TY - JOUR
T1 - Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation
AU - Song, Jimmy Y.
AU - Larson, Nicholas R.
AU - Thati, Sharadvi
AU - Torres-Vazquez, Irma
AU - Martinez-Rivera, Noraida
AU - Subelzu, Natalia J.
AU - Leon, Martin A.
AU - Rosa-Molinar, Eduardo
AU - Schöneich, Christian
AU - Forrest, M. Laird
AU - Middaugh, C. Russell
AU - Berkland, Cory J.
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/1/10
Y1 - 2019/1/10
N2 - Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing-remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3 nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5 MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients.
AB - Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing-remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3 nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5 MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients.
KW - Copaxone®
KW - Glatiramer acetate
KW - Multiple Sclerosis
KW - SC injection simulation
UR - http://www.scopus.com/inward/record.url?scp=85056776746&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2018.11.007
DO - 10.1016/j.jconrel.2018.11.007
M3 - Article
C2 - 30414463
AN - SCOPUS:85056776746
SN - 0168-3659
VL - 293
SP - 36
EP - 47
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -