TY - JOUR
T1 - Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers
AU - Zhang, Fan
AU - Nance, Elizabeth
AU - Zhang, Zhi
AU - Jasty, Venkatasai
AU - Kambhampati, Siva P.
AU - Mishra, Manoj K.
AU - Burd, Irina
AU - Romero, Roberto
AU - Kannan, Sujatha
AU - Kannan, Rangaramanujam M.
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/9/10
Y1 - 2016/9/10
N2 - Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated ‘neutral’ (D-OH) and carboxyl-terminated ‘anionic’ (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis.
AB - Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated ‘neutral’ (D-OH) and carboxyl-terminated ‘anionic’ (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis.
KW - Blood-placental barrier
KW - Dendrimer
KW - Intra-amniotic delivery
KW - Microglia
KW - Neuroinflammation
KW - Surface functionality
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UR - http://www.scopus.com/inward/citedby.url?scp=84977674961&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.06.046
DO - 10.1016/j.jconrel.2016.06.046
M3 - Article
C2 - 27378700
AN - SCOPUS:84977674961
SN - 0168-3659
VL - 237
SP - 61
EP - 70
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -