Due
to their relatively large molecular sizes and delicate nature,
biologic drugs such as peptides, proteins, and antibodies often require
high and repeated dosing, which can cause undesired side effects and
physical discomfort in patients and render many therapies inordinately
expensive. To enhance the efficacy of biologic drugs, they could be
encapsulated into polymeric hydrogel formulations to preserve their
stability and help tune their release in the body to their most favorable
profile of action for a given therapy. In this study, a series of
injectable, thermoresponsive hydrogel formulations were evaluated
as controlled delivery systems for various peptides and proteins,
including insulin, Merck proprietary peptides (glucagon-like peptide
analogue and modified insulin analogue), bovine serum albumin, and
immunoglobulin G. These hydrogels were prepared using concentrated
solutions of poly(lactide-
co
-glycolide)–
block
-poly(ethylene glycol)–
block
-poly(lactide-
co
-glycolide) (PLGA–PEG–PLGA),
which can undergo temperature-induced sol–gel transitions and
spontaneously solidify into hydrogels near the body temperature, serving
as an in situ depot for sustained drug release. The thermoresponsiveness
and gelation properties of these triblock copolymers were characterized
by dynamic light scattering (DLS) and oscillatory rheology, respectively.
The impact of different hydrogel-forming polymers on release kinetics
was systematically investigated based on their hydrophobicity (LA/GA
ratios), polymer concentrations (20, 25, and 30%), and phase stability.
These hydrogels were able to release active peptides and proteins
in a controlled manner from 4 to 35 days, depending on the polymer
concentration, solubility nature, and molecular sizes of the cargoes.
Biophysical studies via size exclusion chromatography (SEC) and circular
dichroism (CD) indicated that the encapsulation and release did not
adversely affect the protein conformation and stability. Finally,
a selected PLGA–PEG–PLGA hydrogel system was further
investigated by the encapsulation of a therapeutic glucagon-like peptide
analogue and a modified insulin peptide analogue in diabetic mouse
and minipig models for studies of glucose-lowering efficacy and pharmacokinetics,
where superior sustained peptide release profiles and long-lasting
glucose-lowering effects were observed in vivo without any significant
tolerability issues compared to peptide solution controls. These results
suggest the promise of developing injectable thermoresponsive hydrogel
formulations for the tunable release of protein therapeutics to improve
patient’s comfort, convenience, and compliance.