Assembles And Applications Of PH-Sensitive And Photothermal-Responsible Amphiphilic Diblock Copolymers

The self-assembly of stimuli-responsive amphiphilic diblock copolymers have caused an increasing attention among researchers attribute to their ability to self-assembly into various microstructures, such as nanoparticles, rods, discs, polymersomes, compound vesicles and so on. Different structures have different defects and advantages. For example, polymersomes and compound vesicles are often used to synchronically load with both hydrophilic and hydrophobic payloads, which could highly enlarge the application of these structures. Furthermore, using the special characters of cancer and tumor cells like pH, ionic intensity or external stimulus including laser irradiation, temperature, electronic and magnetic fields to trigger the changes in chemical structures of polymers could also induce the structure changes of those self-assemblies. In this dissertation, some systems which can use above properties were studied and applied them in the drug delivery system. This dissertation includes the following parts:1. The fabrication of pH-responsive polymersomes via supramolecular self-assembly of amphiphilic diblock copolymers, PEO-6-PTTAMA, which were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization of pH-responsive TTAMA monomer using a PEO-based macroRAFT agent was reported. The resultant amphiphilic diblock copolymer could self-assemble into polymersomes, which are relatively stable under neutral pH, whereas they undergoes spontaneous hydrolysis with the liberation of hydrophobic 2,4,6-trimethoxybenzaldehyde small molecules and the simultaneous generation of hydrophilic diol moieties upon exposure to acidic pH milieu. Additionally, the enhanced bilayer permeability of the polymersomes due to the pH-triggered degradation was also confirmed by enzyme-activated fluorogenic reaction with turn-on emission, where the enzyme and its corresponding substrate were initially spatially segregated by the bilayers of polymersomes, exhibiting negligible fluorescence emission. After encapsulating hydrophobic model drug (Nile red) and hydrophilic chemotherapeutic drug (doxorubicin hydrochloride, DOX·HC1) within the bilayers and aqueous interiors of the polymersomes, controlled release of Nile red and DOX·HC1 payloads were achieved by facilely tuning the solution pH values. In vitro experiments, the pH-responsive polymersomes were readily taken up by HeLa cells and mainly located in the acidic organelles after internalization, where the pH-responsive cyclic acetal moieties were hydrolyzed and the embedded payloads were therefore released, allowing for on-demand release of the encapsulants regulated by intracellular pH.2. Acid-responsive amphiphilic polyprodrug, PEO-6-PCMA, which contain cyclic benzylidene acetals and cinnamaldehyde were synthesized. The resultant polyprodrug could self-assemble into nanoparticles and load hydrophobic drug CPT. The nanoparticles are relatively stable under neutral pH, whereas they undergoes spontaneous hydrolysis with the liberation of cinnamaldehyde and hydrophobic CPT upon exposure to acidic pH milieu. The vitro experiments showed that these nanoparticles were readily taken up by HepG2 cells and mainly located in the acidic organelles after internalization, where the acid-responsive cyclic acetal moieties were hydrolyzed and the embedded payloads were therefore released, allowing for on-demand release of cinnamaldehyde and CPT and kill HepG2 cells more effectively than those non-polyprodrug system.3. The amphiphilic diblock copolymer bearing urea bond, PEO-6-PDiPBMA, self-assembled into compound vesicles consisting of hydrophilic PEO coronas and thermal-responsive hydrophobic bilayers. The compound vesicles containing urea bond in the hydrophobic bilayers were relatively stable under room temperature, whereas they underwent hydrolysis with the generation of primary amine upon incubation under high-temperature environment. By loading hydrophobic photothermal agent (ICG) as well as hydrophilic chemotherapeutic drug (camptothecin, CPT), the subsequent release of CPT payloads was remarkably regulated by the laser irradiation time, and a longer irradiation led to a faster drug release profile. In vitro experiment revealed that the compound vesicles were easily taken up by HepG2 cells and were primarily located in the endolysosome after internalization. Once the HepG2 cells were irradiated under 808 nm laser, the urea bond moieties could be hydrolyzed and the embedded payloads were therefore released, allowing for on-demand release of the encapsulants mediated by laser irradiation. Significantly, both photothermal therapy and chemotherapy can be combined to kill cancer cells in this system.