Doctor of Philosophy / Department of Agronomy / Masaaki Tamura / Over the years proteins/peptides have evolved as promising therapeutic agents in the
treatment of cancer. Considering the advantages of peptides such as their small size, ease of
synthesis, tumor-penetrating ability and bio-compatibility, present report discusses proof of
concept for 1. C1B5 peptide of protein kinase Cγ and a low dose of gemcitabine combination
treatment for peritoneally disseminated pancreatic cancer and 2. dTAT peptide nanoparticles
mediated gene (angiotensin II type 2 receptor gene) therapy for lung cancer. 1. A significant
reduction in intraperitoneally (IP) transplanted pancreatic carcinoma growth was demonstrated
with C1B5 peptide and gemcitabine co-treatment in an immunocompetent mouse model.
Increased number of Granzyme B positive cells was observed in treated mice ascites, suggesting
the involvement of immune response in tumor attenuation. The strong effect observed in
combination treatment might be because of increase in lymphocyte recruitment by gemcitabine
followed by C1B5 peptide mediated CD8+ T-cells or NK cells activation apart from direct
cancer cell apoptosis. 2. To test dTAT peptide nanoparticles (dTAT NPs) mediated therapeutic
gene delivery, luciferase reporter gene containing dTAT nanoparticles were synthesized
(dTAT/pLUC/Ca2+). Synthesis conditions for nanoparticles were optimized based on
dTAT/pLUC/Ca2+ nanoparticles transfection efficiency. With the optimized conditions, dTAT
NPs containing AT2R, TRAIL or miR-34a pDNA (dTAT/pAT2R, dTAT/TRAIL or dTAT/miR-
34a) were synthesized. Therapeutic potential of these NPs was analyzed in lung adenocarcinoma
containing mice by administering them intravenously (IV) or/and intratracheally (IV).
Combination treatment with the IV injection of the new dTAT/pAT2R/Ca2+ formulation and the
IT injection of the original dTAT/pAT2R/Ca2+ formulation is effective in attenuation of
developed human bronchioloalveolar carcinoma in the SCID mouse lungs. Findings from the
above mentioned studies have vital clinical relevance as it implies that peptides alone or when
used as gene delivery systems may prove to be beneficial in the treatment of various stages of
cancer.
| Identifer | oai:union.ndltd.org:KSU/oai:krex.k-state.edu:2097/35231 |
| Date | January 1900 |
| Creators | Uppalapati, Lakshmi |
| Publisher | Kansas State University |
| Source Sets | K-State Research Exchange |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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