Investigation Of Carboxybetaine Polymers In Drug Carriers And Medical Implantable Materials

The non-specific protein adsorption on surfaces is a challenging problem faced by nano drug carriers and medical implantable materials. At present, there are few materials that can effectively resist non-specific protein adsorption from complex media for practical applications, such as drug carriers and medical implants. Polyzwitterionic materials such as poly(2-methacryloyloxyethyl phosphorylcholine)(PMPC), poly(sulfobetaine methacylate)(PSBMA) and poly(carboxybetaine methacylate)(PCBMA) are believed as ideal candidate materials for those applications in recent years due to their excellent nonfouling and biocompatibility properties. Both excellent properties mainly originated from the high levels of hydration and biomimetic-like structures, respectively. In this dissertation, we systematically investigated the in vivo compatibility of carboxybetaine polymer, the blood stability of reversible cross-linked carboxybetaine polymer micelles, and the cancer therapeutic efficacy of targeted cross-linked micelles of doxorubicin-encapsulated polycaprolactone-b-polycarboxybetaine. In addition, we developed a new biocompatible silicone baesd on a carboxybetaine ester analogue. The main contents and conclusions of this dissertation include the following four parts:1. Four star carboxybetaine polymers with different molecular weights via atom transfer radical polymerization (ATRP) from a β-CD initiator were prepared for investigating the in vivo compatibility of carboxybetaine polymer. Results show that the internalization of macrophage cell RAW264.7in vitro is dramatically reduced. The circulation half-life of the largest star polymer (123KDa) in mice is prolonged to40hours. Furthermore, the circulation time of repeated injections shows similar results to the first injection; no appreciable damage or inflammation was observed in major organ tissues, and no obvious increase of antibody occured in blood. These results suggest that the CBMA coatings for nanoparticles have advantages such as reducing cellular uptake, no immune response and long circulation time, which might be a good alternative of PEG.2. The cross-linked micelles based on a copolymer composed of carboxybetaine methacrylate (CBMA) as hydrophilic and nonfouling segment,2-(methacryloyloxy)ethyl lipoate (MAEL) as hydrophobic and cross-linked segment were prepared for investigating the blood stability of the micelles with CBMA protection layer. The micelles can easily encapsulate the anticancer drug doxorubicin (DOX), and quickly release DOX in response to an intracellular reductive environment. With the advantages in excellent stability in fibrinogen (1mg/mL) PBS solution and50%fetal bovine serum (FBS), and accelerated intracellular drug release, the biocompatible zwitterionic micelle stabilized by reversible cross-linkage is a promising drug carrier candidate.3. It has been demonstrated that the active targeting of doxorubicin-encapsulated polycaprolactone-b-polycarboxybetaine cross-linked micelles to the integrin on cancer cells can be realized by the conjugation of cyclic pentapeptide c(RGDyK) on CBMA shell. The doxorubicin encapsulated cross-linked micelles show a prolonged circulation time in plasma in respect of the modification of c(RGDyK). Under the guide of c(RGDyK), the antitumor effeciveness of doxorubicin was enhanced, while the cardiac toxicity and biotoxicity of doxorubicin reduced. These results indicate that the c(RGDyK)-modified zwitterionic cross-linked micelle is a promising drug carrier.4. A new biocompatible silicone comprising a carboxybetaine (CB) ester analogue,3-methacryloxypropyltris-(trimethylsiloxy)silane (TRIS) and an organic silicone macromer bis-a,co-(methacryloxypropyl) polydimethylsiloxane using photo-polymerisation was developed. Following interfacial hydrolysis of the CB ester, the resulting zwitterionic material coated silicone became significantly more hydrophilic and exhibited high resistance to both non-specific protein adsorption and bacterial adhesion. Moreover, the stability of these nonfouling properties was dramatically improved by using a slow and controlled rate of ester hydrolysis of the original protective hydrophobic matrix. Meanwhile, the original optical and mechanical properties of the bare silicone remained unchanged after surface activation. These results indicate that this material is an ideal candidate for preparing contact lenses and other medical devices.