Showing papers on "Drug carrier published in 1989"

Influence of Vesicle Size, Lipid Composition, and Drug-to-Lipid Ratio on the Biological Activity of Liposomal Doxorubicin in Mice

Abstract: The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD50 of free drug by approximately twofold. Removing cholesterol or decreasing the drug-to-lipid ratio in EPC/cholesterol preparations led to significant decreases in the LD50 of liposomal doxorubicin whereas, the LD50 increased 4- to 6-fold when distearoylphosphatidylcholine was substituted for EPC. The results suggest that the stability of liposomally entrapped doxorubicin in the circulation is an important factor in the toxicity of this drug in liposomal form. In contrast, the antitumor activity of liposomal doxorubicin is not influenced dramatically by alterations in lipid composition. Liposomal doxorubicin preparations of EPC, EPC/cholesterol (55:45; mol:mol), EPC/egg phosphatidylglycerol (EPG)/cholesterol (27.5:27.5:45; mol:mol), and distearoylphosphatidylcholine/cholesterol (55:45; mol:mol) all demonstrated similar efficacy to that of free drug when given at doses of 20 mg/kg and below. Higher dose levels of the less toxic formulations could be administered, leading to enhanced increases in life span (ILS) values. Variations in vesicle size, however, strongly influenced the antitumor activity of liposomal doxorubicin. At a dose of 20 mg/kg, large EPC/cholesterol systems are significantly less effective than free drug (with ILS values of 65% and 145%, respectively). In contrast, small systems sized through filters with a 100-nm pore size are more effective than free drug, resulting in an ILS of 375% and a 30% long term (greater than 60 days) survival rate when administered at a dose of 20 mg/kg. Similar size-dependent effects are observed for distearoylphosphatidylcholine/cholesterol systems.

Pharmacokinetics and Tissue Distribution of Doxorubicin Encapsulated in Stable Liposomes With Long Circulation Times

Abstract: We have previously reported on liposome formulations with reduced uptake by the reticuloendothelial system, prolonged circulation time, and enhanced accumulation in transplanted tumors. One of these formulations, consisting of hydrogenated phosphatidylinositol (HPI), hydrogenated phosphatidylcholine (HPC), and cholesterol (Chol) (HPI-HPC-Chol), and a control formulation, consisting of phosphatidylglycerol (PG), phosphatidylcholine (PC), and Chol (PG-PC-Chol), were loaded with doxorubicin (DXR) and injected intravenously into BALB/c mice for pharmacokinetic studies. Although both formulations were similar in vesicle size, fraction of negatively charged lipid, and drug-to-lipid ratio, there were striking pharmacokinetic differences. DXR was cleared much faster in PG-containing liposomes than in HPI-containing liposomes. Liposome-associated drug was detectable in plasma up to 5 hours after injection in the case of PG-PC-Chol and as late as 72 hours after injection in the case of HPI-HPC-Chol. In agreement with the plasma clearance curves, peak drug concentrations in the liver were observed at 1/2, 5, and 24 hours after injection for free DXR, DXR in PG-PC-Chol, and DXR in HPI-HPC-Chol, respectively. Both types of liposomes reduced considerably the amount of drug accumulating in the heart compared with that accumulating after injection of free DXR.

Use of liposomes as injectable-drug delivery systems.

Abstract: The formation of liposomes and their application as delivery systems for injectable drugs are described. Liposomes are microscopic vesicles composed of one or more lipid membranes surrounding discrete aqueous compartments. These vesicles can encapsulate water-soluble drugs in their aqueous spaces and lipid-soluble drugs within the membrane itself. Liposomes release their contents by interacting with cells in one of four ways: adsorption, endocytosis, lipid exchange, or fusion. Liposome-entrapped drugs are distributed within the body much differently than free drugs; when administered intravenously to healthy animals and humans, most of the injected vesicles accumulate in the liver, spleen, lungs, bone marrow, and lymph nodes. Liposomes also accumulate preferentially at the sites of inflammation and infection and in some solid tumors; however, the reason for this accumulation is not clear. Four major factors influence liposomes' in vivo behavior and biodistribution: (1) liposomes tend to leak if cholesterol is not included in the vesicle membrane, (2) small liposomes are cleared more slowly than large liposomes, (3) the half-life of a liposome increases as the lipid dose increases, and (4) charged liposomal systems are cleared more rapidly than uncharged systems. The most advanced application of liposome-based therapy is in the treatment of systemic fungal infections, especially with amphotericin B. Liposomes are also under investigation for treatment of neoplastic disorders. Liposomes' uses in cancer therapy include encapsulation of known antineoplastic agents such as doxorubicin and methotrexate, delivery of immune modulators such as N-acetylmuramyl-L-alanine-D-isoglutamine, and encapsulation of new chemical entities that are synthesized with lipophilic segments tailored for insertion into lipid bilayers. Liposomal formulations of injectable antimicrobial agents and antineoplastic agents already are undergoing clinical testing, and most probably will receive approval for marketing in the early 1990s. Liposomal encapsulation of drugs represents a new drug delivery system that appears to offer important therapeutic advantages over existing methods of drug delivery.

Drug delivery systems. 1. site-specific drug delivery using liposomes as carriers.

Abstract: Drug delivery systems, offering controlled delivery of biologically active agents, are rapidly gaining importance in pharmaceutical research and development. To achieve controlled drug delivery, i.e., the administration of drugs so that optimal amount reaches the target site to cure or control the disease state, increasingly sophisticated systems containing different carriers have been developed. Macromolecules represent one of the carriers involved, and they have taken on a significantly prominent role in various modes of administration of therapeutic agents. Among macromolecules, for example, synthetic copolymers, polysaccharides, liposomes, polyanions and antibodies, as drug carriers, liposomes have proved most effective for diseases affecting the reticuloendothelial system and blood cells in particular. Liposomes, which are vesicles consisting of one or more concentrically ordered assemblies of phospholipids bilayers, range in size from a nanometer to several micrometers. Phospholipids such as egg phosphatidylcholine, phosphatidylserine, synthetic dipalmitoyl-DL-alpha-phosphatidylcholine or phosphatidylinositol, have been used in conjunction with cholesterol and positively or negatively charged amphiphiles such as stearylamine or phosphatidic acid. Alteration of surface charge has been shown to enhance drug incorporation and also influence drug release. Because of the multifold characteristics as drug carriers, liposomes have been investigated extensively as carriers of anticancer agents for the past several years. Liposomal entrapments include a variety of pharmacologically active compounds such as antimalarial, antiviral, anti-inflammatory and anti-fungal agents as well as antibiotics, prostaglandins, steroids and bronchodilators to name a few. The liposomal entrapment has been shown to have considerable effect on the pharmacokinetics and tissue distribution of administered drugs. Despite the potential value of liposomes as unique carriers, the major obstacles are the first order targeting of a systemically given liposomes, physical stability and manufacture of the liposomal products and these problems still remain to be overcome. Drug delivery systems evolving in the 1980s have become increasingly dependent on fundamental cell-biology and receptor-mediated endocytotic mechanisms. Drug delivery systems during the 1990s may take advantage of the specificity of receptor-mediated uptake mechanisms as well as polymer chemistry and cell-biology in order to introduce more precise and efficient target-specific delivery systems that are based especially on the liposome technology.

Novel drug delivery and its therapeutic application

Abstract: The need for improved drug delivery in clinical practice improved drug delivery: a perspective from industry absorption of difficult drug molecules: carrier-mediated transport of peptides and peptide analogues absorption enhancers - mechanisms and application assessment of gastrointestinal transit and drug absorption pharmacokinetic evaluation of novel drug delivery systems - assessment of rate noncompliance - the ultimate absorption barrier intranasal administration of peptide hormones - the current status with insulin, glucagon and calcitonin prospects for drug therapy via the respiratory tract the prodrug approach for improved rectal delivery clinical use and future of parenteral microsphere delivery systems considerations in the psysiological delivery of therapeutic proteins colloidal particles for drug delivery sustained bronchodilator therapy utilizing inhaled liposomal formulations of Beta-2 adrenergic agonists self-regulating insulin delivery s

Poly(amide-and imide-co-anhydride) for biological application

Abstract: Biocompatible, biodegradable poly(amide- and imide-co-anhydride)s are described which are useful for biological applications such as biodegradable controlled release devices for drug delivery, site-specific drug carriers, matrices for cell attachment, and for bioabsorbable sutures.

Drug carrier systems

Abstract: Targeting of Drugs: Implications in Medicine (G. Gregoriadis). The Use of Antibodies and Polymers as Carriers of Cytotoxic Drugs in the Treatment of Cancer (R. Arnon, et al.). The Application of Drug-Polymer Conjugates in Chemotherapy (C. Hoes & J. Feijen). Biodegradable Polymers for Controlled Release of Peptides and Proteins (F. Hutchinson & B. Furr). Microspheres as Drug Carriers (S. Davis & L. Illum). Pharmacological Uses of Resealed and Modified Red Cell Carriers (G. Ihler). Liposomes as a Drug Delivery System in Cancer Chemotherapy (A. Gabizon). The Use of Liposomes as Drug Carriers in the Immunotherapy of Cancer (I. Fidler). Liposomes as Drug Carriers in the Therapy of Infectious Diseases (R. Juliano). Targeting of Liposomes to Liver Cells (G. Scherphof, et al.). Implantable Infusion Pumps for Drug Delivery in Man: Theoretical and Practical Considerations (P. Blackshear & T. Rohde). Index.

Polyhydroxybutyrate as a drug carrier.

Abstract: Polyhydroxybutyrate (PHB) can be used as an alternative polymer to polylactide-glycolides for drug carrier production. It is a linear homopolymer biosynthesized by various strains of bacteria by condensation of D(-)-B-hydroxybutyric acid and used as an energy and carbon source. PHB can be obtained by extraction from bacteria or by chemical synthesis. To be suitable as drug carrier the polymer has to be biocompatible, biodegradable in certain applications, and nontoxic. PHB seems to be biocompatible and biodegrades readily to carbon dioxide in bacteria; however, in humans, the reports are few and contradictory. The polymer is nontoxic and its monomer seems to be tolerated well in relatively high concentrations. Possible applications include implants and i.m.-administered particulates for controlled release and i.v.-injected colloidal carriers for drug targeting.

Role of ligand in antibody-directed endocytosis of liposomes by human T-leukemia cells.

Abstract: The rate of uptake and intracellular processing of ligand-directed drug carriers may depend heavily on the endocytic pathway of the target antigen. We examined the role of the target antigen and type of antibody-liposome linkage in determining endocytosis of liposomes by three human T-cell leukemias, Jurkat, CEM, and Molt-4. Liposome-cell binding and internalization over time were studied using two independent assays for intracellular delivery of liposome contents: a new fluorescence assay using a pH-sensitive fluorescent dye; and a growth inhibition assay for delivery of cytotoxic drug, methotrexate-gamma-aspartate. Liposomes targeted against the transferrin receptor showed greater surface binding, internalization, and growth inhibition than liposomes targeted against the T-cell surface antigens, CD2, CD3, or CD5. Furthermore, liposomes made by conjugating the targeting antibody directly to the liposome surface were more efficiently internalized and retained than were liposomes linked to antibody-coated cells via Protein A. Selection of the type of antibody-liposome conjugate as well as the appropriate surface receptor to facilitate endocytosis is essential in antibody-directed drug treatment of cancer.

Liposome preparations: A step forward in topical drug therapy for skin disease?: A review

Abstract: The production of liposomes, which was described in 1961, soon was claimed to be a useful technology for drug encapsulation. The first preparation (containing a topical antifungal agent), however, was registered only recently. Additional preparations, including some for topical therapy of skin disease, are under clinical investigation. Moreover, a variety of cosmetic products that contain liposomes is available today. In this article we review the literature on liposomes as it pertains to dermatology, including the basic principles of liposome structures and preparations, pharmacoldnetics of liposomes and liposome-encapsulated drugs, and the influence on drug activity. Moreover, future applications of liposome preparations are discussed.

Delivery of anticancer drugs.

Abstract: Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since anticancer drugs are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge. Scientists are working to increase the availability of drug for tumor uptake by 1) delaying the release preparations for long-lasting actions; 2) using liposome-entrapped drugs for prolonged effect or reduced toxicity; 3) administrating inert, non-toxic prodrugs for specific activation at the tumor site; 4) delivering the antibody-mediated drugs; or 5) conjugating site-specific carriers to direct the drug to the tumor target. The latter depends heavily on pharmacokinetic investigations. Some success has been achieved in enhancing the efficacy and reducing the toxicity of drugs. Pharmacokinetic and pharmacodynamic considerations are two areas which have been focused toward the quantitative pharmacological studies of anticancer drugs in this manuscript. This review covers biodistribution and elimination, furnishing information on body clearance and unveiling sites of major metabolism; administration of anticancer drugs via various routes for optimal utilization; intra-arterial infusion for localized tumors, intrathecal, intraperitoneal and intrapleural injection for regional cavity administration. Conventional delivery routes, doses, pharmacokinetics data and elimination routes of therapeutic anticancer drugs are tabled. General approaches for delivery of anticancer drugs in achieving therapeutic improvements are outlined and correlated. Mechanism of drug resistance, and specific changes affecting the delivery of available chemotherapeutic agents, as well as the drugs to restore the sensitivities to agents of resistant tumor cells, are discussed. This monograph covers the developments and progress in the delivery of anticancer drugs in two approaches: the theoretical approach, including pharmacokinetic and pharmacodynamic considerations, therapeutic implications and mechanism of drug resistance, and the practical approach, including the physical, chemical, biochemical and physiological considerations. Among these, the physical approach for the delivery of anticancer agents to target sites (via microparticulate drug carriers: nanoparticles, liposomes, microspheres and activated carbon as well as the magnetic microcapsules) has shown recognizable improvements in prolonging anticancer effects and reducing toxicities. Implantable pumps and reservoirs for regional chemotherapy provide external control of delivery rate. The implanted systems, in general, yield better results than the traditional treatments in the treatment of liver and brain cancer. Chemical approaches for the improvement of drug delivery use prodrugs, biodegradable polymers and macromolecular matrix techniques.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of multidrug resistance in Chinese hamster cells by liposome-encapsulated doxorubicin.

Abstract: A Chinese hamster cell line (LZ), selected for multidrug resistance (MDR), exhibits a 3,000-fold resistance to doxorubicin, compared to parental V-79 cells. These drug resistant cells have amplified MDR genes, overexpress P-glycoprotein, and in the presence of doxorubicin show reduced intracellular drug accumulation. Using liposome-encapsulated doxorubicin (Rahman et al. Cancer Res. 45:796-803; 1985), we observed partial reversal of the resistance of LZ cells to this drug and a higher intracellular drug accumulation, compared to free drug. Parental V-79 cells, however, did not exhibit differences in survival or in drug accumulation when treated with encapsulated or free doxorubicin. Comparison of the effect of liposome-encapsulated doxorubicin with that of verapamil in reversing drug resistance showed that the liposomal preparation was as effective as verapamil used at its maximum clinically relevant concentration (1.5 microM). These results suggest that the use of liposomes as carriers of anticancer drugs may offer a strategy for overcoming MDR in tumor cells.

Erythrocyte membrane-bound daunorubicin as a delivery system in anticancer treatment.

Abstract: Drug encapsulation in erythrocytes has been proposed to extend its biological lifetime. Molecules encapsulated this way are protected against rapid cellular metabolism and body elimination. Unfortunately, drugs such as daunorubicin cannot be efficiently entrapped in erythrocytes since drugs diffuse rapidly from the cells. In order to overcome this problem, we have covalently linked daunorubicin to erythrocyte membranes (ghosts) using two different types of linking arms: glutaraldehyde and cis-aconitic acid. Both ghost-daunorubicin conjugates were tested in vitro on mouse leukemia cells (P388D1) and on human osteosarcoma cells (CRL-1427). Results showed a better cytotoxic activity for ghost-glutaraldehyde-daunorubicin conjugate than for ghost-cis-aconityl-daunorubicin conjugate. Both conjugates were also tested in vivo on CDF1 mice bearing P388D1 cells. T/C% of 161 and 103 respectively were observed with ghost-glutaraldehyde-daunorubicin and ghost-cis-aconityl-daunorubicin conjugate at 6.0 mg/kg. Compared to free drug, the increase in survival time could be explained by a slow release of daunomycin in the circulation from the erythrocyte membranes, leading to a more complete absorption by cancer cells.

Rate-control drug delivery systems: controlled release vs. sustained release.

Abstract: Recently, several technical advancements have been made in the development of new generation of drug delivery systems. These systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic efficacy, and/or targeting the delivery of drug to a tissue. Depending upon the technical sophistication, these rate-control drug delivery systems can be classified into three major categories: (i) pre-programmed drug delivery, (ii) activation-controlled drug delivery, and (iii) feedback-regulated drug delivery. Various types of drug delivery devices which have been recently marketed or under active development are grouped, on technology basis, under each category. The fundamentals behind the development of each type of the rate-control drug delivery systems with the successful examples of biomedical application are analyzed, aiming to gain a better understanding of the science and technology involved as well as to pave a solid foundation for future development of innovative new drug delivery systems.