Development of Poly(ethylene oxide)-block-poly(ε-caprolactone) based Micelles for Tumor Targeted Drug and siRNA Delivery

• Author / Creator

  Garg, Shyam M

• The use of nanotechnology has made significant advancements in cancer diagnosis and treatment. Polymeric micelles are a relatively new generation of nanocarriers mostly intended for the delivery of hydrophobic drugs. In this thesis, our objective was to develop an optimized polymeric micellar platform based on functionalized poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers for tumor targeted drug and/or siRNA delivery. Accordingly, modification of the core and shell structure in this platform was pursued to maximize the delivery of incorporated cargo to malignant tissue, while avoiding its nonspecific distribution to healthy organs. In this context, modification of the core in PEO-b-PCL micelles with a hydrophobic side-group i.e. benzyl carboxylate (PEO-b-PBCL), was shown to increase the stability of micelles. The improved stability of micelles led to enhanced accumulation of nanocarriers into orthotopic breast tumors in mice, which was evidenced through optical imaging of a near infrared (NIR) cy5.5, tagged micelles. Modification of the micellar shell with a breast cancer targeting peptide, i.e. P18-4, on the other hand, resulted in a more rapid homing of the nanocarriers in breast tumors. In the next step, crosslinking of the alkyne modified core of PEO-b-PCL micelles by diazide poly(ethylene glycol) by click chemistry, was shown to further enhance micellar stability. This approach was not able to sustain the release of encapsulated paclitaxel (PTX) or JSI-124 from micelles, however. JSI-124 was then chemically conjugated to the core of PEO-b-PCL micelles. The developed nanocarrier sustained the release of JSI-124 and maintained its STAT3 inhibitory activity in B16 melanoma at lower potency. Interestingly, the JSI-124 polymeric micellar conjugate have shown better potency than the free drug in modulation of immune response in tumor induced immunosuppressed dendritic cells (DCs). We have finally pursued modification of PEO-b-PCL micelles with grafted polyamines to improve the efficacy of these nanocarriers in tumor targeted siRNA delivery. For this purpose, cholesteryl groups were conjugated to the core of PEO-b-P(CL-graft-spermine) (PEO-b-P(CL-g-SP) micelles. The modification improved transfection efficiency of siRNA in breast cancer cells in vitro, but had no significant effect in their in vivo activity in tumor gene silencing following intratumoral or intravenous administration of siRNA delivery system. Modification of the PEO shell with an integrin targeting peptide i.e. RGD4C, led to better siRNA silencing activity in tumor after systemic administration, however. In conclusion, our results show that modification of the core and/or shell of polymeric micelles can be used to fine-tune relevant properties of these nanocarriers leading to their potential use as versatile pharmaceutical excipients for tumor targeted drug/siRNA delivery.

• Subjects / Keywords

  • SiRNA
  • Click chemistry
  • PEO-b-PCL
  • Targeted delivery
  • NIR imaging
  • JSI-124
  • Stability
  • Polymeric micelles

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3FT8F012

• 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.