Characterizing the Effect of Poly(ethylene glycol) Concentration and Surface Modifications on Doxorubicin-Loaded Polymer Nanoparticles
Date
2025-05
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
Triple-negative breast cancer (TNBC) is an extremely aggressive subtype of
breast cancer that accounts for around 20% of all breast cancer diagnoses [1], [2].
Unlike other subtypes of breast cancer, TNBC lacks expression of the three common
receptors of estrogen receptor (ER), progestogen receptor (PR), and human epidermal
growth factor receptor 2 (HER2), making it difficult to treat with current interventions
[3]. The lack of molecular targets combined with TNBC’s aggressive nature leads to
poor prognosis with a ~40% mortality rate within 5 years of diagnosis [4]. Due to this
poor prognosis, it is important to develop novel methods to treat TNBC.
Nanoparticles (NPs) are versatile drug-delivery vessels with highly tunable
characteristics making them adaptable for a variety of therapeutic applications [5].
Poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs have favorable
characteristics such as biodegradability and biocompatibility, and the individual
components of PLGA and PEG are both FDA approved polymers [6], [7]. These NPs
have the ability to encapsulate and deliver Doxorubicin, a chemotherapeutic, which
can enhance the drugs’ effectiveness and safety in treating solid tumor cancers by
improving the relative amount of the payload that reaches tumors versus other tissues
[7]. NPs also prevent the adverse off target effects normally characteristic of
chemotherapies. To advance the use of PEG-PLGA NPs in cancer nanomedicine, this
thesis investigates how PEG concentration influences the characteristics of PEG PLGA NPs as well as how surface modifications affect the NPs’ characteristics.
PEG-PLGA NPs are prepared by mixing different combinations of PEG-PLGA
with PLGA through a single emulsion oil-in-water method. In this thesis, three ratios
of PEG-PLGA to PLGA (25% PEG-PLGA/75% PLGA, 50% PEG-PLGA/50%
PLGA, 75% PEG-PLGA/25% PLGA) were used to produce NPs containing
doxorubicin-HCl (DOX), a chemotherapy drug used to treat TNBC and other forms of
cancer. Each formulation was characterized for its’ initial DOX loading, stability in
storage conditions, and DOX release kinetics in physiologic conditions. Through these
studies, it was identified that the 25/75 PEG-PLGA/PLGA formulation shows optimal
characteristics such as remaining stable in size and charge in storage conditions,
having a high initial DOX loading, superior DOX retention in storage conditions, and
favorable release kinetics in physiologic conditions. Based on these favorable
characteristics, the 25/75 formulation was selected for additional experiments to study
the influence of surface modifications on NP characteristics. NPs were coated with
either Frizzled7 (FZD7) antibodies or TNBC cell-derived plasma membranes, as both
of these coatings have been shown to enable TNBC cell targeting of NPs in prior
research. In this thesis, it was determined that both FZD7 antibody-coated NPs and
TNBC cell membrane-coated NPs showed similar DOX release kinetics to the
unmodified core, although the initial DOX loading in the NPs was reduced compared
to the uncoated NPs. These findings suggest that further optimization of the coating
process may be needed to ensure minimal loss of cargo during NP surface
functionalization.
Collectively, this thesis shows that a lower ratio of PEG-PLGA to PLGA is
preferable when developing NPs for hydrophobic drug delivery and that there is some
loss in cargo loading during the surface functionalization of these NPs. These findings
are important for the future development of NPs with improved characteristics to
enhance cancer treatment outcomes.