Current Search: Therapeutic targets (x)
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- Title
- Folate conjugated hyperbranched polyester nanoparticles for prostate tumor-targeted delivery of a cytotoxic peptide via prostate specific membrane antigen.
- Creator
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Flores-Fernandez, Orielyz, Perez Figueroa, J. Manuel, Campiglia, Andres, Yestrebsky, Cherie, Harper, James, Khaled, Annette, University of Central Florida
- Abstract / Description
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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...
Show moreProstate 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 ?1 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.
Show less - Date Issued
- 2015
- Identifier
- CFE0006216, ucf:51112
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006216
- Title
- INVESTIGATING THE ROLE OF THE CASPASE-6 CLEAVAGE FRAGMENT OF MUTANT HUNTINGTIN IN HUNTINGTON DISEASE PATHOGENESIS.
- Creator
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McKinnis, Jourdan A, Southwell, Amber, University of Central Florida
- Abstract / Description
-
Huntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A...
Show moreHuntington disease (HD) is a devastating and fatal neurodegenerative disease. At the moment, no disease modifying therapies are available, with only symptomatic treatment offered to alleviate psychiatric and some types of motor deficits. As a result, many people will continue to suffer and die from this disease. Small molecule therapies have failed to provide benefit in HD, necessitating more complex gene therapy approaches and the identification of less traditional therapeutic targets. A previous study demonstrated that preventing cleavage of the huntingtin (HTT) protein, the protein that when mutated causes HD, by caspase 6 (C6) at amino acid 586 prevents the onset of disease in transgenic HD model mice. This suggests that inhibiting the toxicity initiated by N586 cleavage could be a promising therapeutic strategy, but a safe and specific way to do this in humans has not been identified. General C6 inhibition is not a feasible strategy due to the vital functions it plays throughout life. Thus, the purpose of this study was to investigate whether the C6 cleavage fragment of HTT, N586, is itself a toxic species of HTT or if it initiates a toxic proteolytic pathway in order to identify more viable therapeutic strategies for HD. To accomplish this, we are using novel and highly sensitive immunoprecipitation and flow cytometry (IP-FCM) protein detection assays, specific for the N586 neoepitope of HTT, to evaluate the in vivo persistence of N586 in HD model mice. If N586 is detected, it is likely that it is itself toxic and promoting its degradation may be beneficial. Conversely, if it is not detected, N586 cleavage likely initiates a toxic degradation pathway and promoting its stability may be beneficial. The results of these studies have the potential to define new therapeutic strategies for HD that can be addressed more specifically than generalized C6 inhibition for the prevention of N586-mediated toxicity. The selective targeting of N586 toxicity, either to promote or prevent its degradation depending on our results, would ensure that therapeutic activity is restricted to HTT and reduce the potential for deleterious off-target effects
Show less - Date Issued
- 2018
- Identifier
- CFH2000395, ucf:45801
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000395