(678b) Optimizing the Surface Property-Activity Relationship of Nanoscale Hydrogel Drug Delivery Systems
is the deadliest of all gynecological cancers and the fifth leading cause of
death due to cancer in women, resulting in more than 15,500 deaths each year
. Screening for ovarian cancer in the general population is not recommended
by any medical group as many other benign conditions also exhibit expression of
the same biomarkers, including endometriosis-induced irritation, pregnancy, and
liver disease, leading to a significant rate of false diagnosis . As a
result, the development of improved therapies remains a key challenge. Despite
broadly increased research into the development of new anti-cancer therapies,
there has been no change in the mortality rate for ovarian cancer in the last
30 years .
treatment plans typically include chemotherapy with radiation or surgical
removal of the tumors. However, traditional chemotherapy does not distinguish
between healthy and cancerous cells and typically leads to significant side
effects. The use of nanoparticles as delivery vehicles has shown promise for
enhancing the systemic delivery of chemotherapeutic agents and solving some of
the limitations that conventional administration presents . There are three major requirements
for nanoparticles to deliver their payload to the tumor. They need to: (i) be
stable in the circulation without releasing drug prematurely, (ii) evade
opsonization and accumulate in the tumor efficiently, and (iii) intelligently
release drug inside the tumor cells. This means the nanogel must have
sufficient time in blood circulation to reach intended sites of the body and
accumulate in and around the tumors via leaky vasculature. Ultimately, localizing and controlling drug release
at the disease site would offer advantages over the current chemotherapeutic
regimens because it limits the toxicity to healthy tissues and decreases the
side effects for the patient.
In this work, we have developed
long-circulating, biocompatible nanoscale hydrogels (nanogels) that respond to
the acidic intracellular environment for controlled delivery of
chemotherapeutics. The nanogels are comprised of: (i) hydrophilic, cationic
2-(diethylamino)ethyl-methacrylate, (ii) tetraethylene-glycol-dimethacrylate
crosslinker, and (iii) surface-grafted poly(ethylene-glycol). First, we show
that the nanogel molecular architecture can be tailored to carry a variety of
cargos with varying physicochemical properties, and the release kinetics can be
tuned to a desired stimuli. The physical properties of the resulting nanogels
were compared using dynamic light scattering, zeta potential, titration, pyrene
fluorescence, and red blood cell hemolysis to elicit the influence of polymer
composition on swelling ratio, surface charge, pKa, hydrophile-hydrophobe phase
transition, and erythrocyte membrane disruption capability. The delivery
capacity was analyzed using carboplatin and paclitaxel.
Next, we optimized the nanogel
surface properties to avoid the bodys natural clearance mechanisms and
increase circulation time, while still maintaining the necessary characteristics
to promote cellular uptake. Stealth coatings shield the particle surface
charge and thereby reduce opsonization by blood proteins and uptake by macrophages
of the mononuclear phagocyte system. Yet, after localizing at the tumor site,
the coating may hinder drug release and target cell interaction and can
therefore be an obstacle in the realization of the therapeutic response. To
this extent, we developed a novel stimuli-responsive coating on the particle
surface that unmasks a ligand that binds to cell surface receptors
overexpressed in ovarian cancer cells. Using hyaluronic acid, PEG, and
dextran, a library of nanoparticles with varying degrees of surface density was
synthesized, and the impact to particle physicochemical properties, protein
binding, drug release, and binding affinity was investigated. The influence of
the surface properties to cellular cytocompatibility, uptake, degree of nanogel-cell
specificity, and therapeutic efficacy was evaluated with OVCAR-3 cells as a
function of time and concentration.
We demonstrated that both the surface-grafted
and hydrophobic monomer composition can be varied to enable precise control
over the nanogel surface and core characteristics to enable effective,
controlled delivery. Varying both chain length and steric bulk allowed for
precise control over the thermodynamic response (swelling ratio), dynamic
behavior (pKa, membrane disruption), and drug-polymer interaction (delivery
capacity). Ultimately, we demonstrated that the tunability of our
multicomponent nanogel can be exploited to enable long-circulation and effective
transport of the drugs to the tumor site.
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Kalscheuer SM, Panyam J. Exploiting nanotechnology to overcome tumor drug
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