Cancer is the second leading cause of death and still threaten our human health. The metastasis and recurrence are the main cause of cancer related death, while the conventional adjuvant therapies after the surgery face with the problem of unsatisfied selectivity and passive release. This study has developed a drug carrier with specific mechanical and structural conditions which could selectively capture and eliminating residual cancer cells in the normal tissues surround the lesion, aimed for a better postoperative treatment.
In chapter 2, a fibrous gel matrix with independently tunable mechanical and structural factors was developed by electrospinning then photo-crosslinking and swelling.
The mechanical factor, i.e. fiber elasticity, was controlled by photo-crosslinking condition;
while the structural factor, i.e. matrix porosity, was controlled by compression rate. Due to the stiffness-dependent modulation of cell adhesivity, the differences in deformability between cells and the pore size related cell phenotype changes, tumorigenic cells MDA-MB-231 exhibited the highest MMP-independent invasion into matrix composed of fibers with mean Young’s modulus of 20 kPa in the presence of enough void space; while non-tumorigenic cells MCF-10A did not invade a matrix with the same mechanical and structural conditions.
In chapter 3, based on the obtained mechanical/structure condition, a drug-loaded fibrous gelatinous matrix was developed for selectively capturing and eliminating cancer cells, for reducing passive release and enhancing selectivity. Due to unchanged invasion tendency of cells, drug-loaded matrix with optimized mechanical/structure condition could selectively captured and separated MDA-MB-231 cells from MCF-10A cells. With limited passive diffusion of hydrophobic anticancer drug, this matrix exerted a gradually anticancer effect only on invaded MDA-MB-231 cells and had a reduced toxic effect on normal MCF-10A cells.
In chapter 4, the above-mentioned matrix was embedded into collagen gel to mimic
matrix, the potential of gelatin as the chemoattractants was confirmed by transwell experiment, which could induce the migration of MDA-MB-231 cells. Furthermore, induced migration of MDA-MB-231 cells was confirmed in collagen gel model with concentration gradient in the gel. Finally, these migrated cells were captured by StG matrix with soft fiber elasticity as expected, demonstrated the potential application in cancer treatment.
Acknowledgement
First, I would like to express my deep gratitude to my supervisor, Prof. Satoru Kidoaki, for his support and encouragement throughout the period of my stay in Kyushu University. I am grateful for his willingness to share his knowledge and I benefit a lot from every discussion with him, all of those will be my precious wealth. The professional and hard-working spirits will always be a role model in my future life. It is my great honor to be his student.
Secondly, I would like to thank my referees: Prof. Yoshiki Katayama and Prof.
Noriho Kamiya for their precious time to review the thesis.
Thirdly, I would like to give my acknowledgement to all the members of the laboratory. I would like to thank Assoc. Prof. Hirohiho Ise, Assoc. Prof. Thasaneeya Kuboki. Dr. Hiroyuki Ebata, Dr. Kosuke Moriyama, Dr. Saori Sasaki and Dr Ayano Fujita, for their kindly advice on my study. I would like to thank technical staffs, for their assistance on the experiment. I would also like to thank all the students in laboratory.
In addition, my thanks go to my parents. They inspire me to follow my dreams no matter what happens, encourage me in all my pursuits selflessly.
Finally, I am grateful to the scholarship provided by the Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT).
Fukuoka, Japan Daoxiang Huang 2019
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