Authors:	Chen, Mingjia
Advisor:	Butt, Hans-Jürgen
Title:	Photo activated ruthenium-containing polymer micelles to overcome multidrug resistance
Online publication date:	7-Dec-2023
Year of first publication:	2023
Language:	english
Abstract:	Cancer is one of the leading causes of human death in the world. Although significant improvement has been made in chemotherapy for cancer treatment, complete regression is still challenging. A great obstacle in chemotherapy is the acquired resistance when chemotherapeutics are used, inducing tumor recurrence and therapeutic failure. A main mechanism of multidrug resistance (MDR) is via expression of drug efflux transporters on the surface of tumor cells such as permeability glycoprotein (P-gp). They not only inhibit the uptake of chemotherapeutics, but also pumps them out from tumor cells. Moreover, high systemic toxicity of chemotherapeutics is another problem that hurdles the clinical treatment of cancer. The development of nanocarriers brings new hope for chemotherapy. They exhibit a long circulation time in the bloodstream and can deliver drugs to tumor cells through nanotechnology-mediated passive or active targeting. What is important, in the process of uptake: nanocarriers can bypass P-gp so that the drugs are not recognized by P-gp as substrates. Thus, the drugs escape from the capture of the transporters, allowing a high intracellular drug accumulation. Although substantial progress has been made using nanocarriers, the entire eradication and cure of cancer remains a challenge. Nanocarriers need combine with other strategies to overcome MDR. Compared to other external stimuli, light-triggered drug release has the potential advantage of its noninvasive nature and ease of spatiotemporal control. Most phototherapy studies used ultraviolet (UV) light or short-wavelength visible light to trigger the release of drugs. However, the depth of light penetration into tissue depends on the wavelength. When setting the the same light intensity, the light penetrates only ~1.00 mm at wavelength of 408 nm, but ~6.3 mm at wavelength of 633 nm and ~7.5 mm at wavelength of 705 nm. UV light or short-wavelength visible light not only shows limited penetration depth into tissue but also has the risk of photodamage to biological systems. In contrast, red or near infrared radiation (NIR) light can penetrate deeper into tissue and cause less photodamage, which is more suitable for in vivo applications. The success of platinum (Pt) complexes such as cisplatin in cancer treatment motivates the development of new metallodrugs. Some Ruthenium (Ru) complexes are promising metallodrugs for anticancer therapy. More than three of them are in clinical trials. Photoactivation is a way to improve selectivity of Ru complexes in cancer therapy. Some of them are responsive to red or NIR light. The successful delivery of photoactivatable Ru complexes to cancer cells requires that they must be stable in the dark under physiological conditions. However, the ligands of photoactivatable Ru complexes may be substituted by water and biomolecules such as dissolved proteins before they are delivered to cancer cells. Therefore, the question arise: what need to do for overcoming MDR of cancer cells more efficiently? Combined nanocarriers with phototherapy of Ru complexes using red light may settle this problem. The aim of this thesis is a prerequisite to answer the question, namely to improve the stability of photoactivatable Ru complexes under physiological conditions. In this thesis, I first systematically studied the stabilities of two Ru-containing block polymers and their corresponding Ru complexes under imitated physiological conditions. I concluded from results that in the different media, the corresponding Ru complexes were stabilized by their Ru-containing polymer assemblies, which made these assemblies potential candidates for biomedical applications. Then, red-light-triggered Ru-containing block copolymer (PEG-b-P(CPH-co- RuCHL)) micelles with doxorubicin (DOX) encapsulation (DOX@PEG-b-P(CPH-co- RuCHL)) were designed. Red light induced the destruction of DOX@PEG-b-P(CPH- co-RuCHL) micelles, resulting in the release of Ru complexes and DOX simultaneously. Finally, DOX@PEG-b-P(CPH-co-RuCHL) micelles were used to overcome MDR. After bypass P-gp, DOX@PEG-b-P(CPH-co-RuCHL) micelles were accumulated in drug-resistant Michigan Cancer Foundation-7 (MCF-7R) breast cells. The intracellular release of DOX was controlled by red light. Deoxyribonucleic acid (DNA) damage was caused via DOX interacted with DNA by intercalation and Ru complexes crosslinked with DNA by photobinding. I also studied the effect of overcoming MDR in vitro and in vivo. DOX@PEG-b-P(CPH-co-RuCHL) micelles that were activated by red light irradiation induced the significant death of MCF-7R cells and the excellent inhibition of the growth of MCF-7R tumor. I believe that the design of the controlled release of dual drugs from red-light-responsive Ru-containing polymer micelles will open up an avenue for photochemotherapy to overcome MDR.
DDC:	540 Chemie 540 Chemistry and allied sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-9724
URN:	urn:nbn:de:hebis:77-openscience-7bdeba04-73da-4308-9c83-cf3c52eb19574
Version:	Original work
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	http://rightsstatements.org/vocab/InC/1.0/
Extent:	V, 96 Seiten ; Illustrationen, Diagramme
Appears in collections:	JGU-Publikationen