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Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation.

ABSTRACT: N-Acetyl cysteine (NAC) is a vital drug currently under clinical trials for the treatment of neuroinflammation in maternal-fetal applications. The free sulfhydryl groups in NAC lead to high plasma protein binding, resulting in low bioavailability. Preparation and activity of conjugates of NAC with thiol terminated multi-arm (6 and 8) poly(ethylene-glycol) (PEG) with disulfide linkages involving sulfhydryls of NAC are reported. Multiple copies (5 and 7) of NAC were conjugated on 6 and 8-arm-PEG respectively. Both the conjugates released 74% of NAC within 2h by thiol exchange reactions in the redox environment provided by glutathione (GSH) intracellularly (2-10mM). At physiological extracellular glutathione concentration (2 microM) both the conjugates were stable and did not release NAC. MTT assay showed comparable cell viability for unmodified PEGs and both the PEG-S-S-NAC conjugates. The conjugates were readily endocytosed by cells, as confirmed by flow cytometry and confocal microscopy. Efficacy of 6 and 8-arm-PEG-S-S-NAC conjugates was evaluated on activated microglial cells (the target cells, in vivo) by monitoring cytokine release in lipopolysaccharide (LPS) induced inflammatory response in microglial cells using the reactive oxygen species (ROS), free radical nitrile (NO), anti-inflammatory activity and GSH depletion. The conjugates showed significant increase in antioxidant activity (more than a factor of 2) compared to free drug as seen from the inhibition of LPS induced ROS, NO, GSH and tumor necrosis factor-alpha (TNF-alpha) release in microglial cells.

SUBMITTER: Navath RS

PROVIDER: S-EPMC2833236 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation.

Navath Raghavendra S RS Wang Bing B Kannan Sujatha S Romero Roberto R Kannan Rangaramanujam M RM

Journal of controlled release : official journal of the Controlled Release Society 20091105 3

N-Acetyl cysteine (NAC) is a vital drug currently under clinical trials for the treatment of neuroinflammation in maternal-fetal applications. The free sulfhydryl groups in NAC lead to high plasma protein binding, resulting in low bioavailability. Preparation and activity of conjugates of NAC with thiol terminated multi-arm (6 and 8) poly(ethylene-glycol) (PEG) with disulfide linkages involving sulfhydryls of NAC are reported. Multiple copies (5 and 7) of NAC were conjugated on 6 and 8-arm-PEG r ...[more]

PMID: 19896998

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Project description:Stimuli-responsive biomaterials are used to facilitate drug and gene delivery by shielding the drug/gene during circulation times and selectively releasing the cargo at the desired target. Within stimuli-responsive materials, pH-responsive materials are exploited for delivery to specific organs, intracellular compartments, cancer cells, site of inflammation or infection as those sites are characterized by pH that is different from the blood pH. In this paper we use molecular dynamics (MD) simulations to design such pH-responsive biomaterials where the balance between the various intermolecular interactions (e.g., electrostatics, van der Waals) within the biomaterials allow biofunctional molecules to be reversibly shielded and exposed to the environment with change in pH. In our model the shielding aspect is imparted by a polyethylene glycol (PEG) brush and the pH-responsive component is a PEG-tethered oligopeptide that undergoes changes in conformations via protonation of residues upon changes in pH. Starting with a PEG-tethered peptide in a monodisperse short PEG brush, we first vary the composition and sequence of histidine (H), lysine (K), and glutamate (E) along the oligopeptide sequence to find the design parameters that maximize the shielding and exposure of the oligopeptide at pH ? 7.0 and pH < 7.0, respectively. Then, we probe the effect of the PEG brush on the conformations of the oligopeptides by simulating PEG-tethered peptide in a bimodal PEG brush containing short PEG and long PEG chains. We characterize the intermolecular interactions involving the PEG, peptide, and solvent that influence the shielded and exposed conformations of the oligopeptides at the two different pHs. In a short monodisperse PEG brush, with a longer PEG-tethered peptide containing large blocks of histidines that undergo change in protonation state as a response to pH change, placed between a protonated lysine and deprotonated glutamate, the PEG brush exhibits maximum shielding and exposure with pH change. This change from shielded to exposed state is driven by electrostatic repulsion upon H protonation. The presence of long PEG chains in a bimodal PEG brush leads to dominating PEG-peptide attractive interactions that reduces the contrast in shielded and exposed conformations of the PEG-tethered peptide upon protonation of histidines.

Dataset Information

Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation.

Publications

Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation.

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