Imitation Of The Membrane Structure Of Polymer Cross-linked Micelles And Its Application

Recently, amphiphilic polymeric micelles as potential nanometer-sized drug delivery vehicles for enhanced therapeutic efficacy and reduced systemic toxicity have aroused extensive attention. However, the assembled architecture is formed under the driven of certain physical interaction, but no covalent linking. A fundamental limitation facting their intravenous application is the dissociation of core-shell micellar structures in physiological environment, especially upon highly dilution in the bloodstream. On the other hand, most of the hydrophobic or charged materials are rapidly cleared from systemic circulation by the mononuclear phagocyte system (MPS), which is thought to be preceded by the absorption of serum proteinaceous molecules to the surface of polymeric nanoparticles. Therefore, the design of prolonged circulating nanomicellar drug carriers with enhanced stability and good biocompatibility is the current crucial objective.In this thesis, by mimicking the chemical functionality as well as the molecular structure of phospholipids in the plasma membrane, a series of random phospholipid copolymers PMS used as a control and crosslinkable terpolymers PMST comprising 2-methacryloyloxyethyl phosphorylcholine (MPC) as a hydrophilic monomer, stearyl methacrylate (SMA) as a hydrophobic part, and trimethoxysilylpropyl methacrylate (TSMA) as a crosslinker were specially designed as drug delivery systems. The micellization behavior of these amphiphilic polymers in aqueous medium and the condition of intramicellar crosslinking were studied. The self-associative property of stearyl group in the polymers ensure that drugs with a hydrophobic character can be easily incorporated into the inner-core by a non-covalent bonding through hydrophobic interactions. The research was mainly concerned with the following aspects.(1) Firstly, the most important polymerizable monomer MPC, having the biomimicing structure, was prepared according to the traditional synthetic route. The structure and purity was confirmed by 1H-NMR. Then a series of crosslinkable terpolymers PMST with different compositions and reference copolymers PMS were synthesized using a free radical polymerization through "monomer-starved" approach. The formulation of resulting materials were characterised by 1H-NMR in 1:1 CDCl3:CD3OD, which gives the best resolution of groups within different moieties, and proved that the average polymer compositions approximately correspond to their feed ratios.(2) Polymeric micelles were prepared using proper methods according to the solubility of different polymers. Fluorescence technique was used to determine the critical micelle concentration (CMC) using pyrene as probe. The results showed that the CMC value of those crosslinkable phosphllipid polymers were at the level of 10-6g/mL and decreased remarkably after intramicellar crosslinking. Scanning electron microscope (SEM) characterization suggested that these amphiphilic random polymers formed 50-300 nm regularized spherical aggregates in water and the crosslinked micellar shape was more uniform and exhibited a narrow size distribution. Finally, the crosslinked micelle stability against dilution in water and the shell permeability were studied. The results demonstrated that covalent crosslinking technique is an effective way to enhance the stability of the corresponding self-assembled structure and improve temporal control for drug delivery.(3) Anti-cancer drug adriamycin (ADR) was chosen as a hydrophobic drug model to be incorporated into the inner-core of micelles by oil-in-water method. Ultraviolet and visible spectrophotometry (UV-Vis) analysis suggested that high ADR loading capacities are obtained. In vitro drug release evaluation was performed using a dialysis method and proved that the drug-loaded crosslinked nano-micelles present a sustained and remarkably slower release behavior without any burst effect while free ADR release very quickly under the same experimental conditions. Moreover, the release rate decreased with the increase of SMA molar ratio in polymer and the amount of the drug entrapped. These experimental results suggested that the crosslinked micelles prepared from PMST random terpolymers with a biomimetic and anti-biofouling shell could be a promising candidate for prolonged circulating drug delivery carriers, especially for intravenous administration.