Showing papers on "Targeted drug delivery published in 1998"

Drug delivery and targeting

Abstract: When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible. This has provided the impetus for active study of the design of degradable materials, intelligent delivery systems and approaches for delivery through different portals in the body.

Cancer Treatment by Targeted Drug Delivery to Tumor Vasculature in a Mouse Model

Abstract: In vivo selection of phage display libraries was used to isolate peptides that home specifically to tumor blood vessels. When coupled to the anticancer drug doxorubicin, two of these peptides-one containing an alphav integrin-binding Arg-Gly-Asp motif and the other an Asn-Gly-Arg motif-enhanced the efficacy of the drug against human breast cancer xenografts in nude mice and also reduced its toxicity. These results indicate that it may be possible to develop targeted chemotherapy strategies that are based on selective expression of receptors in tumor vasculature.

Charged lipids and uses for the same

Abstract: The present invention is directed to charged lipids, compositions comprising charged lipids, and the use of these compositions in drug delivery, targeted drug delivery, therapeutic imaging and diagnostic imaging, as well as their use as contrast agents.

MR-visible medical device for neurological interventions using nonlinear magnetic stereotaxis and a method imaging

Abstract: The present invention comprises a device and method for targeted drug delivery, and especially intracranial inflsion or retroperfusion drug delivery using nonlinear magnetic stereotaxis in combination with magnetic resonance (MR) imaging and/or X-ray visualization. An MR-visible and/or X-ray visible drug delivery device is positioned by non-linear magnetic stereotaxis at a site such as an intracranial target site, its location is verified via MR imaging, and it is then used to deliver a biologically active material such as a diagnostic or therapeutic drug solution into that site (such as the brain) at constant or variable rates. The spatial distribution kinetics of the injected or infised drug agent may be monitored quantitatively and non-invasively using real-time MR-imaging such as water proton directional diffusion MR imaging, to establish the efficacy of targeted drug delivery.

Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor

Abstract: [125I]-Aβ1-40 was mono-biotinylated and conjugated to a blood-brain barrier drug delivery and brain targeting system comprised of a complex of the 83-14 monoclonal antibody (MAb) to the human insulin receptor, which is tagged with streptavidin (SA) to produce a marked increase in rhesus monkey brain uptake of the [125I]-bio-Aβ1-40 at 3 hours following intravenous injection compared to no measurable brain uptake of [125I]-bio-Aβ1-40 in the absence of a BBB drug.

Colonic Drug Targeting

Abstract: Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohn's disease is more effective with direct delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents require smaller doses. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. For this purpose, the anatomy and physiology of the lower gastrointestinal tract are surveyed. Furthermore, the biopharmaceutical aspects are considered in relation to drug absorption in the colon and hence various approaches to colon-specific drug delivery are discussed.

Hyaluronate derivatives in drug delivery.

Abstract: Hyaluronan (HA), an abundant nonsulfated glycosaminoglycan component of synovial fluid and the extracellular matrix, is an attractive building block for new biocompatible and biodegradable polymers that have applications in drug delivery, tissue engineering, and viscosupplementation. This review consists of three subtopics: (i) chemical modification of HA; (ii) physicochemical and biochemical characterization of HA derivatives; and (iii) in vitro and in vivo bioevaluation studies. Important new products have already reached the marketplace, and the approval and introduction of a variety of new medical applications of HA-based biomaterials can be anticipated in the next decade.

A new look at lipid-membrane structure in relation to drug research

Abstract: Lipid-bilayer membranes are key objects in drug research in relation to (i) interaction of drugs with membrane-bound receptors, (ii) drug targeting, penetration, and permeation of cell membranes, and (iii) use of liposomes in micro-encapsulation technologies for drug delivery. Rational design of new drugs and drug-delivery systems therefore requires insight into the physical properties of lipid-bilayer membranes. This mini-review provides a perspective on the current view of lipid-bilayer structure and dynamics based on information obtained from a variety of recent experimental and theoretical studies. Special attention is paid to trans-bilayer structure, lateral molecular organization of the lipid bilayer, lipid-mediated protein assembly, and lipid-bilayer permeability. It is argued that lipids play a major role in lipid membrane-organization and functionality.

Thermodynamic adaptive phased array system for activating thermosensititve liposomes in targeted drug delivery

Abstract: A thermodynamic therapy system including a thermally activated drug delivery system which is provided within the bloodstream of a patient under therapy, and an adaptive phased array radiation transmission system operable for transmitting and focusing radiation to heat a treatment area within the patient. The drug delivery system releases a selected drug at the treatment area in response to the treatment area being heated by the focused radiation.

The potential of liposomes in oral drug delivery.

Abstract: Oral liposome drug delivery has been the subject of much cynicism. Results have been quite variable and, for the most part, have not been predicated on specific objectives that would lead to success. Prerequisites are stability in the gastrointestinal environment and binding to specific sites. Transport via paracellular and transcellular routes from normal epithelial tissue or Peyer's patches leads to different outcomes of drug delivery and immunization, respectively. Polymerized, microencapsulated, and polymer-coated liposomes have all increased the potential of oral liposomes. Using targeted liposomes and a greater understanding of their cellular processing will ultimately lead to effective therapies from oral liposomes.

Enhancement of bioavailability by use of focused energy delivery to a target tissue

Abstract: Targeted tissue in vivo is altered using focused energy to specifically control endothelial permeability and interstitial integrity. Image guidance may be used in combination with physical energy deposition to facilitate the targeted delivery of materials. The method of the invention serves as a platform for delivering pharmaceutical agents, nucleic acids, proteins, liposomes, etc. to cells.

Targeting of drugs 6 : strategies for stealth therapeutic systems

Abstract: Interactions between Blood Components and Artificial Surfaces KD Caldwell The Mononuclear Phagocyte System: Features Relevant to Interactions with Liposomes S Gordon StealthTM Therapeutic Systems: Rationale and Strategies DJA Crommelin, G Storm Long Circulating Liposomes: Evolution of the Concept G Gregoriadis Sterically Stabilized Immunoliposomes: Formulations for Delivery of Drugs and Genes to Tumor Cells in Vivo JW Park, et al Pegylation of Liposomes in Cell-Specific Targeting: It Does Not Always Make Sense GL Scherphof, et al StealthTM Liposomes for the Targeting of Drugs in Cancer Therapy TM Allen, et al StealthTM Liposomes as Carriers of Doxorubicin D Goren, et al Liposome-Mediated Delivery of Retinoids K Mehta, et al Applications of Liposome Technology to Overcome Multidrug Resistance in Solid Tumors R Krishna, LD Mayer Use of Radiolabeled Liposomes for PEG-Liposome-Based Drug Targeting and Diagnostic Imaging Applications WT Phillips Diagnostic and Therapeutic Targeting of Infectious and Inflammatory Diseases Using Sterically Stabilized Liposomes G Storm, et al Biologically Active Ligand-Bearing Polymer-Grafted Liposomes S Zalipsky, et al 11 Additional Articles Index

Drug targeting systems for cancer chemotherapy.

Abstract: Tumour specific drug targeting has been a very actively investigated area for over 2 decades. Various approaches have involved the use of drug delivery systems that can localise the anticancer agent at the tumour site without damaging the normal cells. For this purpose, various delivery systems that have been utilised are liposomes, microspheres and recently, nanoparticles. Two liposome formulations containing anticancer drugs for example, adriamycin and daunomycin are already on the market in the USA and Europe. Microspheres are also being investigated for delivering various anticancer drugs and protein/peptides for anticancer treatment, and several formulations are in Phase I/II clinical trials. Antitumour drugs have also been linked to tumour specific monoclonal antibodies via various chemical linkages. Doxorubicin was linked to a chimeric monoclonal antibody that was targeted to the Lewis Y antigen. Though this conjugate initially showed potential, it was recently dropped from Phase II clinical trials. Another approach with monoclonal antibodies has been the use of immunotoxins. Immunotoxins initially showed promise as potential anticancer agents at picomolar concentrations but several clinical and preclinical studies have not shown much promise in this regard. Drug containing liposomes and microspheres have been further linked to tumour specific monoclonal antibodies to enhance their tumour specificity. Most of the studies with immunoliposomes or targeted microspheres have not gone beyond the preclinical studies. New therapeutic approaches are presently emerging based on natural products like cytokines, peptide growth factor antagonists, antisense oligonucleotides and specific genes. These approaches need the help of delivery systems to deliver these complex molecules to tumour cells. One of the current pursued approaches is the use of cationic liposomes. Several clinical studies are undergoing with various cationic liposomes and the next few years will demonstrate the usefulness of this approach. In recent years, the problems in cancer treatment have been complicated with the emergence of resistance strains leading to resistant and cross-resistant tumour cells. Several agents have been used to overcome or reverse drug-resistance in solid tumours and it remains a highly pursued area in cancer treatment.

Controlling the Drug Delivery Attributes of Lipid-Based Drug Formulations

Abstract: (1998). Controlling the Drug Delivery Attributes of Lipid-Based Drug Formulations. Journal of Liposome Research: Vol. 8, No. 3, pp. 299-335.

Method and apparatus for targeted drug delivery into a living patient using magnetic resonance imaging

Abstract: The invention is an apparatus and method for targeted drug delivery into a living patient using magnetic resonance (MR) imaging. The apparatus and method are useful in delivery to all types of living tissue and uses MR Imaging to track the location of drug delivery and estimating the rate of drug delivery. An MR-visible drug delivery device positioned at a target site (e.g., intracranial delivery) delivers a diagnostic or therapeutic drug solution into the tissue (e.g., the brain). The spatial distribution kinetics of the injected or infused drug agent are monitored quantitatively and non-invasively using water proton directional diffusion MR imaging to establish the efficacy of drug delivery at a targeted location.

Future developments in the selectivity of anticancer agents: Drug delivery and molecular target strategies

Abstract: In the past, our limited understanding of the processes involved in the initiation and growth of cancer hindered our ability to effectively treat most human malignancies and therapies were often associated with significant toxic side effects as well as re-emergence of disease. The development of drug delivery systems such as liposomes has improved the specificity of various conventional anticancer agents by enhancing drug accumulation in tumors while often decreasing exposure to susceptible healthy tissues. More recently, the identification of a wide range of genes and corresponding protein products that are altered in various human cancers has revealed new molecular targets for cancer therapy that may provide improved selectivity for tumor cells over traditional cytotoxic agents. This review discusses how advances in the sophistication of liposomal delivery systems may open new opportunities for combining novel molecular targeting strategies with pharmacological targeting via liposomes to optimize the therapy of many human malignancies.

CHAPTER 4.6 – Targeted sterically stabilized liposomal drug delivery

Abstract: This chapter provides an overview of targeted liposomal drug delivery and potential problems with targeted liposomes. Drug carriers, such as liposomes, are used in attempts to improve the therapeutic index of associated therapeutic molecules. Selective drug delivery to cancer cells requires the presence of markers on the cancer cell surface, which distinguishes them from non-tumor cells. These markers are often referred to as tumor-associated antigens. In some cases, the antigen is well characterized and is known to be a receptor, which is mutated or over expressed on the tumor cells, while in other cases the antigen is simply characterized as a cell surface glycoprotein with uncharacterized structure or function. Ligands that are used specifically to target cancer cells are monoclonal antibodies. Several problems identified with targeted liposomes are: rapid clearance of immunoliposomes, target tissue heterogeneity, and binding site barrier. In recent years, significant progress has been achieved in attempts to gain specific targeting of drugs in vivo . These include: development of long-circulating immunoliposomes, adaptation of existing chemistries, and the development of new strategies for coupling ligands to the surface of liposomes.

New Methods for Drug Delivery

Abstract: As scientists in academia and industry invent new ways to give medicines to patients, the biotechnology and pharmaceutical industries are promising to develop drugs of the future that are better targeted to a patient's disease and can be more easily administered. A selection of patches, nasal sprays, pumps, liposomes, and viral vectors is now making its way through the pharmaceutical pipeline, and these various technologies may soon render the spoonful of sugar obsolete. To make drug delivery needle-free, researchers have found ways to bypass drug absorption barriers in the skin and mucosa. Key advances in chemical formulation have enabled the development of medicines that are absorbed through the skin or that can be inhaled into the lungs. In addition to being user-friendly, some new drug-delivery systems have made treatments more focused. With several new techniques, higher concentrations of drugs can be delivered to specific diseased tissue, which allows greater potency and less toxicity to healthy tissue. By making drugs more palatable, researchers hope to improve patient compliance and even to lower the costs of hospitalization. About 10% of hospital admissions are said to result from noncompliance with drug regimens. Anything that results in fewer administrations by physicians has significant economic advantages, noted Mark Ratain, professor of hematology and oncology and chairman of the Committee on Clinical Pharmacology at the University of Chicago. Advanced drug-delivery technology generates an estimated $10 billion in sales revenue annually. Accordingly, Ratain cited a motivation for profit in drug delivery. What's driving this R and D is money, said Ratain. It's a way to patent-protect an old drug; you patent the reformulation. Regardless of the motivation, researchers have developed several innovative drug formulations. Most novel drug-delivery systems have stemmed from work on new polymers, lipid vesicles, cyclodextrins, pro-drugs, and viral vectors. Polymers By being linked with a polymer, the drug slowly diffuses into the bloodstream over a long period. Levonorgestrel implant contraceptives and injected complexes that release luteinizing hormones are examples of polymers that produce sustained drug levels. Polymer-linked drugs that are deliberately oversized can also better target diseased tissues by escaping through leaky microvasculature and then entering cells by endocytosis. In a model of melanoma, this approach has enabled researchers to achieve levels of the antineoplastic drug doxorubicin that are up to 70 times higher in tumor tissue than those achieved with conventional formulations. Researchers are also perfecting drug-polymer complexes that are linked to antibodies for active-tissue targeting. Some polymer systems can be rendered smart (that is, sensitive to a tissue environment). Thus, a drug-polymer complex can be designed to undergo a conformational change or enzymatic breakdown that results in release of the active drug only under certain conditions. Drug-polymer complexes that release insulin after sensing glucose, or naltrexone in the presence of morphine, have been described in the literature and may become clinically practical in the future. Similar advances in chemistry have also allowed many drugs to be administered through the skin. It's primarily a polymer-based approach, explained Russ Potts, executive vice president of research at Cygnus Inc. in Redwood City, California, in discussing his company's transdermal drug-delivery method. You take medical adhesives and dissolve drugs in them. You apply the drug to the skin, and it diffuses. Drug delivery through the skin has the advantage of maintaining consistent blood levels. Patches that can be worn for several days also appear to help compliance. According to Potts, the new technology can be economical. Hormones that are effective at low concentrations are good candidates for transdermal delivery systems. But patches are not ideal for delivering the large doses of drugs that are needed in antibiotic therapy and not economical for such low-cost drugs as aspirin. Liposomes The liposome is another construct that serves as an envelope for active drug particles and can, like polymers, deliver high concentrations of drugs to infected or neoplastic tissue. Liposome delivery systems are similar to polymer systems but the drug is encompassed by a vesicle instead of being physically linked to a polymer. In liposomes, a hydrophilic drug can be trapped in aqueous channels that course between successive phospholipid bilayers, whereas a hydrophobic medicine can reside within the bilayer itself. The nontoxic, nonimmunogenic bilayers dissipate, allowing slow diffusion of the active medicine into the tissue. Liposomal amphotericin is widely used, and liposomal formulations for daunorubicin and doxorubicin were recently approved by the Food and Drug Administration for treatment of HIV-associated Kaposi sarcoma. The philosophy is greater efficacy with lower toxicity, said Lora Armstrong, director of drug information services at the University of Chicago hospitals. The drug is not free in the circulation, she said, explaining the formulation's reduced toxicity. Liposomes can have a large capacity for carrying drugs, and they accumulate in inflamed tissue where endothelial barriers break down. Researchers are also exploring ways to target liposomes for neoplastic cells. If you can increase the amount of drug in the tissue, you can theoretically increase the kill, Armstrong asserted. Cyclodextrins Another chemical innovation currently being used for drug delivery involves the taming of a naturally occurring class of molecules known as cyclodextrins, which were once too toxic to be used in medicines. A cyclodextrin is 7 dextrose units held together by a lipophilic core and a hydrophilic exterior, explained Valentino Stella, University Distinguished Professor in Pharmaceutical Chemistry at the University of Kansas and director of the Higuchi Bioscience Center for Drug Delivery Research in Lawrence, Kansas. It takes an insoluble drug and forms an inclusion complex. Stella described how the molecules, which were first discovered in the 1890s, were adapted for medical use. Orally, cyclodextrins are fine, but with injection, they are nephrotoxic we engineered a modification of cyclodextrins to decrease their toxicity. They are not delivery systems, they are enabling systems. Because they are safe solubilizers, cyclodextrins are used in formulations of antipsychotic drugs, in a new formulation of itraconazole, and even in Shiseido perfumes. Pro-Drugs Stella's team is also developing pro-drugs like fosphenytoin. Pro-drugs are therapeutically inert when administered but become bioactive at or near the site of action in the body. Fosphenytoin is to be sold as cerebyx, a reformulation of the anticonvulsant phenytoin that can be given safely by intravenous injection. Conventional phenytoin can cause cardiovascular collapse when given parenterally. The pro-drug concept is popular: About 15% to 20% of new drugs that are approved are pro-drugs. Gene Delivery According to Stella, the Higuchi group would also like to contribute to the area of gene delivery. We're not competing with the big boys in gene therapy, he said. We're focusing on DNA fragments for vaccines. Institutions that are committed to meeting the gene therapy challenge have faced their own drug-delivery problems, and the progress is gradual. Physician-scientists have devoted attention to gene replacement in monogenic deficiency diseases, such as cystic fibrosis, and to many strategies for manipulating the genomes of cancer cells. Getting the right DNA into the right tissue is the challenge. The vector delivery systems can be broken down into two areas: viral and nonviral. Viral is the dominant use because viruses are the most efficient parasites, according to Nelson Wivel, deputy director of the Institute for Human Gene Therapy at the University of Pennsylvania School of Medicine in Philadelphia. Wivel said that early work using disabled retroviruses failed because of the inability of retroviruses to infect nonreplicating cells. Adenovirus vectors are now more common, although they are more vulnerable to host immune systems and their longevity of transcription is less. Nonviral vectors for gene therapy, such as liposomes that are combined with plasmid DNA, have also been studied. According to Wivel, the efficiency of expression is very low because many of the liposomes are absorbed by cells and degraded. We don't have any targeted vectors, he commented. Tissue-specific targeting is the Holy Grail of this field. Diabetes Treatment Mechanisms The heritable disease that has received the most attention from drug-delivery researchers is diabetes. Over the years, researchers have tried various approaches to introduce insulin into the bloodstream of diabetic patients and to achieve predictable levels that might mimic the secretion of insulin in a human pancreas. Insulin has been given by oral and nasal routes, but neither has been shown to be clinically practical. Intranasal insulin relied on enhancers to improve mucosal absorption, but the enhancers, in some cases a bile salt, proved to be too irritating. Implantable insulin pumps that provide a basal rate of insulin secretion and can be directed by remote control to give boluses of insulin at mealtimes may finally become popular. Recent literature suggests that these pumps can control blood sugar as well as intensive insulin injection regimens can. Endocrinologists have long recognized that diabetes can best be controlled with meticulous dietary compliance and frequent doses of insulin. The most current innovation in diabetes treatment, however, is inhaled insulin. Two California biotechnology companies have developed competing insulin-delivery devices that take advantage of the lungs' design as a diffusion membrane. John Patton, vice president for re

Drug delivery system with two-step targeting

Abstract: The present invention relates to a drug delivery system with two-step targeting, which comprises a combination: (a) a lipid carrier provided with cell targeting agent(s) to target the drug delivery system to specific cells or tissues; and (b) a drug enclosed in said lipid carrier and provided with a DNA targeting agent to target the drug to the nuclei of specific target cells Furthermore, the invention relates to a method of cancer therapy in which the above drug delivery system is administered to a cancer patient The goal is to treat or analyse both large tumour masses as well as small tumour cell clusters and single spread tumour cells According to the invention, drug uptake in tumours will be markedly increased at the same time as the interaction of the drug with healthy organs and tissues can be minimized The invention gives potential to convert palliative into curative treatment

Microspheres as a drug delivery system in cancer therapy

Abstract: Microspheres are an example of a drug delivery system that has been evaluated extensively in cancer chemotherapy. They are essentially solid porous particles (1 - 100 μm diameters) which can both target their drug cargo by physical trapping in blood vessels (chemoembolisation) and sustain the action of a therapeutic agent through controlled release. Microspheres can be made from a broad range of polymeric materials, including proteins, polysaccharides, polyesters and lipids by a variety of different techniques (emulsification, heat stabilisation, coacervation and phase inversion technology). Their diversity identifies the microsphere as a drug delivery system with considerable flexibility. The present review develops the hypothesis that the matrix material and method of preparation are critical determinants in defining pharmaceutical characteristics, which in turn dictate biologic activity. Examples are cited of different approaches adopted with cytotoxic drugs (chiefly doxorubicin, mitomycin C, cisplatin...