铝合金穿线盒
pH-Responsive Biodegradable Polymers for Intracellular Drug Delivery
A. Proposed area of research
The aim of this proposed PhD project is to develop and evaluate pH responsive, endosomolytic polymers for efficient intracellular delivery of biological drug payloads.
There is a need to better understand the mechanisms of entry into the cell cytoplasm and nucleus in order to design optimal delivery systems for biological molecules. On the one hand, this would open up significant opportunities to deliver potent drug payloads against intracellular targets to positively impact human health. In addition the project aims to develop a more general understanding门牌制作 of the rules governing the uptake of biological molecules into cells. This project proposes to investigate the use of synthetic, biodegradable polymers for intracellular delivery of drug payloads (including siRNA, therapeutic peptide and antibody) against a well-validated intracellular drug target, such as Bcl-2. The novel pH-responsive po
汽水
热交换器lymers have been designed by Dr Rongjun Chen’s Lab to mimic the activity of viruses, both in their cell entry and endosomal escape mechanisms. Using cancer cell lines (Jurkat or HL-60 cells) as a model system, the polymers would be tested with a variety of different biological payloads in a quantitative comparison of their ability to enter the cell and trigger apoptosis and subsequently cell death. With an efficient model system established, there would then be scope to optimize the system in terms of the kinetics and mechanisms of cell entry, cytoplasmic and nuclear localization, and the biodegradation of the polymers. There would also be scope to explore the efficiency in other cell systems and with further intracellular targets. This multidisciplinary project is at the interface of Chemistry, Biology and Medicine, and will provide the student with a real opportunity to be involved in the development and evaluation of new nanomedicines. B. Background
Advances in genomics and proteomics have enabled the development of macrodrugs, such as nucleic acids and proteins, with potential for the treatment of a wide variety of dis
eases. Amongst other problems, their clinical applications may be greatly impaired by low cellular uptake and lysosomal degradation before they can reach their target organelles or cell nuclei. In order to achieve efficient intracellular delivery of such biological molecules, delivery systems are required to enable high cell entry via endocytosis and efficient release into the cytoplasm by endosomal membrane disruption under mildly acidic conditions.
Recombinant viruses and fusogenic viral peptides have been used to mediate gene transfection, but their clinical use is potentially limited by safety issues and difficulties in large-scale production. A variety of synthetic polymers have therefore been developed as non-viral vectors. Cationic polyethyleneimine, poly(2-(dimethylamino)ethyl methacrylate) and polyamidoamine dendrimers mediate gene delivery through the ‘proton sponge’ effect, but suffer from cytotoxicity and relatively low transduction efficiencies. The intensively studied vinyl-based anionic polymers, poly(a-alkylacrylic acid)s, display pH-responsive membrane disruptive behavior, but they are not biodegradable, thus low molecular weights have to be strictly required to allow renal excretion and their clinical ap毛发生长剂
plications are seriously limited.
编织袋折
边器Dr Rongjun Chen’s Lab has recently developed a class of novel, biodegradable, pH-responsive polymers to mimic factors that enable efficient viral transfection, but they are safe, easy to manufacture and have more controllable structures.审批流 The parent polymer is a polyamide, poly(L-lysine isophthalamide), which was based on polycondensation of diacyl chlorides and natural metabolite tri-functional amino acids containing both α- and ω-amine groups. Hydrophobic amino acids and/or poly(ethylene glycol) were grafted onto its pendant carboxylic acid groups to manipulate its amphiphilicity and structure. The metabolite-derived biomimetic polymers can undergo pH-mediated coil-globule changes in conformation. This property enables these polymers to be significantly membrane-disruptive within pH range typical of endosomal compartments, but necessarily non-toxic at physiological pH. Based on previous successful intracellular delivery of the model-drugs such as calcein, dextran (with molecular weight ranging from 3kDa to 70kDa), and therapeutic protein apoptin and siRNA, it is thought that these polymers may be able to deliver a wide variety of different biological molecules (nucleic acids and proteins) into cel
ls for the treatment of various diseases including cancers.
C. Applicant’s work preparation in China
The applicant is an expected bachelor majoring in Polymer Science and Engineering from Beijing University of Chemical Technology (BUCT). After four years of undergraduate studies (2007-2011), I have obtained a strong research background in organic chemistry, polymer physics and chemistry, physical chemistry, etc. Working in the State Key Laboratory of Polymer Physics and Chemistry in the Institute of Chemistry of Chinese Academy of Science for more than half of a year has set up my mind in researching polymer drug carriers. Our group cast our eyes towards synthesizing graft copolymers with amino acids as the main monomers, to create a novel carrier which is both pH and temperature sensitive.
We had synthesized a polymer brush from Z-lysine and 2-Bromoisobutyryl bromide through ring-opening polymerization. Then we grafted specific temperature sensitive residues onto the polymer brush via atomic transfer radical polymerization, followed by ch
aracterization and theoretical analysis of the polymers.
In addition, I was a Research Assistant in the state key laboratory of Beijing University of Chemical Technology, working on the characterization of copolymers by NMR. I was also a Research Assistant in the Environmental Materials Laboratory of China Building Materials Academy, working on synthesis of FEVE coating. These research experiences have enriched my knowledge and experimental skills for polymer synthesis and enabled me to operate many facilities deftly, such as NMR, GPC, FTIR, vacuum glove box and rotary evaporator.
In the summer of 2010, I was selected to attend the program “BUCT-Cambridge Summer School” in the University of Cambridge. During the three weeks in the UK, I visited the Department of Chemical Engineering and Biotechnology and did experiments relevant to my research its labs. In Cambridge, I also did a case study about the biopharmaceutical market. This deepened my understanding of commercial prospects of drug delivery technologies, such as the demands of different patients for drug delivery systems and co
mpetitiveness of different health testing equipments. Besides the University of Cambridge, I also visited the University of Oxford, Imperial College London, University of Birmingham, and University of Loughborough. I also established the contact with Dr Rongjun Chen who is the Group Leader of Biomaterials and Drug Delivery Group at the University of Leeds when I was in the UK, and have been communicating with him via emails since then, discussing about polymer synthesis and characterization and drug delivery research.
