Biotinylated PAMAM dendrimers as nanocarriers for targeting cisplatin to ovarian cancer : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2011]
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| Subjects: |
| Abstract: | ABSTRACT: Ovarian cancer is one of the leading causes of death in women and ranks fifth in cancer deaths among women. Efficacy of cisplatin in treatment of ovarian cancer is limited due to systemic toxicity and tumor relapse due to resistance. Strategies to improve efficacy of chemotherapy to ovarian cancer include targeted biologics, inhibitors of efflux transporters and/or nanoparticulate delivery systems. Poly (amidoamine) (PAMAM) dendrimers are unique carriers which are precisely monodisperse and nanoscale in size with easily modifiable charged surface groups and can extravasate through microvasculature. We hypothesized that specific delivery of high concentrations of cisplatin to tumor cells may result in optimal efficacy with minimal side effects. In the present study, we have developed biotin-conjugated PAMAM dendrimers with NH₂ and COOH groups as nanocarriers for targeting cisplatin to ovarian cancer. Cancer cell specificity of biotin-conjugated dendrimers was characterized using spectrometry and fluorescence microscopy. Preformulation parameters of cisplatin-loaded dendrimers were validated using differential scanning calorimetry and inductively coupled plasma mass spectrometry. Cytotoxicity and mechanism of cytotoxicity of cisplatin loaded dendrimers was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cells lines. In vivo survival studies and biodistribution after intraperitoneal administration of cisplatin-loaded dendrimers was performed on SKOV xenografted BALB/c athymic nude mice. The loading of cisplatin in dendrimers was ~ 11%(w/w). PAMAM dendrimers with amine surface groups (biotinylated and native) have shown 2.5 to 3 fold reduction in IC₅₀ values in ovarian cancer cells including cisplatin-resistant cells when compared with carboxylate surface dendrimers (p < 0.05). A correlation was observed between cytotoxicity of the complexes, enhanced cellular uptake and platinum DNA adduct formation. Treatment with cisplatin-loaded dendrimers resulted in a 7.0 fold increase (p < 0.05) in expression of apoptotic genes (Bcl2, Bax, p53) and 12.7 to 24.7 fold increase (p < 0.05) in activity of caspases 3, 8, and 9 in vitro. Survival percentage of tumor bearing mice increased by 25.8% after treatment with cisplatin-loaded biotinylated PAMAM NH₂ dendrimers. Results suggest that biotinylated PAMAM dendrimers can be used as potential carriers for cisplatin chemotherapy in ovarian cancer. |
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| Item Description: | "Submitted to the School of Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2011". "Major Subject: Medical Sciences". Approved as to style and content by: Srinath Palakurthi, Cynthia J. Meininger, Lacy Daniels, Alison C. Rice-Ficht, Van G. Wilson. Vita. |
| Physical Description: | xi, 157 leaves : illustrations (some color) ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 139-140). |