| dc.identifier.uri | http://hdl.handle.net/11401/77150 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Cancer is the second leading cause of death in the United States and is responsible for one in eight deaths worldwide. Traditional chemotherapeutics target the processes involved in cell division and consequently produce dangerous and dose-limiting side effects. In an effort to identify the therapeutic windown of these drugs, tumor targeted drug conjugates (TTDCs) are currently under development. The Ojima lab has developed and extensive panel of next-generation taxoids that possess the requisite sub-nanomolar potency for incorporation into effective conjugates. A small library of 17 taxoids was synthesized and their cytotoxicity investigated. Selected taxoids were synthesized on the half-gram to multi-gram scales for use in TTDCs. Polyunsaturated fatty acids (PUFAs) have been widely used as tumor-tageting moieties (TTMs), due to their high binding affinity for human serum albumin. These strategies are best exemplified by Taxoprexin® and Abraxane®. Selected taxoids were conjugated to the PUFAs DHA and/or LNA and were evaluated in vitro and in vivo, demonstrating promising results. The PK profile for DHA-1214 was also investigated. In addition, a novel conjugate bearing a cytotoxic DHA-Propofol moiety was synthesized and evaluated in vitro. Vitamins have also been successfully applied to TTDCs. The most notable example is folic acid and the folate-drug conjugate Vintafolide®. A novel synthetic route to a solubilized folate- taxoid conjugate was developed via solid phase pepetide synthesis and Cu-free click chemistry.Biotin is also under investigation in our lab as a promising new TTM. Biotin conjugates were synthesized and their efficacy evaluated in vivo, demonstrating clear evidence for tumor-targeting. To facilitate the preclinical development of the various taxoid-based TTDCs in our lab, an efficient route to radio-labeled next-generation taxoids was developed through a vinylstannyl taxoid intermediate. Using a Cu/Pd catalyzed Stille coupling, we can efficiently indroduce a methyl group in the last step of the synthesis, amenable for labeling with 11C for PET, and tritium or 14C for liquid scintigraphy. This tool has the potential to greatly enhance our understanding of the protein binding kinetics and biodistribution of our taxoids and their respective drug conjugates. | |
| dcterms.abstract | Cancer is the second leading cause of death in the United States and is responsible for one in eight deaths worldwide. Traditional chemotherapeutics target the processes involved in cell division and consequently produce dangerous and dose-limiting side effects. In an effort to identify the therapeutic windown of these drugs, tumor targeted drug conjugates (TTDCs) are currently under development. The Ojima lab has developed and extensive panel of next-generation taxoids that possess the requisite sub-nanomolar potency for incorporation into effective conjugates. A small library of 17 taxoids was synthesized and their cytotoxicity investigated. Selected taxoids were synthesized on the half-gram to multi-gram scales for use in TTDCs. Polyunsaturated fatty acids (PUFAs) have been widely used as tumor-tageting moieties (TTMs), due to their high binding affinity for human serum albumin. These strategies are best exemplified by Taxoprexin® and Abraxane®. Selected taxoids were conjugated to the PUFAs DHA and/or LNA and were evaluated in vitro and in vivo, demonstrating promising results. The PK profile for DHA-1214 was also investigated. In addition, a novel conjugate bearing a cytotoxic DHA-Propofol moiety was synthesized and evaluated in vitro. Vitamins have also been successfully applied to TTDCs. The most notable example is folic acid and the folate-drug conjugate Vintafolide®. A novel synthetic route to a solubilized folate- taxoid conjugate was developed via solid phase pepetide synthesis and Cu-free click chemistry.Biotin is also under investigation in our lab as a promising new TTM. Biotin conjugates were synthesized and their efficacy evaluated in vivo, demonstrating clear evidence for tumor-targeting. To facilitate the preclinical development of the various taxoid-based TTDCs in our lab, an efficient route to radio-labeled next-generation taxoids was developed through a vinylstannyl taxoid intermediate. Using a Cu/Pd catalyzed Stille coupling, we can efficiently indroduce a methyl group in the last step of the synthesis, amenable for labeling with 11C for PET, and tritium or 14C for liquid scintigraphy. This tool has the potential to greatly enhance our understanding of the protein binding kinetics and biodistribution of our taxoids and their respective drug conjugates. | |
| dcterms.available | 2017-09-20T16:52:05Z | |
| dcterms.contributor | Scharer, Orlando | en_US |
| dcterms.contributor | Ojima, Iwao | en_US |
| dcterms.contributor | Goroff, Nancy | en_US |
| dcterms.contributor | Horwitz, Susan. | en_US |
| dcterms.creator | Seitz, Joshua | |
| dcterms.dateAccepted | 2017-09-20T16:52:05Z | |
| dcterms.dateSubmitted | 2017-09-20T16:52:05Z | |
| dcterms.description | Department of Chemistry. | en_US |
| dcterms.extent | 471 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77150 | |
| dcterms.issued | 2013-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:52:05Z (GMT). No. of bitstreams: 1
Seitz_grad.sunysb_0771E_11542.pdf: 17977387 bytes, checksum: dc2166f0f0780aacb44d84e2b19f0eb8 (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | cancer, conjugation, drug delivery, synthesis, taxoid, tumor-targeting | |
| dcterms.subject | Chemistry | |
| dcterms.title | The design, synthesis and biological evaluation of novel taxoid anticancer agents and their tumor-targeted drug conjugates | |
| dcterms.type | Dissertation | |
