Exploiting Biomarkers Assists in Degradation of Breast Cancer Cells and Reduces Extravasation

Open Access
Author:
Zaki, Peter Maged
Area of Honors:
Bioengineering
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Cheng Dong, Thesis Supervisor
  • James Hansell Adair, Thesis Supervisor
  • Peter J Butler, Honors Advisor
Keywords:
  • breast cancer
  • pancreatic cancer
  • melanoma
  • nanoparticles
  • nanoliposomes
  • docetaxel
  • ceramide
  • CD71
  • CD44
  • metastasis
Abstract:
Cancer is the second leading cause of death in the United States. Conventional chemotherapeutics kill 5% of patients and outcomes are very poor for stage 3 and stage 4 patients. Most current treatment methods, based on the conventional paradigm that rapidly replicating cells have the most uptake of the chemotherapeutic agent, harm benign, rapidly replicating cells in addition to cancerous cells. Therefore, a novel approach involves targeting cancer cells specifically and preventing them from growing and metastasizing. Healthy cells should be minimally harmed if not completely unharmed during the treatment process. Ceramide nanoliposomes are one possible treatment that could specifically target cancerous cells. The ceramide nanoliposomes inhibit primary breast, pancreatic, and melanoma tumors that express CD44 while having no effect on benign epithelial cells. The effects of ceramide nanoliposomes on the migration of MDA-MB-231 (human breast adenocarcinoma) cells were tested since a treatment for metastasized cancer would be especially efficacious. Survival rates decrease as cancer cells migrate in a body and metastasize. The five-year survival rate for breast cancer patients decreases from 100% for stage 1 (located only in primary tissue) to 22% for stage 4 (located in multiple remote organs). Ceramide nanoliposomes were shown to use lysosomal degradation of the membrane protein, CD44, to mediate anoikis and reduce extravasation. Similar results were observed when siRNA was used to downregulate CD44. The data collected indicates that ceramide nanoliposomes could be used to prevent and treat CD44-dependent tumor metastasis. While ceramide nanoliposomes have yet to be used on humans, docetaxel is one of the most common drugs currently being used to treat breast cancer. However, docetaxel does not specifically target malignant cells. Since docetaxel disrupts the assembly of the mitotic spindle, it can inhibit various cells from dividing, not just cancerous ones. Delivery via calcium phosphosilicate nanoparticles (CPSNPs) is currently being tested as a proper technique for specific targeting of cancerous cells. CPSNPs encapsulate the drug and provide intracellular release. In addition, the surface of the CPSNPs can be bioconjugated with molecules that bind to cell receptors. In order to potentially maximize the exploitation of cell markers, receptor proteins on cancerous cells other than CD44 were investigated. CPSNPs were conjugated with anti-CD71, which allows the nanoparticles to bind specifically to cells that express CD71 on their membrane. MDA-MB-231 breast cancer cells were used because they are one type of cell line that overexpresses the membrane protein CD71. The docetaxel CPSNPs are further being studied for their effects on cell growth and extravasation.