ABSTRACT
This thesis is focused on fabrication of biodegradable implantable
devices for extended localized drug release. Paclitaxel (PT) was used as
cancer drug in the study. Poly lactic –co- glycolic acid (PLGA) is a
polymer used for drug elution. In this work, the role of enzymes on the
degradation of PLGA, Effect of different pH on the degradation of PLGA
and the kinetics of drug release was elucidated. PLGA ratios of 75:25
and 85:15 were used. The enzyme used in the study is lipase enzyme. The
pH used was 4.0, 6.0, 6.5, 7.0 and 7.4. From the study, it was observed
that lipase enzyme increased the rate of polymer degradation and thus
the rate of drug release from PLGA. This experiment also shows that PLGA
degrades faster in acidic medium. This also caused the kinetics of drug
release to be higher in acidic medium than in alkaline or neutral
medium.
Chapter One
1.0 Introduction
In 2008, the World Health Organization (WHO) estimated all global
deaths arising from cancer to be up to 84 million (WHO, 2008). In recent
years, the increasing incidence of cancer has been associated with high
cancer mortality rates across the globe (WHO, 2014). It was also
reported that the different types of cancer causes more deaths than
those due to HIV/AIDS, tuberculosis and malaria all combined (WHO,
2014). In any case, early detection and improved treatment are crucial
for a successful management of cancer (Anand P et al., 2008).
However, it is difficult to detect breast cancer at the early stages.
This causes late detection and reduces the chances of effective
treatments especially for cases in which the metastatic stage, before
detection.
Furthermore, the current cancer treatment methods such as bulk
systemic chemotherapy (American Cancer Society (ACS), 2013; Kushi et al., 2012; Parkin et al.,
2011; WHO, 2014) and radiotherapy (Gotzsche and Jorgensen, 2013;
National Cancer Institute (NCI), 2014) have severe side effects. Such
severe side effects can be reduced by a sustained and controlled release
of cancer drugs into regions containing cancer cells/tissue (NCI, 2014;
WHO 2014). There is, therefore, a strong interest in the localized
delivery of cancer drugs from implantable drug delivery systems (NCI,
2014; WHO 2014WHO, 2014; Dubas and Ingraffea, 2013). Recent work focused
on the development of implantable non-resolvable systems for cancer
drug delivery (ACS, 2014). However, such systems remain in the body, or
require surgical removal, after drug release. Hence there is a need for
resorbable structures for the controlled release of cancer drugs (Cakir et al., 2012; Jemal et al.,
2011; ACS, 2013; WHO, 2014) to tumor regions. Such resorbable
structures have been studied over the past decade (ACS, 2014), using
biodegradable polymers that facilitate the controlled release of cancer
drugs. These include polymers, such as poly (lactic-acid) (PLA) and
poly(glycolic-acid) (PGA), and their copolymers (PLGA)
Biodegradable microparticles have also been formulated from PLA or
PLGA for controlled drug release (National Cancer Institute, NCI, 2013).
PLA or PLGA have also been shown to be biocompatible and biodegradable
(NCI 2013; Hanahan and Weinberg, 2000). Furthermore by altering their
molecular weight, sample size and surface morphologies (Hanahan and
Weinberg, 2011) well-defined degradation rates can be achieved and used
to control the release of encapsulated therapeutic agents. This will be
explored in the current study of minirods of PLGA that encapsulate
PT.The degradation and drug release kinetics are studied using a
combination of optical microscopy and UV-Vis spectrophotometry. The
implications of the results are also discussed for the development of
resorbable/implantable devices for multipulse cancer drug delivery