The 2000 Glaxo Wellcome international achievement award was presented to Professor Robert Langer (Massachusetts Institute of Technology) on September 10. In his award leture, Professor Langer described advances in drug delivery and tissue engineering
The view in the late 1970s had been that polymers could only be used for the
slow release of small molecules, Professor Robert Langer (Massachusetts Institute
of Technology) told the meeting. However, his group’s initial studies had
shown that polymers could be used to deliver large molecules, for example, catalase,
which has a molecular weight of around 250,000.
Proteins had poor permeability through polymers, and for them to be administered
over long periods, they would need to be in an unaltered form and protected
from harm. Professor Langer’s work had involved the development of hydrophobic
polymers that could be used to achieve slow release of therapeutic agents.
One example of his group’s approach had been to use a hydrophobic polymer,
such as ethylene-vinyl acetate or poly(lactic-co-glycolic acid), dissolved in
organic solvent, and then mixed at low temperature with the protein intended
for delivery. Microspheres in which the protein was encapsulated were produced
once the solvent had been evaporated off. At first, the systems that had been
developed produced only quick bursts of drug release, but using modelling approaches
Professor Langer’s group had been able to determine how controlled release
over 50 to 100 days could be achieved.
Insulin delivery
Studies in vivo had demonstrated that polymers could be used to deliver insulin.
Raised plasma glucose concentrations in diabetic rats treated with the insulin-polymer
system had fallen to concentrations similar to those for a control group of
non-diabetic rats, whereas plasma glucose concentrations in untreated diabetic
rats had remained high.
An oscillating magnetic field could be applied to the polymer system, which
had the effect of squeezing out more drug through the pores in the polymer.
This had been demonstrated in diabetic rats in which a polymer delivery system
for insulin had been implanted under the skin. Exposure of these rats to an
oscillating magnetic field had achieved an in vivo response in terms of lowered
plasma glucose concentrations.
This work had led to the development of a prototype device — a microchip
— for the controlled delivery of drugs. The device comprised a silicon
wafer with drug wells on one side covered by a thin layer of gold (which had
been applied by techniques such as photolithography). The application of a slight
voltage (1V) caused the gold to dissolve in around 10 seconds. The device had
been designed so that each well could be released individually. Potentially,
different drugs or doses could be contained in different wells and could be
released at different times, said Professor Langer.
Working on the basis that approximately one gram of drug could be held in a
cubic centimetre, and that a system of that size could be administered to a
patient, it was estimated that such a device could be used to deliver one thousand
0.5mg doses.
Remote control delivery
It was possible that the process could ultimately be regulated by remote control
using pre-programmed devices or, in the future, as better biosensors were developed
it might be possible to build a whole self-regulated system. “That’s
the direction we are trying to head in,” Professor Langer said.
Professor Langer went on to discuss the development of polymers that underwent
surface erosion (ie, in a similar manner to the erosion seen with a bar of soap)
and which could be used for controlled drug delivery. They had developed very
hydrophobic polyanhydrides, such as a copolymer of carboxyphenoxypropane and
sebacic acid. What was particularly exciting about this copolymer was that its
erosion could be controlled by altering the sebacic acid content — the
higher the sebacic acid content, the greater the degradation. For example, with
0 per cent sebacic acid, only 8 per cent of the polymer would have dissolved
in 14 weeks, whereas with 79 per cent sebacic acid, almost all of the polymer
would dissolve within two weeks.
Professor Langer’s group had begun to explore these systems for several
applications. One was the development of delivery systems for carmustine, a
highly toxic drug used in the treatment of glioblastoma multiformae, a severe
form of brain tumour where patients had a mean survival time of less than one
year.
His group had considered whether polymer-protected carmustine could be given
locally towards the end of brain surgery to remove the tumour. Their approach
was to line the patient’s surgical cavity following brain surgery with
dime-sized discs of a surface-degrading carmustine-polymer delivery system.
This method of drug delivery had two advantages. First, carmustine would be
protected from degradation (carmustine has a half-life of 12 minutes following
intravenous administration) and the rate of release could be controlled by adjusting
the ratio of the polymer components. Second, a high concentration of the drug
would be delivered locally, thus largely avoiding the exposure of non-tumour
cells to carmustine and reducing the possibility of adverse effects. The treatment
had been tested in phase three clinical trials and had achieved good survival
rates, compared with those seen for patients in a control group.
Summing up this work, Professor Langer said that his group had found solutions
to several problems that others had said could not be overcome, including:
Tissue engineering
Biodegradable polymers could be used to deliver human cells, said Professor
Langer.
Tissue engineering techniques had been used to make a small diameter (<6mm)
capillary tube. The process had involved the use of modified polyglycolic acid
tubes, with a high attachment density, cultured for eight weeks with smooth
muscle cells added to the outside of the tubes. Endothelial cells had been added
to the inside to give the system blood compatibility.
The way the cells were grown was central to getting the process to work, said
Professor Langer. His group’s approach had been to connect up the cell
culture system to a pulsatile pump beating at 165 beats per minute, thus mimicking
an embryonic heart (without this pulsatile radial system, the blood vessels
had fallen apart). Using this approach, vessels with a diameter of 3mm and the
same properties (eg 50 per cent collagen content, rupture strength of >2000mm
Hg) and pharmacology as those of normal blood vessels, could be produced. Angiography
performed several months after insertion of tissue-engineered blood vessels
into pigs, had shown that the vessels were still patent.
Other examples of Professor Langer’s work in this field had included engineering
“new” ears using cartilage cells and a polymer scaffold moulded in
the shape of a human ear, and new skin for burns victims using a polymer system
and neonatal dermal fibroblasts.
A future potential application was the use of this type of system for patients
who had been paralysed. His group had developed a system that involved neuronal
stem cells and oriented polymer fibres to provide axonal guidance. This polymer-stem-cell
system had been tested in rats paralysed by removing a part of the spinal cord.
Rats in which the excised part of the spinal cord had been replaced by the polymer-stem-cell
system had been able to walk, whereas control rats had continued to be paralysed.
Concluding, Professor Langer remarked that some people might not immediately
see what relevance tissue engineering had to pharmacy. In his view, it was relevant
in many ways. The delivery of drugs and growth factors was key in achieving
vascularisation of tissues for transplant, which was a particular issue in tissue
engineering. Professor Langer was presented with his award by Dr Rosemary Leak
(Glaxo Wellcome) (PJ, September 16, p403).