Study Of Poly (N-vinyl Pyrrolidone) Based Nano Drug Delivery Systems

The application of nanotechnology to nanomedicine research and therapy has enormous potential in fundamental research, clinical application and disease diagnosis. In fact, the use of biocompatible and biodegradable polymer nanoparticles for drug delivery and targeting is one of the most active topics in modern scientific community. The polymer nanoparticles prepared by self-assembly using amphiphilic block copolymers in aqueous medium are generally comprised of hydrophilic outer shell and hydrophobic inner core that can incorporate lipophilic drugs into their core and release the drug in a controlled manner at a later stage. Hydrophilic poly(ethylene glycol) (PEG) is often used to decorate carriers'surface and got overwhelming success in biomedical applications. However, with in-depth study, the shortcomings of PEG have also being found. Thus, looking for an attractive alternative to PEG has become an important issue and is highly desirable.Poly(N-vinyl pyrrolidone) (PVP) is a well-known hydrophilic biocompatible polymer and used in antibacterial agents, imaging probes, or even drug conjugates. However, conventional radical polymerization of PVP is uncontrollable and hardly to bear functional endgroups on the chain ends. In this dissertation, we used living radical polymerization to prepare PVP in a controlled manner with functional moieties on ends. Further, the PVP-based nanoparticles were used for nanomedicine research including passive tumor targeting and active tumor targeting.This dissertation constituted of four parts:1. Synthesis of PVP with hydroxyl end via chain transfer radical polymerization based on the optimization addition of mercaptan and isopropyl alcohol in the system. MALDI-Tof-MS successfully elucidated the attribution of peaks, leading to a rational explanation of polymerization dynamics. The mono hydroxy PVP were directly used as macromolecular precursor to synthesize Poly(N-vinylpyrrolidone)-b-Poly(?-caprolactone) (PVP-b-PCL) via ring opening polymerization.2. PVP-b-PCL copolymers were used to prepare paclitaxel (PTX) loaded PVP-PCL nanoparticles of 100 nm-sized hydrophilic diameter with satisfactory drug loading content (>25%) and high encapsulation efficiency (> 85%). The in vitro cytotoxicity experiment demonstrated that PTX loaded PVP-PCL nanoparticles had distinct antitumor effect. The near infrared fluorescence (NIRF) imaging demonstrated that such nanoparticles could be accumulated in tumor regions according to EPR effect. In the meanwhile, in vivo experiment showed that the antitumor efficacy PTX-loaded nanoparticles was prior to commercial Taxol" formulation.3. Three living radical polymerization techniques:NMP, ATRP, RAFT were employed in order to synthesize bifunctional PVP with controlled molecular weight (MW) and molecular weight distribution (MWD). MALDI-Tof-MS, GPC and NMR were used to analysis synthesized PVP. The results demonstrated that bifunctinal PVP achieved via RAFT method, and the functional endgroups could be ester, hydroxy, alkyne, aldehyde and thiol, leading to versatile usage in biomedical science.4. RAFT moiety was conjugated onto Poly(?-caprolactone) via two steps and mediated N-vinyl pyrrolidone polymerization in a controlled manner. Then, the reactive endgroups obtained on copolymer PCL-b-PVP were readily modified to hydroxl and aldehyde for further conjugating fluorescent dye and tumor targeting iRGD. Thus, prepared functional PVP-PCL nanoparticles was capable to accumulation in tumor and confirmed by NIRF.5. Preparation of PTX-loaded PVP-PCL nanoparticles with satisfactory drug loading content (15%) and encapsulation efficiency (> 90%). PVP-PCL nanoparticles' basic properties as well as the influence of PVP block length and tumor targeting iRGD to their in vivo circulation time and antitumor efficacy were characterized according to in vitro/in vivo experiment. NIRF was observed for semiquantitative detection the blood circulation half time and organ accumulation in H22 tumor model. Furthermore, nanoparticles'tumor penetration ability was explored by immunofluorescence staining. These results indicated that functional PVP-PCL nanoparticles occupied the properties of passive targeting, active targeting and tumor penetration and possessed significant antitumor ability.