THE GGPF FALL SYMPOSIA:
"POLYMERS IN CONTROLLED RELEASE"
All day, Monday, Oct. 22
Michael's At Shoreline Restaurant
Mountain View, CA
All Day Event
$125 Includes Continental Breakfast, Lunch Buffet & Wine and Cheese Social
Registration Closes After First 70 Enrolled. Register on the web: http://ggpf.org/ However, your registration is not complete until you have sent $125 c/o Russ Beste, . Make your check out to Golden Gate Polymer Forum.
Agenda. All presentations include time for 15 minute Q+A:
8:00 to 9:00 Registration and Continental Breakfast
9:00 to 9:15 Introduction and Announcements
9:15 to 10:30
Prof. Kam Leong, Dept. of Biomedical
Engineering, Johns Hopkins Univ. --
"Polymers in Drug and Gene Delivery"
10:30 to 11:45
Prof. Allan Hoffman, Dept. of Bioengineering,
Univ. of Washington, Seattle -- "Use of
pH-sensitive Polymers in Drug Delivery"
11:45 to 1:15 Lunch
1:15 to 2:15
Dr. Guohua Chen, Research Scientist, ALZA Corporation --
"Controlled Release from Depot and Osmotically
2:15 to 3:15
Dr. John Barr, Vice President of R&D, AP Pharma -- "Controlled
Release from Bioerodible Implants"
3:15 to 3:30 Break
3:30 to 4:30
Dr. Rom Eliaz, Staff Engineer, ALZA Corporation -- "Tissue
Engineering via Gene Delivery"
4:30 to 5:30
Dr. S. Guna Gunasekaran, President/CEO,
ENCOLL Corp. Newark, CA -- "Modified Patented Collagen for Tissue Regeneration as well as Delivery of Genes and Stem-Cells"
5:30 to 6:30
Dr. Stelios Tzannis, Senior Scientist, Inhale Therapeutics-- "Polymers in Pulmonary Delivery"
6:30 to 7:30 Wine and Cheese
I. POLYMERIC CONTROLLED GENE DELIVERY
Professor Kam W. Leong
Department of Biomedical Engineering
Johns Hopkins School of Medicine
Baltimore, MD 21205
Non-viral vectors have been increasingly proposed as alternatives to viral vectors for in vivo gene transfer because of their potential advantages in addressing the pharmaceutical issues of applying gene as a drug. We have studied the complexation of DNA with natural biopolymers such as gelatin and chitosan, and biodegradable synthetic polymers, such as poly(phosphoester)s, in forming nanospheres. In addition to benefits common to other non-viral gene delivery systems of protecting the DNA from nuclease degradation and allowing active targeting, characteristics unique to these biodegradable DNA nanospheres include co-encapsulation of bioactive agents and sustained release of the DNA. The former raises the possibility of combining drug and gene therapy in one single vehicle, and the latter may improve the tissue bioavailability of DNA. Positive gene transfer has been observed in vivo in the lung, muscle, bladder, and gastrointestinal tissues in animal models. While the transfection efficiency of these DNA nanospheres remain low, their application in DNA vaccination, where high antigen expression may not be required, is promising because of their ability to encapsulate and deliver cytokines in a local and sustained manner to stimulate the infiltrating immune cells.
One of the possible rate-limiting steps in the non-viral gene transfer process is release of the DNA from the cationic carrier-complex. However, a tight binding of the DNA by the carrier is presumably required to condense the DNA to a compact size for cell internalization and to protect the DNA from enzymatic degradation. While it might be able to achieve the balance of stability by chance, a more elegant solution would be to design a biodegradable gene carrier that initially condenses the DNA efficiently and then gradually releases the DNA. Such a gene delivery system for extracellular sustained release of plasmid DNA should prove valuable in gene medicine and genetic immunization applications. We have synthesized a new biodegradable polycation, poly(4-methyl-2-oxo-2-aminoethyloxy-1,3,2-dioxaphospholane) [PPE], to achieve sustained release of plasmid DNA. Complexes between PPE and DNA were synthesized by charge interaction to enhance the plasmid stability and gene expression. DNA release profiles from PPE-DNA complexes and gene expression after intramuscular injection of the complexes will be discussed.
About Professor Kam W. Leong
Kam W. Leong received his PhD from Department of Chemical Engineering at University of Pennsylvania. After a postdoctoral fellowship at MIT, he joined the faculty of Biomedical Engineering in the Johns Hopkins University School of Medicine in 1986. He is now a professor in the Department of Biomedical Engineering, with joint appointment in the Department of Chemical Engineering and Orthopedic Surgery. He is one of the original inventors of the polyanhydride controlled release system. He has also recently developed another class of biodegradable polymers, the poly(phosphoester)s. His work has been recognized by a Young Investigator Research Achievement Award conferred by the Controlled Release Society in 1994. He is on the editorial board of Biomaterials, Molecular Therapy, Current Pharmaceutical Technology, Journal of Controlled Release, PharmSci, and Advanced Drug Delivery Review.
Dr. Leong's research focuses on biomaterials design for tissue engineering and polymeric controlled delivery of drugs and genes, with specific projects described below:
• synthesis of new biodegradable polymers for drug and gene delivery and tissue engineering
• development of biodegradable and biomimetic fibrous tissue engineering scaffolds
|Controlled Drug and Gene Delivery:
• gene therapy for hemophiliac A; gene delivery to the spinal cord
• mechanistic investigation of non-viral gene delivery
• mechanism and optimization of genetic immunization by controlled release technology
• delivery of cytokines for cancer immunotherapy
• tissue-engineered bioartificial trachea
• tissue engineering of intervertebral disc
II. USE OF pH-SENSITIVE POLYMERS IN DELIVERY OF DNA, ODNs, PROTEINS AND PEPTIDES
Professor Allan S. Hoffman
Department of Bioengineering
University of Washington
Seattle, WA 98195
The biotechnology field has identified many new biomolecular drugs, but the effective delivery of these biomacromolecules remains a significant challenge. One of the most important barriers is the intracellular delivery of proteins, peptides, DNA, and RNA to appropriate compartments. Passive or receptor-mediated endocytosis results in localization of biomolecules to the endosomal compartment, where the predominant trafficking fate is fusion with lysosomes and subsequent degradation. A variety of viruses and toxins have evolved pH-dependent fusogenic proteins to overcome this barrier by enhancing transport to the cytoplasm from the low pH environment of the endosome. Inspired by the principle behind this biological strategy, we have designed a family of new pH-responsive polymeric carriers that incorporate biomolecular drugs and also enhance their delivery to the cytoplasm from the endosomes.
The first type of polymer is based on poly(alkylacrylic acids) which become hydrophobic and disrupt cell membranes when a sufficient fraction of the carboxyl groups are protonated within the acidic endosomal environment. We have found that poly(propylacrylic acid, PPAA) is very effective at enhancing transfections in cell culture, even in the presence of serum. PPAA also works to enhance transfections in vivo in a mouse model.
A second type of polymer is designed with a hydrophobic backbone that is disruptive per se to lipid membranes, and to render it soluble as well as to mask it from lysing non-targeted cells, we have grafted hydrophilic PEG groups to it via disulfide bonds and acid-labile, acetal linkers. Drug molecules and targeting ligands may be linked ionically or chemically at the distal ends of the grafted PEG molecules, or they may be linked directly to the backbone via acid labile or –S-S- bonds. Then, at the low pH of the endosome, the acetal bonds are hydrolyzed, “unmasking” the membrane disruptive backbone, which leads to endosomal membrane disruption and enhanced delivery of the therapeutic to the cytoplasm. We have found that these polymer carriers effectively bypass the lysosomal targeting of oligonucleotides (ODNs) that have been internalized through the asialoglycoprotein receptor of hepatocytes. Recent data show that we can also deliver the antisense ODN to the iNOS enzyme in vitro in Macrophage RAW cell cultures. We are currently working on cytosolic delivery of peptides using this polymer carrier.
These novel polymers should be useful to enhance intracellular delivery of a variety of biomolecular drugs where cytoplasmic localization is a critical step.
About Prof. Allan S. Hoffman
Professor Hoffman studied at M.I.T., where he received B.S., M.S., and Sc.D. degrees in Chemical Engineering between 1953 and 1957. He taught on the faculty of M.I.T. Chemical Engineering Department for a total of ten years and also spent four years in industry. Since 1970 he has been Professor of Bioengineering and Chemical Engineering at the University of Washington in Seattle, Washington.
Professor Hoffman’s main research interests include the principles and applications of polymer materials science, surface science, and biological sciences in the design and study of new materials and devices for a wide range of uses in medicine and biotechnology.
He is on the Editorial Boards of Bioconjugate Chemistry, Journal of Biomedical Materials Research; Biomaterials; Journal of Biomaterials Science (Polymer Edition); Journal of Bioactive and Compatible Polymers; and Biomaterials, Artificial Cells and Immobilization Biotechnology.
Some of his professional activities and awards have included: Chairman, Gordon Conference on Biomaterials, 1977; President, Society for Biomaterials, 1983-1984; Clemson Award for Outstanding Contributions to the Scientific Literature of Biomaterials, 1984; Japanese Biomaterials Society award, “Biomaterials Science Prize,” 1990. In December, 1992, his colleagues organized a symposium on “Future Perspectives of Biomedical Polymers” in Maui, Hawaii in honor of his 60th birthday. In May, 2000 Prof. Hoffman received the Founders’ Award of the Society for Biomaterials at the 6th World Congress on Biomaterials, held in Hawaii. This award is the highest award of the society, and recognizes “long-term commitment and landmark contributions to the biomaterials field”.
III. Controlled Release from Depot and Osmotically Driven Implants"
Dr. Guohua Chen
Mountain View, CA
Two different implantable drug delivery systems will be presented. One is a zero-order, osmotic-driven implantable system, the DUROS® implant, which has been developed for the delivery of peptides and proteins for periods of 1 month to over 1 year. DUROS® implant release rate and system duration are determined by the semi-permeable membrane composition. Examples using DUROS® implant to deliver proteins and peptides in both solution and suspension formulations will be demonstrated. The other system presented is the ALZAMER® depot technology, which consists of a biodegradable polymer, a solvent, and formulated drug particles. The ALZAMER® depot uses biocompatible solvents of low water miscibility, which help control the initial drug release. These formulations are easy to process and can be stored with the drug particles preformulated into the gel, enhancing convenience of use. The sustained release-rate profiles of bioactive proteins such as human growth hormone (hGH) and small molecule drugs such as Bupivacaine etc., have been demonstrated in the systems in vivo with minimal initial drug burst.
About Dr. Guohua Chen
Guohua Chen is a research scientist in the implant R&D division, Alza Corp and Affiliate Professor of Bioengineering at the University of Washington. He received a BS in chemistry, a MS in Polymer Chemistry from Nankai University, China and a Ph.D. in Polymer & Biomaterials Technology from University of Twente, The Netherlands, with Professor Adriaan Bantjes. He was a postdoc fellow in the Department of Bioengineering at the University of Washington with Prof. Allan S. Hoffman.
After joining Alza Implant R & D division, his initial focus was to develop the DUROS® osmotic-driven implantable system for delivering proteins and peptides. His work included selection and characterization of polymeric materials used in DUROS® system, especially the semi-permeable membranes. Recently he has been focusing on the research and development of ALZAMER® depot technology, heavily involved in both depot gel and drug particle formulations for delivering proteins, peptides as well as small molecule drugs. He has always utilized his polymer and biomaterials expertise in his work to develop novel drug delivery systems. Dr. Chen authored or co-authored over 30 papers or book chapters, mainly on applications of polymeric materials in biomedical fields.
IV. Synthesis, Properties and Drug Release from Autocatalyzed Poly(Ortho Esters)
Dr. John Barr, Vice President, Research & Development
A.P. Pharma has developed a family of unique, and highly versatile bioerodible polymers, based on ortho ester linkages. The uniqueness of this poly(ortho ester) polymer system is derived from our ability to control erosion rates by the incorporation of a latent acid catalyst into the polymer backbone that takes advantage of its acid-sensitivity and by our ability to manipulate physical properties by proper choice of monomers. These polymers can be used in a variety of physical forms, ranging from materials that are semi-solids at room temperature and from soft to rigid solid materials. The semi-solid materials are used as is, while the solid material can be fabricated into microspheres, wafers, or strands. Drugs are physically dispersed in this material without any covalent attachment and are released as the polymer erodes. Because the drug is physically dispersed in the polymer, there is no limitation as to size,
r nature of the drug. Erosion rates and hence rate of drug delivery can be varied from days to many weeks, and because the drugs are released by an erosion-controlled mechanism, drug depletion coincides with total polymer erosion. A number of applications will be described.
About Dr. John Barr
John Barr, Vice President, Research & Development, joined AP Pharma in 1997. Dr. Barr has played a key role in evaluating and developing the potential of the company’s novel delivery systems. Prior to joining AP PHARMA, he worked as the Director of Biopharmaceutics for Cortech, Inc, a Denver based biotech firm focused on the development of novel anti-inflammatory agents. In that capacity he was involved with both the research and development aspects of the company’s intravenous and oral programs. Dr. Barr received his Ph.D. in pharmacology from the University of Glasgow in Scotland, after which he pursued post-doctoral studies at
the University of Arizona.
V. Tissue Engineering via Gene Delivery
Doctor Rom E. Eliaz
1501 California Avenue
Palo Alto, CA 94304
In the foreseeable future, DNA will be available as a pharmaceutical for gene replacement, vaccination and tissue engineering. To facilitate this development, biodegradable polymers have been introduced as implantable matrices for the sustained release of genes to augment local gene transfer. These DNA containing implants have been fabricated from biodegradable polymers in a range of shapes and sizes: from microcapsules and microspheres to rods, films, and three-dimensional matrices. All of these implants are solids that are formed outside the body to precise dimensions, and then inserted into the body for gene delivery. Scaffolds for tissue engineering should have the following characteristic: three-dimensional and highly porous with an interconnected pore network and chemical and mechanical properties to match those of the tissues at the site of implantation. An alternative to ex-vivo matrix formation has been proposed recently for protein delivery, where the biodegradable implant forms in situ upon injection. A monolithic gene delivery system where the implant is formed following injection to the site of need was developed and will be presented. Various plasmids were delivered by this polymeric implant. The genes, efficiently transfected cells in mice and the encoded proteins were robustly expressed or mediated a biological response for a prolonged period. This delivery system involves simple preparation procedures and can be injected directly into the site, hence should be a useful approach to plasmid based gene transfer for vaccination and tissue engineering.
About Doctor Rom E. Eliaz
Doctor Eliaz studied at Ben Gurion University of the Negev (BGU) and Weizmann Institute of Sciences, Israel, where he received B.Sc., M.Sc. (cum laude), and Ph.D. (cum laude) degrees in Chemical Engineering between 1989 and 1998. He also received an MBA degree from BGU at 1997. As Academic Reserve he worked in the industry. He taught on the faculty of BGU Chemical Engineering Department for a total of four years. He joined UCSF as a postdoctoral Fellow in 1998. Since 2001 he has been Staff Engineer in Alza Corporation, California.
Doctor Eliaz’s main research interests include the principles and applications of polymer materials science, liposome targeting, drug and gene delivery and tissue engineering.
He is a member of American Association for the Advancement of Sciences, American Society for Gene Therapy, Controlled Release Society, and Israel Society for Polymers and Plastics.
Some of his professional activities and awards have included: Sixth International Tumor Necrosis Factor Congress Outstanding Research Award, 1996; The Nagai Foundation Tokyo – Controlled Release Society Graduate Student Award, 1996; and Post-doctoral Award, 2000; Thrombki Award for Outstanding Graduate Student of BGU, 1997; Rothschild Post-Doctoral Fellowship Honorarium, 1998; Postdoctoral Fellowships from NIH; State of California Tobacco-Related Disease Research Program Award and State of California Breast Cancer Research Program Award, 1998-2001.
VI. Modified Patented Collagen for Tissue Regeneration as well as Delivery of Genes and Stem-Cells
Dr. S. Guna Gunasekaran, President/CEO, ENCOLL Corp. Newark, CA --
To be posted soon.
About Dr. S. Guna Gunasekaran
VII. Polymers in Pulmonary Delivery – An Overview
Dr. Stelios T. Tzannis, Senior Scientist and Group Leader
Inhale Therapeutic Systems
San Carlos, CA
Over the last thirty years, inhalation has been well established as a critical delivery route for local therapy to the lungs. Advances in the field over the past decade have further provided the opportunity for systemic delivery of proteins and peptides. However, the complexity and vital role of this organ, along with our limited understanding of the biology of drug clearance and drug absorption via the lungs, have limited the use of polymeric materials. Research efforts over the past years have targeted the control of drug absorption rate following deposition in the lungs, both for systemic and local treatment. Several polymers are under investigation for preparation of controlled release dosage forms for inhalation. An overview of the current status of pulmonary controlled release is provided.
About Dr. Stelios T. Tzannis
Dr. Stelios T. Tzannis, is a Senior Scientist and Group Leader in the Research department at Inhale Therapeutic Systems (San Carlos, CA). From his current position he directs a research group involved in drug delivery and technology evaluations, while he also leads the technology integration efforts. He joined Inhale in 1998, when he led the efforts on the development of sustained release technologies for pulmonary delivery. Prior to joining Inhale, Dr. Tzannis was a lead formulation scientist at ALZA Corporation, where he focused in the rational design and preparation of biomolecule formulations for transdermal, implantable and injectable therapeutic systems. He earned his Diploma in biochemical engineering from the National Technical University of Athens (NTU), Greece, and his M.S. and Ph.D. degrees as an Isermann Fellow from the Department of Chemical Engineering at Rensselaer Polytechnic Institute.
Dr. Tzannis has published several papers and has presented numerous lectures in the field of protein stabilization, processing and delivery. He is an active member of the AAPS, CRS, ACS and AIChE. He has organized several scientific sessions in international conferences, while has served as the Program Chair and General Chairman of the Western Regional AAPS meetings.