chaturvedi Adjuvant-Active Polymeric Microparticulate Vaccine-Delivery Systems, Douglas Kline, Justin Hanes, and Robert Langer Oral Vaccination by Microspheres, Hitesh R. Bnagat, Paresh S. Dalal, and Ranjani Nellore Biodegradable Gelatin Microspheres for Drug Delivery to Macrophages, Yasuhiko Tabata and Yoshito Ikada Bioadhesive Liposomes for Topical Treatment of Wounds, Rimona Margalit Ultrasound-Triggered Delivery of Peptides and Proteins from Microspehres, Joseph Kost Polyacrylate Microcapsules for Cell Delivery, Julia E. Babensee and Michael V. Sefton

Macromolecular carrier systems for targeted drug delivery: pharmacokinetic considerations on biodistribution.

Abstract: This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokintic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.

Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity.

Abstract: The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.

Phagocytic Uptake and Cytotoxicity of Solid Lipid Nanoparticles (SLN) Sterically Stabilized with Poloxamine 908 and Poloxamer 407

Abstract: Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure homogenisation of melted lipids (glycerolbehenate, cetylpalmitate). Their surface was modified by using hydrophilic poloxamine 908 and poloxamer 407 block-copolymers in order to reduce the phagocytic uptake by the reticuloendothelial system (RES) after i. v. injection. The phagocytosis reducing effect of the polymers was investigated in vitro in cultures of human granulocytes, uptake was quantified by chemiluminescence. Modification of the SLN with poloxamine 908 and poloxamer 407 reduced the phagocytic uptake to appr. 8–15% compared to the phagocytosis of hydrophobic polystyrene particles. The modified SLN proved more efficient in avoiding phagocytic uptake than polystyrene particles surface-modified with these blockcopolymers (48% and 38%, respectively). Viability determinations revealed the SLN to be 10 fold less cytotoxic than polylactide nanoparticles and 100 fold less than butylc...

Targeting of stealth liposomes to erbB-2 (Her/2) receptor : in vitro and in vivo studies

Abstract: Long-circulating (stealth) liposomes coated with polyethylene glycol (PEG), which show reduced uptake by the reticuloendothelial system (RES) and enhanced accumulation in tumours, were used for conjugation to monoclonal antibodies (MAbs) as a drug-targeting device. A MAb (N-12A5) directed against erbB-2 oncoprotein, a functional surface antigen, was used. Amplification and overexpression of the erbB-2 gene product, being unique to malignancy, confer onto this antibody-mediated therapy high tumour specificity. In vitro binding of [3H]cholesteryl ether ([3H]Chol ether) labelled anti-erbB-2 conjugated liposomes to N-87 cells (erbB-2-positive human gastric carcinoma) was compared with the binding of non-targeted liposomes and indicated a 16-fold increase in binding for the targeted liposomes. No difference in binding to OV1063 cells (erbB-2-negative human ovary carcinoma) was observed. These results indicate highly selective binding of antibody-targeted liposomes to erbB-2-overexpressing cells. Despite increased cell binding, doxorubicin (DOX) loaded in anti-erbB-2-conjugated liposomes did not cause increased in vitro cytotoxicity against N-87 cells, suggesting lack of liposome internalisation. In vivo, the critical factor needed to decrease the non-specific RES uptake and prolong the circulation time of antibody-conjugated liposomes is a low protein to phospholipid ratio ( < 60 micrograms mumol-1). Using these optimised liposome preparations loaded with DOX and by monitoring the drug levels and the [3H]Chol ether label, biodistribution studies in nude mice bearing subcutaneous implants of N-87 tumours were carried out. No significant differences in liver and spleen uptake between antibody-conjugated and plain liposomes were observed. Nevertheless, there was no enhancement of tumour liposome levels over plain liposomes. Both liposome preparations considerably enhanced DOX concentration in the tumour compared with free drug administration. Therapeutic experiments with N-87 tumour-bearing nude mice indicated that anti-tumour activity of targeted and non-targeted liposomes was similar, although both preparations had an increased therapeutic efficacy compared with the free drug. These studies suggest that efficacy is dependent on drug delivery to the tumour and that the rate-limiting factor of liposome accumulation in tumours is the liposome extravasation process, irrespective of liposome affinity or targeting to tumour cells.

Niosomes As Drug Carriers

Abstract: The concept of carriers to deliver drugs to target organs and modify drug disposition has been widely discussed1. The majority of such reports have concerned the use of phospholipid vesicles or liposomes2, which exhibit certain disadvantages, such as chemical instability, high cost and variable purity of lipids used, which militates against their adoption as drug delivery vehicle. Alternatives to phospholipids are thus of interest from the technical viewpoint and could also allow a wider study of the influence of chemical composition on the biological fate of vesicles3.

Efficiency of nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-infected human monocytes/macrophages in vitro.

Abstract: Polyhexylcyanoacrylate nanoparticles loaded with either the human immunodeficiency virus (HIV) protease inhibitor saquinavir (Ro 31-8959) or the nucleoside analog zalcitabine (2',3'-dideoxycytidine) were prepared by emulsion polymerization and tested for antiviral activity in primary human monocytes/macrophages in vitro. Both nanoparticulate formulations led to a dose-dependent reduction of HIV type 1 antigen production. While nanoparticle-bound zalcitabine showed no superiority to an aqueous solution of the drug, a significantly higher efficacy was observed with saquinavir-loaded nanoparticles. In acutely infected cells, an aqueous solution of saquinavir showed little antiviral activity at concentrations below 10 nM, whereas the nanoparticulate formulation exhibited a good antiviral effect at a concentration of 1 nM and a still-significant antigen reduction at 0.1 nM (50% inhibitory concentrations = 4.23 nM for the free drug and 0.39 nM for the nanoparticle-bound drug). At a concentration of 100 nM, saquinavir was completely inactive in chronically HIV-infected macrophages, but when bound to nanoparticles it caused a 35% decrease in antigen production. Using nanoparticles as a drug carrier system could improve the delivery of antiviral agents to the mononuclear phagocyte system in vivo, overcoming pharmacokinetic problems and enhancing the activities of drugs for the treatment of HIV infection and AIDS.

Atomic Force Microscopy Studies of Solid Lipid Nanoparticles

Abstract: Purpose. Solid Lipid Nanoparticles (SLN) are an alternative carrier system for the controlled delivery of drugs. In most cases prednisolone loaded SLN show a biphasic release behaviour. The initial phase is characterised by a fast drug release, which is followed by a sustained drug release over several weeks. Methods. The particles are produced by high pressure homogenisation of a lipid (e.g. compritol, cholesterol) dispersed in an aqueous surfactant solution. In this study atomic force microscopy was used to image the original unaltered shape and surface properties of the particles. The crystallinity of the nanoparticles was investigated by differential scanning calorimetry. Results. The AFM investigations revealed the disc like shape of the particles. From differential scanning calorimetry data it can be concluded that the particle core is in the crystalline state. Additionally it was proven that the particles are surrounded by a soft layer. Conclusions. Thus it is conceivable that the fast initial drug release during in vitro dissolution tests takes place by drug release of the outer non-crystalline layers of the particles. The following sustained drug release can be assigned to the predisolone release of the inner crystalline particle layers.