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Development of Novel Stimuli-Responsive Drug Delivery Systems

  • Author / Creator
    Safaei Nikouei,Nazila
  • In this thesis, novel pH and temperature responsive polymers based on triblock of poly(ethylene glycol) (PEG) and functionalized poly(ε-caprolacton) having different levels of carboxyl to benzyl carboxylate on the α-carbon of caprolacton units (0:100, 30:70, 50:50, 100:0) were synthesized. The temperature and pH responsive self-assembly as well as sol-gel transition of prepared triblock copolymers was characterized by different methods including inverse flow method, dynamic mechanical analysis and differential scanning calorimetry. The mechanism of sol-gel transition and viscoelastic properties of the gels was also investigated by 1H NMR and dynamic mechanical analysis, respectively. Our results showed the presence of carboxylic group at 30 and 50 % substitution on the polymer backbone to introduce thermo/pH sensitivity to the polymeric solutions. The sol-gel transition temperature of these block copolymer solutions was around 30 °C at 7-15% w/w concentration. In the next step, the potential of developed hydrogels in stimulus and depot delivery of macromolecular drugs was investigated using a large molecular weight fluorescent probe, i.e., tetramethyl rhodamine-dextrose (TMR-D) at two molecular weights of 10 & 40 kDa, as a model. Loading of TMR-D do not affect the sol-gel transition of polymer solutions. The in vitro release of TMR-D was sustained by thermo-responsive gel only at 37° C and pH 7.4 or 9.0. Reducing the pH to 5.0 (at 37 ° C) or reducing the temperature to 25 ° C (at pH7.4) led to the disruption of gel structure and a consequent rapid release of TMR-D. In further studies, cyclosporine A (CyA) was loaded in the hydrogel to provide an alternative formulation for Restasis® eye drops for chronic dry eye disease. Release of CyA was shown to be controlled by the hydrogel within a 7 day time frame at 37 °C and pH 7.4. We have also developed novel multifunctional polymeric micelles based on diblock copolymers of poly(ethylene oxide)-poly(α-carboxyl-ε-caprolatone) (PEO-PCCL) modified on their surface with GE11, a peptide targeting epidermal growth factor (EGFR). The complexation and pH responsive delivery of cisplatin as well as anti-cancer activity of polymeric micellar cisplatin with and without a tumor targeting peptide on its surface in EGFR+ SKBR3 cells was then investigated. The results showed efficient complexation of cisplatin by the developed polymers and its enhanced release under mild acidic condition (pH=5.0) from polymeric micelles. Moreover, modification of polymeric micelles with GE11 enhanced the anti-cancer activity of cisplatin in SKBR3 cells. In conclusion, our results showed novel di and tri block copolymers developed in this thesis are versatile materials with several potential applications in drug delivery. They can form temperature/pH responsive hydrogels with potential application for in situ and/or depot delivery of large molecular weight entities, and small molecular weight drugs. They can also form pH responsive nano-carriers that can provide acid triggered release of the incorporated anti-cancer drug in tumor for the purpose of targeted drug delivery.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3XX0J
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Lavasanifar, Afsaneh (faculty of Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Jamali, Fakhreddin (faculty of Pharmacy and Pharmaceutical Sciences)
    • Unsworth, Larry (Department of chemical and Materials Engineering)
    • Loebenberg, Raimar (faculty of Pharmacy and Pharmaceutical Sciences)
    • Kaur, Kamaljit (faculty of Pharmacy and Pharmaceutical Sciences)
    • Wu, Shirley X.Y. (Leslie Dan Faculty of Pharmacy)