Systemic 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.
Subject (authority = RUETD)
Topic
Pharmaceutical Science
Subject (authority = ETD-LCSH)
Topic
Polyethylene glycol
Subject (authority = ETD-LCSH)
Topic
Breast--Cancer
Subject (authority = ETD-LCSH)
Topic
Drug delivery systems
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_6127
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xiv, 119 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Zichao Gu
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
Rutgers University. Graduate School - New Brunswick
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Type
License
Name
Author Agreement License
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