Controlled Syntheses Of Polyphosphoesters And Their Applications In Drug Delivery

Polyphosphoesters have received great attention in drug delivery, due to the easy control of its chemical and physical properties. Our research group has previously studied the controlled ring-opening polymerization of polyphosphoester, but the preparations of polyphosphoesters with various topologies are rarely studied. This dissertation has been focused on the syntheses of polyphosphoesters with various topologies, including linear, miktoarm, brush, cyclic and brached structures. The self-assemble properties of these polymers have been studied. Based on the controlled polymerization of polyphosphoesters, we have also constructed pH-responsive zwitterionic polymer based nanoparticles with prolonged blood circulation time and promoted tumor cellular uptaken for enhanced drug delivery to tumor. This dissertation can be further categorized into following parts as described below:1. Novel ABC3-miktoarm star terpolymers composed of poly(s-caprolactone)(PCL), monomethoxy poly(ethylene glycol)(MPEG) and polyphosphoester (PPE) have been synthesized by combination of ring opening polymerization and’’click" chemistry. MPEG was firstly end-capped by epoxide ring, which was opened by sodium azide in the presence of ammonium chloride to give modified MPEG bearing reactive azide and hydroxyl group (MPEG(-OH,-N3))."Click" chemistry was then applied to conjugate a-propargyl-ω-acetyl-poly(ε-caprolactone) and MPEG(-OH,-N3), resulting in diblock copolymer of MPEG and PCL with reactive hydroxyl groups at the junction point (MPEG(-OH)-b-PCL), which further initiated ring opening polymerization of2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) under catalysis of stannous octoate to obtain the desired well defined (MPEG)(PCL)(PEEP)3-miktoarm star terpolymers. Such terpolymers and their intermediates were characterized by1H NMR, FT-IR and gel permeation chromatograph measurements. We further prepared a thermosensitive ABC miktoarm star terpolymer, and it formed a spherical micelles at lower temperature in aqueous solution, which transited to short nano-rod at temperature higher than the cloud point of the polymer.2. Amphiphilic centipede-like brush copolymers with biodegradable poly(ε-caprolactone) and poly(ethyl ethylene phosphate) side segments have been prepared by combination of ring opening polymerization and "click chemistry" via a one-pot syntheses strategy. The syntheses combine ring-opening polymerization of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane through a "grafting from" strategy and "click" reaction with α-propargyl-co-acetyl-poly(s-caprolactone) through a "grafting to" strategy, using multifunctional poly(tert-butyl methacrylate)-co-poly(2-hydroxy-3-azidopropyl methacrylate) that bears hydroxyl and azide groups from junction points. The reactions are controllable, and the structure of obtained centipede-like brush copolymer is well characterized by1H NMR, FT-IR and gel permeation chromatograph measurements. These brush copolymers are amphiphilic and self-assemble into spherical micellar structure in aqueous solution with critical aggregation concentration around10-3mg mL-1and average diameters of50-90nm. Static light scttering studies found that the aggregation number of micelles decreases when the molecule weight of the brush polymer increases.3. A simple and universal route to functional cyclic polyesters has been demonstrated. Macrocyclic polymers have long elicited interest due to the absence of chain-ends, which imposes a topological restriction and results in a variety of physical properties that significantly distinguish them from their linear analogs. In this chapter, by combining two consecutive click reactions of azide-alkyne cycloaddition of linear hetero-difunctional precursor and thiol-ene coupling for post cyclization functionalizations. Functional cationic and thermo-responsive cyclic polyphosphoesters have been synthesized and characterized to demonstrate the efficiency of the procedures.4. Biocompatible nanogels with a branched structure designed as potential carriers for drug delivery are reported. The nanogels were prepared by the reaction of3,6-dioxaoctan-1,8-diyl bis(ethylene phosphate)(TEGDP) with tris(2-aminoethyl)amine (TREN) in an ionic liquid containing miniemulsion; the particle size was tunable in the nanoscopic range. The nanogels could effeciently load the anticancer drug doxorubicin and showed enzyme-responsive drug release behavior. The nanogels were further labelled with fluorescein isothiocyanate through a reaction with with the surface amino groups to demonstrate functionalization. Flow cytometric analyses and confocal laser scanning microscope observations demonstrated that the nanogels could be efficiently taken up by the human breast cancer cell line MDA-MB-231. DOX-loaded naogels showed enhanced inhibition of cell proliferation. The biocompatibility of the nanogels was evaluated using both in vitro and in vivo experiments. 5. Zwitterionic polymer-based nanoparticle with response to tumor acidity has been developed for enhanced drug delivery to tumors. The nanoparticles were neutrally charged at physiological conditions and showed prolonged circulation time; after leaking into tumor sites via the enhanced permeability and retention (EPR) effect, in the acidic extracellular tumor environment (pHe), nanoparticles were activated and become positively charged and therefore efficiently taken up by tumor cells, leading to enhanced therapeutic effects in cancer treatment. The nanoparticles formed from block copolymer of poly(s-caprolactone) and zwiterionic polyphosphoester were netrually charged with a diameter of about50nm and could efficiently encapsulate anticancer drug doxrubicine. Zwitterionic polymer based nanoparticles showed reduced adsorption with bovine serum albumin or fibrinogen and showed prolonged blood circulation time. When accumulated in the tumor site, confocal laser scanning microscopy and flow cytometry measurements demonstrate that the nanoparticles could significantly promote the cellular internalization by MDA-MB-231cells in vitro and in vivo. Since the contradiction of nanoparticles with prolonged circulation time and efficient cellular uptake is one of the great challenges in drug delivery at present, the zwitterionic polymer-based nanoparticles with tunable surface charge properties address these two factors, and hence have great potential to achieving better therapeutic effects in cancer treatment.