Cancer is still a major public health challenge worldwide in 2023, despite the progress madein its treatment. Some types of cancer, like liver cancer and uveal melanoma, still have
poor survival rates, and metastasis, the spread of cancer to other parts of the body, poses
significant challenges for effective management and control. Innovative therapies such as
targeted therapies and immunotherapies have shown promising results in treating various
types of cancer, and further research and development in this field are crucial to addressing
the challenges posed by cancer. One of the innovative therapies is the use of microbubbles
for targeted cancer therapy. Microbubbles can be activated using ultrasound, causing them
to rupture and release therapeutic agents like chemotherapeutic drugs at the tumor site.
Additionally, microbubbles can create temporary pores in the cell membrane, enhancing the
delivery of therapeutic agents to the tumor site. Despite their potential, using microbubbles
for targeted cancer therapy poses several challenges. One major challenge is their stability
and loading capacity, which can reduce their effectiveness in delivering the targeted drug.
Another challenge is producing a monodisperse population of microbubbles, crucial in targeted cancer therapy to improve their circulation and interaction with tumor cells.
Ongoing research is focused on optimizing the design of microbubbles and exploring their potential
in combination with other therapies for a wide range of cancer types. This dissertation
addresses the primary challenges of using microbubbles for theranostic applications by: (i)
creating a simple and effective process for producing stable and monodispersed single emulsion microbubbles (SEBs) using droplet microfluidic technology (ii) creating a simple and
effective process for producing stable double emulsion microbubbles (DEBs) using a microfluidic flow-focusing platform (iii) enhancing the stability and functionality of DEBs by
incorporating a gold nanoparticle (GNP) protective shell.
First, a microfluidic device is designed and optimized to produce monodisperse and stable
single-layer microbubbles. Additionally, a portable and automated gas saturation unit is
introduced to saturate the phospholipid solution with the C4F8 gas before each experiment,
a critical step for the monodispersed production of microbubbles. Our results indicate that
using a microfluidic platform, bubbles with a monodispersity as low as 3% can be produced,
a significant improvement compared to commercial microbubbles with a PDI that can vary
between 20-50%. Two commonly used phospholipid formulations are explored, and the short-
term and long-term stability of the resulting microbubbles are compared. The long-term
stability of the microbubbles is also investigated in RPMI solution, a common cell culture
medium. Our results show that the bubbles produced using the optimized phospholipid
solution from the previous section remain stable inside RPMI and at 37°C for up to eight
days. The effects of flow parameters on SEB size for the chosen phospholipid formulation
are also examined.
Secondly, to address the need for a simple and effective process for producing monodisperse
and stable microbubbles with higher drug loading capacity, a microfluidic device is designed
and optimized to generate highly monodispersed, phospholipid-stabilized oil-shell microbubbles using the optimized phospholipid formulation from the first step. Additionally, the
stability and microstructural evolution of these microbubbles are investigated by microscopy
and machine-learning-assisted segmentation techniques at different phospholipid and gold
nanoparticle concentrations. The double-emulsion microbubbles, formed with the combination of phospholipids and gold nanoparticles, are equipped with a protective gold nanoparticle
shell that is not only acting as a steric barrier against gas diffusion and microbubble coalescence but also alleviating the progressive dewetting instability and the subsequent cascade
of coalescence events. The research findings indicate that the addition of GNPs to the lipid
solution mixture leads to a more than 17-fold increase in the concentration of DEBs that
remain in the sample after 60 minutes. Moreover, when GNPs are added to the phospholipid
mixture, the number of dewetted oil droplets decreases by over 50%.