BIOCONJUGATION OF CALCIUM PHOSPHATE NANOPARTICLES FOR SELECTIVE TARGETING OF HUMAN BREAST AND PANCREATIC CANCERS IN VIVO

Open Access
Author:
Sharma, Rahul
Graduate Program:
Molecular Medicine
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
None
Committee Members:
  • James Hansell Adair, Thesis Advisor
Keywords:
  • bioconjugation
  • transferrin receptor
  • CD71
  • gastrin receptor
  • targeting
  • breast cancer
  • pancreatic cancer
  • calcium phosphate
  • nanoparticles
  • indocyanine green
  • near-infrared
  • whole animal imaging
Abstract:
This study describes the design and synthesis of targeted calcium phosphate nanoparticles (CPNPs) through bioconjugation of human holotransferrin, anti-CD71 antibody, and short gastrin peptides via avidin-biotin- or PEG-maleimide-coupling strategies. Furthermore, this study evaluates the specificity of these targeted CPNPs in vivo in models of breast and pancreatic cancer. These bioconjugated CPNPs potentially permit enhanced drug delivery, targeting and imaging of breast and pancreatic cancer tumors. This is the first report on avidin-conjugated CPNPs for use in improving cellular uptake. The conjugation of biotinylated human holotransferrin (diferric transferrin) and biotinylated anti-CD71 antibody (anti-transferrin receptor antibody) to avidin conjugated CPNPs (avidin-CPNPs) permits targeting of the transferrin receptor on cells. Early studies have shown that the transferrin receptor is specifically over-expressed on breast cancer cells in comparison to healthy cells. Thus, conjugation of biotinylated human holotransferrin or biotinylated anti-CD71 antibody to avidin-CPNPs can potentially be utilized to enhance the targeting of breast cancer. In a manner similar to targeting breast cancer via the transferrin receptor (CD71), the conjugation of biotinylated pentagastrin to avidin-CPNPs and gastrin-10 to PEG-CPNPs via PEG-maleimide coupling permits for targeting of the gastrin receptor; gastrin receptor expression is often increased in pancreatic cancer. This study demonstrates that these targeting strategies can potentially increase the uptake efficiency of CPNPs by breast and pancreatic cancer cells and increase the specificity of CPNPs for these cancer cells, which would decrease the systemic toxicity to normal cells, as a result of reduced amount of toxic anti-cancer drugs in the extracellular fluid.