Design, Synthesis And Biological Properties Of Star-, Brush-shaped Polymers And Cyclodextrin Polyrotaxane

Polymeric nanomaterials have well controllable chemical and morphological structures and thus exhibit many advantages when used as drug carriers, such as widely tunable composition and surface chemistry, high drug loading capacity, desirable anti-biofouling ability, and good biocompatibility and biodegradability. Polymeric nanomaterials can be prepared by self-assembly or covalent synthesis. Compared to the polymeric nanomaterials prepared by self-assembly, the polymeric nanomaterials synthesized covalently have more stable, controllable, narrowly distributed and reproducible structures, which make them very attractive in the applications of biomedical field. Herein, we synthesized several types of star-and brush-shaped polymers and β-cyclodextrin (P-CD) polyrotaxane (PR), and studied their biological properties. The detailed contents are as follows.1. We synthesized a series of 21 arm star block copolymers by ATRP with β-CD as a core. The size of the multiarm star copolymers could be tuned from ten to several tens nanometers as determined by DLS. Zwitterionic poly(carboxybetaine) (PCB), polyethylene glycol (PEG) and phenylboronic acid-incorporated PCB were selected as the peripherial hydrophilic blocks of the multiarm copolymers, respectively, and doxorubicin was conjugated to the copolymers through pH-sensitive acylhydrazone linkages. Desirable drug loading content was achieved. The precise and stable structures of the multiarm copolymer therapeutics ensured their reproducible pharmacokinetic and pharmacological profiles. The 11 nm multiarm copolymer with PCB surface showed stronger tumor permeability when compared to the copolymers with PEG surface or larger size. The incorporation of phenylboronic acid group into the peripherial block of the multiarm copolymer therapeutics significantly enhanced their cellular uptake, tumor accumulation, and tumor permeability.2. We synthesized two types of polymer brushes with poly(3-phenylthiophene) as backbone and PEG or PCB as side chains, respectively. The fluorescence of the polymer brushes can be used to trace their cellular uptake and penetration behavior in multicellular spheroids. Our results indicate that comparing to the polymer brushes with PEG side chains, the polymer brushes with PCB side chains exhibit higher cellular uptake and higher penetration ability in multicellular spheroids.3. We synthesized β-CD PR by using PPG terminated by 3,4,5-tris(prop-2-yn-1-yloxy)-benzamide groups as the axle and 2-Azidoethanol as the end-capping reagent. Being different to the traditional preparation strategy of CD PR where bulky end-capping reagents are generally used, our strategy is to use small-sized 2-Azidoethanol as the end-capping reagent to produce 3 triazole rings at each end in Cu(Ⅰ)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) to block the CD rings on the polymer axle. By doing so, the steric hindrance can be effectively reduced. After modified by PEG, the PR can be internalized by cancer cells without detectable cytotoxicity.