Responsive Polymer-Based Imaging Agent And Drug Carriers

Because of their outstanding advantages, stimuli-responsive polymers and polymeric assemblies have been widely explored in nanomedicine for delivery of drugs and imaging agents. While responsive polymers for modulating magnetic resonance imaging contrast performance, bacteria detection and inhibition, as well as antibiotics delivery are rarely reported. The dissertation included the following four parts:1. Fabrication of responsive amphiphilic diblock copolymer micelles exhibiting light-triggered hydrophobic-hydrophilic transition within micellar cores and the concomitant enhancement of magnetic resonance (MR) imaging contrast performance and release rate of physically encapsulated hydrophobic drugs. POEGMA-b-P(NIPAM-co-NBA-co-Gd) diblock copolymer covalently labeled with Gd3+ complex (Gd) was synthesized, where OEGMA, NIPAM, and NBA are oligo(ethylene glycol) monomethyl ether methacrylate, N-isopropylacrylamide, and o-nitrobenzyl acrylate, respectively. The amphiphilic diblock copolymer spontaneously self-assemble in aqueous solution into micellar nanoparticles possessing hydrophobic P(NIPAM-co-NBA-co-Gd) cores and hydrophilic POEGMA coronas, which can physically encapsulate doxorubicin (Dox) as a model chemotherapeutic drug. Upon UV irradiation, hydrophobic NBA moieties within micellar cores transform into hydrophilic carboxyl derivatives, triggering micellar swelling. During this process, the microenvironment surrounding Gd3+ complexes were subjected to a transition from being hydrophobic to hydrophilic, leading to prominent enhancement of MR imaging contrast performance. In addition, the release rate of encapsulated Dox was also considerably enhanced.2. Four-arm star-shaped amphiphilic copolymers, TPE-star-P(DMA-co-BMA-co-Gd), consiting of a single tetraphenylethylene (TPE) core with well-documented aggregation-induced emission (AIE) feature and four antibacterial P(DMA-co-BMA) arms covalently labeled with magnetic resonance (MR) imaging contrast agent, was synthesized via atom transfer radical polymerization (ATRP) and successive post-modification procedures, where DMA, BMA and Gd are 2-(dimethylamino)ethyl methacrylate, butylmethacrylate and T1-type MR imaging contrast agent, respectively. Upon contacting with negatively-charged bacterial surfaces, the intramolecular rotation of TPE moieties and the tumbling mobility of Gd moieties would be confined via the formation of electrostatic complexes, thus resulting in synergistically increased fluorescence emission and MR imaging performance, which therefore allowed for bimodal detection of bacteria. Furthermore, broad-spectrum antibacterial activities against both Gram-negative bacteria and Gram-positive bacteria of the star polymers were achieved.3. We designed a novel nanosystem capable of both bacterial detection and inhibition, where polyion complex (PIC) micelles are constructed from negatively-charged tetraphenylethylene (TPE) sulfonate derivatives, which exhibit the AIE feature, and cationic diblock copolymers, poly(ethylene oxide)-b-quaternized poly(2-(dimethylamino)ethyl methacrylate) (PEO-b-PQDMA). Upon contacting with bacteria, the PIC nanosystem disintegrates presumably due to competitive binding of polycation blocks with negatively-charged bacterial surfaces. This process is accompanied by a conspicuous quenching of TPE fluorescence emission, serving as a real-time module for microbial detection. Furthermore, the sharp decrease in CFU is indicative of prominent anti-microbial activities. Thus, PIC micelles possess dual functions of fluorometric detection and inhibition for bacteria in aqueous media.4. We aim to establish a general strategy to construct bacterial strain-selective delivery nanocarriers for antimicrobial agents based on block copolymer vesicles, which are responsive to enzymes relevant to clinically important bacterial strains. PGA and Bla-responsive polymeric vesicles were self-assembled from amphiphilic diblock copolymers consisting of hydrophilic poly(ethylene glycol) (PEG) block and hydrophobic block containing enzyme-cleavable self-immolative side linkages. During vesicle formation, antimicrobial agents were loaded into either hydrophobic bilayers or aqueous interiors. Upon incubation with specific enzymes, the chemical structural transformation, morphology transition, drug release profile, and antibacterial activities of polymeric vesicles were investigated.