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Molecular-size effects of poly(ethylene glycol) doxorubicin nanocarriers on the intraductal treatment of ductal carcinoma in situ (dcis)
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Gu, Zichao. Molecular-size effects of poly(ethylene glycol) doxorubicin nanocarriers on the intraductal treatment of ductal carcinoma in situ (dcis). Retrieved from https://doi.org/doi:10.7282/T3FJ2JG9

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TitleMolecular-size effects of poly(ethylene glycol) doxorubicin nanocarriers on the intraductal treatment of ductal carcinoma in situ (dcis)
NameGu, Zichao (author); Sinko, Patrick (chair); Michniak, Bozena (internal member); You, Guofeng (internal member); Love, Susan (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2015
Other Date2015-01 (degree)
SubjectPharmaceutical Science, Polyethylene glycol, Breast--Cancer, Drug delivery systems
Extent1 online resource (xiv, 119 p. : ill.)
DescriptionSystemic chemotherapy is not a first-line treatment option for early stage breast cancer due primarily to the limited blood supply in mammary ducts and the variable and limited drug concentration reaching to the tumor within the ducts. To enhance local drug concentration and avoid excess systemic exposure, an intraductal approach for delivering the anti-cancer agents directly to mammary glands provides an alternative method for treating DCIS. Doxorubicin (DOX) is a widely used anti-cancer drug but it rapidly diffuses from the mammary gland into the systemic circulation. Therefore, techniques for retaining drugs locally in the mammary gland are needed. The objective of this thesis project is to design, develop, and evaluate breast intraductal drug delivery systems that provide higher drug retention in the mammary gland, thereby minimizing systemic exposure and achieving maximal local therapeutic effect. PEG polymers with different molecular weights (5, 10, 20 and 40 kDa) and molecular architectures (linear, four-arm and eight-arm) were conjugated to DOX to develop PEG DOX (PEG-DOX) nanocarriers. The hydrodynamic radii studies showed the hydrodynamic radii increased with increasing molecular weight for the linear PEGs and decreased with increased branching in the polymer structure. The mammary gland retention half-lives demonstrated the influence of molecular weight and structure of nanocarriers on mammary gland retention. Pharmacokinetic profiles indicated that nanocarriers with longer retention half-life tend to distribute into the blood stream with a delayed plasma peak time. Histological studies showed no local damage or inflammation in the nanocarrier treated mammary gland, but altered ductal structure was observed in DOX treated mammary gland. A F344 tumor model, developed by inoculating 13762 Mat B III cells into female F344 rats intraductally, exhibited cell load- and time-dependent tumor development in the rats. Efficacy studies demonstrated slower tumor growth in the intraductal treatment groups than in the intravenous treatment groups. The survival rate in the intraductal treatment groups was significant higher than the untreated group. In summary, the developed PEG-DOX nanocarriers improved DOX retention and reduced DOX toxicity in mammary gland, leading to a significantly improved survival percentage in treating DCIS in a F344 tumor rat model.
NotePh.D.
NoteIncludes bibliographical references
Noteby Zichao Gu
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3FJ2JG9
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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