Traditional drug treatment involves the introduction
of substances into the bloodstream, which then circulate through
the entire body in search of their target organs - a rather hit-and-miss
approach. More recently, drug delivery systems have been developed
based on the principles of antigen-antibody interaction, whereby
specific molecular forms are recognised and taken up selectively
by only specific organs. Such 'smart' systems improve the therapeutic
indices of drugs immensely, allowing a significant reduction in
both therapeutic dosages, side effects and health-care costs.
This project focused on the production of nanocapsule delivery systems
from biodegradable and bioerodable polymers with well-balanced hydrophilic/hydrophobic
characteristics. These were found to be best suited to the loading
of proteic drugs and to the targeting of specific biochemical receptor
sites. The targeting ability of synthetic nanocapsules, that is
their ability to deliver their contents to specific sites within
the body, depends to a large extent on their surface characteristics,
which have to be carefully selected and designed.
Prior to the preparation of the polymeric systems,
toxicological screening and selection of the best-suited materials
were carried out. Hybrid combinations of synthetic and natural polymers
appeared extremely well suited to incorporating peptide and proteic
drugs in desirable doses and were very versatile with respect to
the production of nanocapsules.
Nanocapsules were produced displaying good dimensional and shape
uniformity, morphological and physical integrity and suitability
for pharmaceutical processing into injectable dosage forms. The
manufacturing process, via a simple and novel a laboratory-scale
procedure, can be easily scaled up for industrial-scale production.
Surface modification was then carried out to impart targeting attributes
through three-dimensional molecular dynamics modelling.
The prepared hybrid mixes, the individual components and the finished
nanocapsules themselves were all found to be substantially safe
in preliminary in-vitro and in-vivo toxicology studies. Further
test results, such as those from the biodistribution of soluble
radiolabelled nanocapsules, indicated that the prepared systems,
once injected into the blood stream, targeted the hepatocyte receptors
- that is, the elective targeting site.
Kinetic studies on the release of active components or mimicking
proteins carried out on nanocapsules under different conditions
showed the systems to be of the prolonged-release type, with a satisfactory
life time in the blood stream and maintenance of good activity levels.
Further clinical testing is now under way to confirm the safety
of these delivery systems.
Implications and benefits
The project partners describe the new treatment
as intelligent nanocapsules for targeting the delivery of proteic
drugs for treating cancer, hepatitis C and other socially paramount
diseases. A significant increase in the therapeutic index of powerful
protein drugs and the ability to target specific organs will mean
a great improvement in clinical therapy, improving quality of life
for patients, reducing side effects and, of course, significantly
reducing both social and medical expenses.
The use of such systems could be beneficial in a wide range of pharmaceutical
applications outside of those already mentioned. For example, their
use in radiotherapy would allow the reduction of dangerous isotopic
dispersion throughout the body. Finally, the increasing replacement
of synthetic drugs by natural protein-based ones could lead to a
reduction in environmental pollution by the pharmaceutical industry.
The potential global market for human
leukocyte alpha interferon has been estimated at about 300 million
euro over the next ten years. Further estimates show a competitive
product of the type described obtaining a 7 to 10% share representing
about 30 million euro over the same period.
The follow-up research ongoing at the Istituto Sierovaccinogeno
Italiano SpA and the University of Pisa, is aiming to refine and
standardise production procedures for nanoparticles suited to the
administration of alpha interferon and other drugs.