Biomimetic nanoscale systems for pH-triggered intracellular drug delivery
File(s)
Original Permission documents for copyright
PhD Thesis
Author(s)
Chen, Siyuan
Type
Thesis
Abstract
Efficient intracellular delivery remains a major challenge for non-viral delivery systems. Insufficient endosomal escape leads to enzymatic degradation of bioactive compounds in lysosomes. This thesis presents the work involving the development of a series of biomimetic nanoscale systems for pH-triggered intracellular drug delivery.
A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus via surface modification of cholesterol-containing liposomes with L-phenylalanine grafted poly(L-lysine isophthalamide) (PLP). Desirable pH-triggered liposomal release behavior was achieved by controlling key parameters. The pH-triggered, reversible liposomal size change was observed and the release mechanism was elucidated. The endosomal-escape ability, intracellular delivery efficiency and cytotoxicity of this system loaded with an anticancer drug, doxorubicin (DOX), were further evaluated and compared to conventional liposomes and free drugs.
A library of novel, pH-responsive, comb-like polymers were synthesized by grafting PLP with different lengthed alkyl chains which act as membrane anchors. The effects of the hydrophobic alkyl side chains on pH-responsive aqueous solution properties, cell membrane destabilization activity and in vitro cytotoxicity were investigated. The optimal polymer was almost non-hemolytic at pH 7.4, but induced nearly complete destabilization of red blood cell membrane at endosomal pH. The mechanism of membrane destabilization was investigated.
The optimal comb-like pseudopeptidic polymer displayed a superior endosomal-escape ability to release endocytosed materials into the cytoplasm of various cell lines compared to its parent polymer PLP. When the extracellular environment was mildly acidic, the intracellular delivery was considerably enhanced. The effect of side chain length, polymer concentration, treatment time, extracellular pH, serum and payload size on the delivery efficiency were systemically investigated. A variety of cell types, including stem cells and multidrug resistant cell line, were employed to explore its wide applicability in drug delivery.
The optimal membrane-anchoring, comb-like polymer was further employed to develop a novel multifunctional liposomal delivery platform. The pH-responsive hybrid liposomes were characterized and their pH-dependent drug release profiles were examined. The intracellular delivery of DOX-loaded multifunctional liposomes and their cytotoxic effects toward four different cancer cell lines were evaluated.
A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus via surface modification of cholesterol-containing liposomes with L-phenylalanine grafted poly(L-lysine isophthalamide) (PLP). Desirable pH-triggered liposomal release behavior was achieved by controlling key parameters. The pH-triggered, reversible liposomal size change was observed and the release mechanism was elucidated. The endosomal-escape ability, intracellular delivery efficiency and cytotoxicity of this system loaded with an anticancer drug, doxorubicin (DOX), were further evaluated and compared to conventional liposomes and free drugs.
A library of novel, pH-responsive, comb-like polymers were synthesized by grafting PLP with different lengthed alkyl chains which act as membrane anchors. The effects of the hydrophobic alkyl side chains on pH-responsive aqueous solution properties, cell membrane destabilization activity and in vitro cytotoxicity were investigated. The optimal polymer was almost non-hemolytic at pH 7.4, but induced nearly complete destabilization of red blood cell membrane at endosomal pH. The mechanism of membrane destabilization was investigated.
The optimal comb-like pseudopeptidic polymer displayed a superior endosomal-escape ability to release endocytosed materials into the cytoplasm of various cell lines compared to its parent polymer PLP. When the extracellular environment was mildly acidic, the intracellular delivery was considerably enhanced. The effect of side chain length, polymer concentration, treatment time, extracellular pH, serum and payload size on the delivery efficiency were systemically investigated. A variety of cell types, including stem cells and multidrug resistant cell line, were employed to explore its wide applicability in drug delivery.
The optimal membrane-anchoring, comb-like polymer was further employed to develop a novel multifunctional liposomal delivery platform. The pH-responsive hybrid liposomes were characterized and their pH-dependent drug release profiles were examined. The intracellular delivery of DOX-loaded multifunctional liposomes and their cytotoxic effects toward four different cancer cell lines were evaluated.
Version
Open Access
Date Issued
2017-03
Date Awarded
2017-05
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
License URL
Advisor
Chen, Rongjun
Sponsor
Imperial College London
Publisher Department
Chemical Engineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)