Engineering polymeric matrices for controlled drug delivery applications: from bulk gels to nanogels
Date
2016
Authors
Journal Title
Journal ISSN
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Publisher
University of Delaware
Abstract
Over the past few decades, drug delivery systems have been designed using a
wide array of materials and chemical strategies to improve the specificity of therapeutics
by increasing drug stabilities, controlling release profiles and localizing therapeutic
effects. Among various types of drug delivery systems, hydrogels have emerged as a
promising class of materials for the controlled release of bioactive molecules.
Composed of hydrophilic three-dimensional polymer networks, hydrogels have several
advantageous properties including high water content, tunable viscoelasticity, and
biocompatibility, which allow bioactive molecules to be protected against degradation
and released from the hydrogel matrix in a controlled manner over an extended period
of time. Particularly, polyethylene glycol (PEG) hydrogels have been extensively used
for controlled drug delivery applications with encouraging preclinical and clinical
results, owing to the non-immunogenic nature, hydrophilicity and chemical versatility
of PEG polymers. PEG hydrogel-based materials have received approval for use in a
number of medical products including wound healing matrices, medical implants, and
drug delivery depots. In this work, we have specifically engineered PEG hydrogel matrices from bulk
to nanoscale, including bulk hydrogels, nanoparticle-crosslinked hybrid hydrogels and
nanogels for different delivery applications. Firstly, a library of hydrophilic and
hydrolytically degradable PEG hydrogels has been developed for the sustained delivery
of an anthrax toxin-neutralizing monoclonal antibody from 14-56 days. The hydrogels
were formed via a Michael-type addition between multi-arm PEG-SH and hydrolytically degradable crosslinkers of linear PEG-diacrylate. By varying the polymer architectures and molecular weights of the precursors, the degradation rate of the matrix
can be systematically tuned, which in turn tailors the rate of antibody release from the
hydrogels. In-gel and post-release analysis of the antibody samples indicate that the
conformational properties and biological activity of the protein were well maintained.
In addition to bulk hydrogels for the long-term delivery of therapeutics, stimuliresponsive,
nanoparticle-crosslinked hybrid hydrogels have also been introduced for the
triggered and targeted release of therapeutic molecules. These hybrid hydrogels were
constructed using maleimide-functionalized liposomes (~100nm) as structural elements
to crosslink with thiolated 4-arm PEG polymers via Michael-type addition. Degradation
of these hydrogels was selectively triggered upon exposure to thiol-containing
molecules such as glutathione (GSH), offering great advantages for controlled and
triggered release of therapeutic cargos under reducing environments that are analogous
to the GSH-overproduced tumor microenvironment. The hierarchical structure of these
hybrid hydrogels allows dual encapsulation and prolonged, sequential delivery of
multiple therapeutic molecules with different release mechanism.
Motivated by the significant impact of nanotechnology on the development of
nanoscale drug delivery vehicles, PEG nanogels that combine the advantages of both
nanoparticulate and polymeric hydrogel systems were prepared via the use of liposome
templates. The nanogels were formed by photo-triggered Michael-type addition of PEG
polymer precursors encapsulated within the aqeuous lumen of liposomes under UV
irradiation. The production of nanogels was confirmed via dynamic light scattering
(DLS) and transmission electron microscopy (TEM). The surface functionality of the lipid-coated nanogels was demonstrated by surface modification with a reactive
fluorescent dye as a proof of concept. These PEG-based polymeric matrices provide a powerful platform for different
specific delivery applications. The bulk, hydrolytically degradable PEG hydrogels
present a simple yet efficient strategy to provide protein stabilization and long-term
delivery of therapeutic proteins. The liposome-crosslinked hybrid hydrogels, on the
other hand, suggest significant potential in the triggered and temporal release of multiple
therapeutic molecules. Lastly, the PEG nanogels offer a unique strategy for the
development of multifunctional nanoparticle therapeutics.