Transfer of PAMAM dendrimers across human placenta: Prospects of its use as drug carrier during pregnancy

Abstract

Dendrimers offer significant potential as nanocarriers for targeted delivery of drugs and imaging agents. The objectives of this study were to evaluate the transplacental transport, kinetics and biodistribution of PAMAM dendrimers ex-vivo across the human placenta in comparison with antipyrine, a freely diffusible molecule, using dually perfused re-circulating term human placental lobules. The purpose of this study is to determine if dendrimers as drug carriers can be used to design drug delivery systems directed at selectively treating either the mother or the fetus. The transplacental transfers of fluorescently (Alexa 488) tagged PAMAM dendrimer (16 kDa) and antipyrine (188 Da) from maternal to fetal circulation were measured using HPLC/dual UV and fluorescent detector (sensitivity of 10 ng / mL for dendrimer and 100 ng /mL for antipyrine respectively). C max for the dendrimer-Alexa (DA) in maternal perfusate (T max = 15min) was 18 times higher than in the fetal perfusate and never equilibrated with the maternal perfusate during 5.5 hours of perfusion (n=4). DA exhibited a significant but low transplacental transport of ~2.26 ± 0.12 μg / mL during 5.5 hours, where the mean transplacental transfer was 0.84 ±0.11 % of the total maternal concentration and the feto-maternal ratio as percent was 0.073% ± 0.02. The biochemical and physiological analysis of the placentae perfused with DA demonstrated normal function throughout the perfusion. The immunofluorescence histochemistry confirmed that the biodistribution of DA in perfused placenta was sparsely dispersed, and when noted was principally seen in the inter-villous spaces and outer rim of the villous branches. In a few cases, DA was found internalized and localized in nuclei and cytoplasm of syncytiotrophoblast and inside the villous core; however, DA was mostly absent from the villous capillaries. In conclusion, the PAMAM dendrimers exhibited a low rate of transfer from maternal to the fetal side across the perfused human placenta, which is similar to other investigations of large macromolecules, eg., IgG. These overall findings suggest that entry of drugs conjugated to polymers, i.e., dendrimers, would be limited in their transfer across the human placenta when compared to smaller drug © 2010 Elsevier B.V. All rights reserved. * Corresponding author: Rangaramanujam M. Kannan, Department of Chemical Engineering and Material Science, Wayne State University, Detroit, Michigan 48202; rkannan.wsu@gmail.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscr...

Nitric oxide releasing-dendrimers: an overview

“…Major applications are related to the drug delivery systems development (Gillies, Fréchet, 2005;Medina, El-Sayed, 2009;Nanjwade et al, 2009;Wijagkanalan, Kawakami, Hashida, 2011;, solubility (Devarakonda, Hill, Villiers, 2004) and biocompatibility improvements (reduce toxicity) (Duncan, Izzo, 2005;Sadekar, Ghandehari, 2010;Ciolkowski et al, 2012), magnetic resonance image (MRI) contrast (Wiener et al, 1994;Margerum et al, 1997;Kobayashi et al, 2003;Kojima et al, 2011;Tang et al, 2012), targeted drug delivery (Yang et al, 2009;Menjoge et al, 2011) and gene delivery (Dufès, Uchegbu, Schätzlein, 2005;Kim et al, 2007;Mintzer, Simanek, 2009;Shcharbin, Klajnert, Bryszewska, 2009;Nam et al, 2012).…”

Transport of Nanoparticles through the Placental Barrier

“…They might function as pressure-dependent valves regulating fetal water and biomolecules transport by changing the effective molecular diameter in the range of 2-25 nm. However, the presence and physiological role of these channels is uncertain and remains disputed among scientists (Bonatelli et al 2005;Menjoge et al 2011).…”

“…The ex vivo human placenta perfusion model was also employed for the assessment of polyamidoamine (PAMAM) dendrimers penetration to the fetus (Menjoge et al 2011). The diameter of fluorescently labelled NP was in the range of 5-6 nm.…”

“…The proposed transport mechanisms are different for NP of distinct size ranges: paracellular diffusion dominates in the case of small (~5.5 nm) NP (Menjoge et al 2011) and transcellular transfer is more likely for larger (50-240 nm) NP (Wick et al 2010). However the penetration pathways are still hypothetical and experimentally unproven.…”

“…The NP penetration into the conceptus is becoming an important factor in veterinary and medicine as NP are actively developed as agents for optical and magnetic imaging, drugs and vaccines for both animals and humans (Adair 2009). Molecule penetra-tion across the placental barrier limits applications of some conventional drugs during pregnancy, and nanotechnology might offer solutions to this problem by developing drug-NP conjugates that would accumulate in specific targeted tissue but would not be transported to fetus because of the size of the complex (Menjoge et al 2011). Such nanotechnological approaches open new frontiers in veterinary and medicine, but the in-depth understanding of physiological processes remains of crucial importance before developing and applying NP during pregnancy.…”