Abstract

Prostate Cancer is the second most deadly cancer in men, after lung cancer. The need for new and effective therapeutics that can constrain prostate cancer progression are challenged by the lack of suitable delivery strategies that target prostate cancer tissue. To study CT20p as potential chemotherapeutic agent in the treatment of prostate cancer we proposed the use of targetable hyperbranched polyester (HBPE) based nanoparticles as delivery system. Folic acid was conjugated to the nanocarrier to improve the selectivity of the nanoparticle towards specific cell surface targets in prostate cancer cell lines. Specifically we evaluated LNCaP that up-regulated the PSMA receptor. The synthesis of folate conjugated hyperbranched polyester nanoparticles was accomplished using an aliphatic and biodegradable hyperbranched polyester (HBPE). HBPE was prepared from commercially available diethyl malonate and 4-bromobutyl acetate. Our AB2 type monomer displays a three-bond connectivity that grows three-dimensionally under specific polymerization conditions. The product, HBPE, is a polymer with globular configuration that contains surface carboxylic acid groups and holds hydrophobic cavities. Carboxylated HBPE nanoparticles were synthesized via solvent diffusion method. A variety of hydrophobic cargos including: dyes (DiR and DiI) and the cytotoxic peptide CT20p were successfully encapsulated. DLS along with STEM imaging reveal nanoparticle preparations with ~100 nm size. Using water-soluble carbodiimide chemistry, surface modifications were accomplished. Available carboxylic acid groups were conjugated to aminated folic acid to yield folate functionalized nanoparticles.We explore the targeting capability of the Folate-HBPE nanoparticles and demonstrated that the cell internalization of Folate-HBPE into prostate cancer cell lines (LNCaP and PSMA (+) PC-3) was attained via a PSMA-mediated targeting mechanism. Furthermore, when CT20p was delivered to PSMA expressing PCa cells, detachment and death was observed; together with a reduction in the levels of β1 integrin (CD29) expression, an integrin implicate in cell communication and cell adhesion. CT20p inhibits cell proliferation within 24 h and produce significant cell death after 48 h post treatment. The IC50 of CT20p was calculated at ~7 nM. Additionally, we investigated the capability of Folate-HBPE(CT20p) to perform as a therapeutic agent, in an in vivo setup, using a murine prostate tumor model. The Folate-PEG-HBPE NPs protected CT20p while in circulation and allowed effective uptake by PSMA-mediated targeting. Treatment with Folate-HBPE(CT20p) display localize tumor targeting and significant tumor growth inhibition in PSMA(+) PCa cell lines within days. Together these results suggest the potential of Folate-HBPE(CT20p) nanoparticles in the treatment of prostate cancer.

Notes

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Graduation Date

2015

Semester

Summer

Advisor

Perez Figueroa, J. Manuel

Degree

Doctor of Philosophy (Ph.D.)

College

College of Sciences

Department

Chemistry

Degree Program

Chemistry

Format

application/pdf

Identifier

CFE0006216

URL

http://purl.fcla.edu/fcla/etd/CFE0006216

Language

English

Release Date

February 2021

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Campus-only Access)

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