Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers

JOURNAL OF CONTROLLED RELEASE

卷:237

Article

Zhang, Fan^1,2  Nance, Elizabeth^1,3,7  Zhang, Zhi³  Jasty, Venkatasai¹  Kambhampati, Siva P.^1,4  Mishra, Manoj K.^1,4  Burd, Irina⁵  Romero, Roberto⁶  Kannan, Sujatha^1,3,5,6  Kannan, Rangaramanujam M.^1,2,3,4,6 

[1] Johns Hopkins Univ, Wilmer Eye Inst, Ctr Nanomed, Sch Med, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Mat Sci, Baltimore, MD 21218 USA

[3] Johns Hopkins Univ, Anesthesiol & Crit Care Med, Sch Med, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Wilmer Eye Inst, Dept Ophthalmol, Sch Med, Baltimore, MD 21231 USA

[5] Johns Hopkins Univ, Dept Gynecol & Obstet, Integrated Res Ctr Fetal Med, Sch Med, Baltimore, MD 21287 USA

[6] Perinatol Res Branch, Detroit, MI 48201 USA

[7] Univ Washington, Dept Chem Engn, Seattle, WA 98195 USA

关键词: Dendrimer;    Surface functionality;    Intra-amniotic delivery;    Blood-placental barrier;    Microglia;    Neuroinflammation;   

DOI  :  10.1016/j.jconrel.2016.06.046

来源: Elsevier

【 摘 要 】

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. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

Free