Abstracts for Invited Talks
INTEGRATING MOLECULAR BIOSENSORS INTO LIPID BASED DELIVERY SYSTEMS
TO ACHIEVE BIORESPONSIVE RELEASE
David J Clarke and Harmesh S Aojula
School of Pharmacy and Pharmaceutical Sciences, University of Manchester,
Manchester, M13 9PL, UK
Closed-loop, self-regulating delivery systems have been considered primarily
using polymer systems responsive to physical and physiochemical triggers,
providing a limited range of biologically specific (bioresponsive) controlled
release systems. This has led to the consideration of diagnostic materials
(eg concanavalin A and glucose oxidase for glucose, antibodies and streptavidin)
to provide the biospecificities desired, using approaches (eg enzyme drive
pH changes, coupled affinity reactions) reminiscent of first generation
biosensors. Major efforts over the last two decades have been devoted to
achieving intimate coupling between these biorecognition elements and the
transducing device. However, few biosensor devices are yet considered reliable
enough to be used in vivo as monitoring devices, or for feedback control
(eg as may be used to close the loop on physically responsive polymer implants).
Alternative non-invasive biosensor devices (eg near IR glucose monitoring)
appear more promising, although they have a limited specificity range.
Minimally invasive, miniaturised enzyme electrodes, microelectronic and
optical immunobiosensors suffer from significant calibration drift and
interference (non-specific reactions at the transducer surface). Like more
recent molecular biosensor and heterogeneous molecular diagnostic methods,
requiring multi-step assay procedures, they are directed largely to lab-based
in vitro diagnostics, requiring expert or automated use.
Biology often uses biomembran es to couple biorecognition events or
sensing to a variety of effector functions, closing the loop locally at
the supermolecular of nanometre size scale. The integration of the biorecognition
elements used in biology and in vitro diagnostics into biomembranes will
be discussed, from the viewpoint of developing small, submicron-sized sample-going
and targeted molecular biosensors for screening and bioresponsive controlled
release systems. We will discuss work in our laboratory on the use of short
biomimetic peptides to produce quantitative, bioresponsive release and
transport of small molecules and proteins across biomembranes, and to bind
reversibly to the variable and non-variable region of immunoglobulins.
UNDERSTANDING SURFACE MACROMOLECULAR INTERACTIONS IN THE DESIGN OF
THERAPEUTIC SYSTEMS
Prof. Martyn Davies
University of Nottingham, UK
Surface interactions play a vital role in the performance of many advanced
drug delivery systems. The adsorption of serum proteins to colloid surfaces
plays a major role in determining their disposition in-vivo. The molecular
recognition between the targeting groups on soluble polymeric delivery
systems and the cell surface receptors is another example of the importance
of surface interactions. In order to provide a greater understanding of
these interfacial properties, one may exploit a number of advanced biophysical
techniques which have been developed to define surface phenomena. This
talk will explore the role of two developing methodologies which show considerable
promise for the study of biomolecular structure and interactions with advanced
biomaterials: atomic force microscopy (AFM) and surface plasmon resonance
(SPR). AFM can provide high resolution imaging of biomolecular and polymer
structure of relevance to controlled drug delivery within an aqueous environment.
Dynamic events such as surface hydration, degradation and biomolecular
interactions can be visualised in situ. Important surface properties such
as compliance, friction and force of interactions between biomolecules
can all be probed. SPR is emerging as one of the most important tools for
studying biomolecular structure and interactions. This talk will describe
how the technique may be adapted to provide kinetic information on the
dynamic events at interfaces including DNA-protein interactions of importance
in gene therapy, macromolecular interactions at membrane interfaces and
protein interactions at nanoengineered surfaces designed for site-specific
delivery and diagnostic applications. The talk will illustrate the complimentarity
of these two approaches, alongside other biophysical, biochemical and in-vivo
data, in gaining a greater insight into understanding the performance of
advanced delivery systems, in certain cases, at the molecular level.
DESIGN OF NEW BIOMATERIALS FOR DRUG DELIVERY: TAILORING THE STRUCTURE
TO SPECIFIC DELIVERY NEEDS AND RELEASE REQUIREMENTS
Nicholas A. Peppas
School of Chemical Engineering, Purdue University, West Lafayette, IN
47907-1283, USA
Recent developments in polymeric materials have played a major role
in improving drug delivery. Drugs, peptides or proteins are now chemically
attached to polymers or antibodies, entrapped in small vesicles that are
injected into the blood, or placed in pumps or controlled release devices
in contract with the body. Recent developments in drug delivery have been
directed towards the preparation of targeted formulations for peptide delivery
to specific sites, use or environmentally-responsive polymers to achieve
pH- or temperature-triggered delivery, usually in modulated mode, and improvement
of the behaviour of mucoadhesive controlled release systems. Renewed interest
is directed towards the study to antibody-directed enzyme prodrug therapy,
tumor suppressor gene therapy for cancer, novel methods of delivery of
insulin, calcitonin, growth hormones and vaccines.
Intelligent biomaterials can be used for a wider range of biomedical
applications such as membranes for bioseparations, carriers for pH- or
temperature-triggered drug delivery, materials in immunologic studies,
and systems for feedback-control devices. We show that the critical behaviour
of such polymers lead to abrupt expansion (swelling)/collapse (syneresis)
of their structure with associated change to the mesh size or correlation
length. These phenomena can be used for the release of insulin, vitamins,
etc. in an oscillatory mode. Success of such systems will depend on our
ability to show that the observed behaviour is reproducible over several
thousand cycles without polymer failure, and that external physiological
changes have minor influence on the release behaviour.
POLYMERIC MICROSPHERES FOR SUSTAINED DELIVERY OF THERAPEUTIC PROTEINS
Stephen E. Zale Alkermes, Inc.,
Cambridge MA, USA
Therapeutic proteins are generally administed by frequent injection
because of their characteristic negligible oral bioavailability and short
plasma half life. Potential benefits of injectable microsphere-based sustained
release delivery systems for protein drugs include improved patient compliance
and convenience, more stable blood levels and a possible reduction in the
dose required to achieve a therapeutic effect. The controlled release of
protein drugs is a serious challenge, however, because the fragile nature
and complexity of protein molecules. Protein stability towards the encapsulation
process, during product storage and during in vivo release are critical
issues that must be confronted in order to develop a sustained release
system for a therapeutic protein. Process and formulation strategies addressing
the issue of protein integrity and stability in injectable, biodegradable
polymeric microsphere products will be discussed.
PHARMACEUTICAL INFORMATION AND THE INTERNET
Antony D'Emanuele
School of Pharmacy and Pharmaceutical Sciences, University of Manchester,
Manchester M13 9PL, UK.
The concept of a global computer network originated in the 1970s, however,
prior to the 1990s, the Internet was in a relatively dormant state and
the primary users were the academic community. The surge of interest in
the Internet can be traced to the development of the World Wide Web (WWW)
and the user-friendly interface it presents. The Internet is evolving into
a powerful and global resource for communications and information retrieval.
Despite major developments, the Internet is still in an embryonic state
and there are several important issues to be addressed if it is to realise
its potential. The main issues in the foreseeable future are bandwidth,
hardware requirements, security and indexing of information. Provided these
issues are addressed, the Internet promises to revolutionise the way we
communicate and exchange information. Indeed, the Internet is probably
the most important development in communications since the telephone.
Information retrieval and communication are two important aspects of
the work of pharmacists and pharmaceutical scientists and the Internet
is an ideal medium by which these activities can be facilitated. PharmWeb
has been developed as an information resource on the Internet for medicine,
pharmacy and health-related professions. PharmWeb has been designed to
be interactive and encourages the exchange of information via a range of
technologies including on-line discussion groups. PharmWeb is mirrored
in several countries around the world and has been accessed by over 110
countries. Current access of the UK servers alone is at a rate of approximately
140,000 page requests per month (November 1996).
A review of current developments on the Internet will be presented together
with the pharmaceutical applications of Internet technology.
AN INDUSTRIAL PERSPECTIVE OF GENE THERAPY
Anthony J. Phillips
Glaxo Wellcome
There have been over 4,000 diseases that have been identified as being
caused by defects in genes. In addition, there are acquired diseases, eg
AIDS, that are potential targets.
Gene therapy offers the potential to cure or greatly reduce the symptoms
of a broad range of disease including:
- Gene-related disorders such as severe combined immune deficiency (SCID)
- Heredity-related disorders such as familial hypercholesterolaemia
and cystic fibrosis.
- Viral-related diseases such as AIDS.
- Diseases such as cancer where there is a combination of causes.
The potential to develop better treatments for a wide range of diseases
has created the enormous interest in gene therapy. The possible market
is very large if the technical and market challenges can be met. Challenges
for the successful commercialisation of gene therapy include:
- Systemic vs local delivery.
- Safety issues, particularly when viral vectors are used.
- Efficacy and duration of achievable therapy.
Until comparatively recently, the technology was largely confined to
academia and specialist Biotech companies. The large pharmaceutical companies
have entered the field by strategic alliances with potential utilisation
in CF, oncology and HIV. The development of such products is very different
from that of conventional drugs but more closely associated with biologicals.
Even then there are differences in approach to production of the DNA vector
system, its characterisation and the evaluation of safety.
The issues that face development of these products are as follows:
- Targeting to the cells of interest.
- Transfection with subsequent expression of the desired protein.
- Manufacture at the scale required.
- Demonstration of safety to the satisfaction of the Regulatory Authorities.
The presentation will explore these issues using examples of viral and
non-viral based systems.
