THESIS
2018
xxi, 127 pages : illustrations (some color) ; 30 cm
Abstract
Micro/nanobubbles have been widely developed as theranostics for a variety of biomedical
applications, such as contrast ultrasound imaging, cancer detection, and imaging-guided drug
delivery. The sonoporation and the formation of openings in the vasculature, induced by
ultrasound-triggered oscillations and destruction of microbubbles offer extra benefits for drug
delivery. Besides, micro/nanobubbles hold great potential to overcome hypoxia in solid tumors
which significantly compromises therapeutic outcomes. However, current microbubbles suffer
from the stability issues and polydispersed populations which still limit their applications in
imaging and therapy. Therefore, monodisperse and stable micro/nanobubbles are still highly
desired.
First, we develop a microfluidic flow foc...[
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Micro/nanobubbles have been widely developed as theranostics for a variety of biomedical
applications, such as contrast ultrasound imaging, cancer detection, and imaging-guided drug
delivery. The sonoporation and the formation of openings in the vasculature, induced by
ultrasound-triggered oscillations and destruction of microbubbles offer extra benefits for drug
delivery. Besides, micro/nanobubbles hold great potential to overcome hypoxia in solid tumors
which significantly compromises therapeutic outcomes. However, current microbubbles suffer
from the stability issues and polydispersed populations which still limit their applications in
imaging and therapy. Therefore, monodisperse and stable micro/nanobubbles are still highly
desired.
First, we develop a microfluidic flow focusing approach to produce monodisperse
microbubbles stabilized by poly (lactic-co-glycolic acid) as the polymer shell. The size and size
distribution of polymer microbubbles can be tightly controlled for ensuring highly
homogeneous echogenic behavior of the bubbles in ultrasound fields. Both in vitro and in vivo
experiments showed that the monodisperse polymer microbubbles had excellent echogenicity
and elongated sonographic duration time (>3 times) for ultrasound imaging in comparison with
the commercial lipid microbubbles.
Second, we designed an ultrasound-responsive stable oxygen microbubble to sensitize
hypoxic areas in solid tumors for the brachytherapy. A modified emulsion freeze-drying method
was developed to prepare microbubbles that could be lyophilized for storage and easily
reconstituted in situ before administration. The filling gases of the microbubbles were modified
by addition of sulfur hexafluoride into oxygen so that the obtained microbubbles achieved ~3
times higher in half-life time and greatly enhanced ultrasound contrast. The post-treatment
results of the brachytherapy combined with ultrasound-triggered microbubbles revealed ~1.15
times decrease in tumor growth rate, compared to the brachytherapy alone, manifesting
ultrasound-mediated oxygen delivery with oxygen microbubbles as a promising strategy to
improve the therapeutic outcome of the brachytherapy on hypoxic tumors.
Besides, we developed a lipid-polymer bilaminar oxygen nanobubble with chlorin e6 (Ce6)
conjugated to the polymer shell as a novel self-oxygen supplement photodynamic therapy (PDT)
platform. The resultant nanobubbles showed excellent stability to reduce risk of premature
oxygen release and were stored as freeze-dried powders to avoid shelf storage issues. In vitro
and in vivo experimental results demonstrated that the nanobubbles exhibited much higher
cellular uptake rate and tumor targeting efficiency compared to free Ce6. Using the oxygen
nanobubbles for PDT, a significant enhancement of therapeutic efficacy and survival rates was
manifested on C6 glioma tumors with no noticeable side effect thanks to the greatly enhanced
single oxygen generation powered by oxygen encapsulated in nanobubbles.
This thesis presents novel fabrication methods of monodisperse microbubbles and exploits
the application of micro/nanobubbles to tackle the hypoxia in the solid tumors which haunts
many therapeutic modules. We believe our work surely has shed new light on the treatment of
tumors with improved therapeutic outcomes.
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