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Pre-existing conditions at reproductive age, and complications arising during pregnancy can be detrimental to maternal and fetal health. Current therapies to combat obstetric ...disorders are limited due to the inherent complexity of pregnancy, and can have harmful effects on developing fetus. Emerging research shows intricate signaling between the cells from mother and fetus at maternal-fetal interface, providing unique opportunities for interventions specifically targeted to the mother, fetus, or placenta. Advancements in nanotechnology, stem-cell biology and gene therapy have resulted in target-specific treatments with promising results in pre-clinical maternal and fetal disorder models. Comprehensive understanding of the effect of physicochemical properties of delivery systems on their uptake, retention and accumulation across placenta will help in the better diagnosis and treatment of perinatal disorders. This review describes the factors leading to obstetric complications along with their effect on pregnancy outcomes, and discusses key targeted therapeutic strategies for addressing conditions related to maternal and fetal health.
Mitochondrial oxidative stress is associated with many neurodegenerative diseases, such as traumatic brain injury (TBI). Targeted delivery of antioxidants to mitochondria has failed to translate into ...clinical success due to their nonspecific cellular localization, poor transport properties across multiple biological barriers, and associated side effects. These challenges, coupled with the complex function of the mitochondria, create the need for innovative delivery strategies.
Neutral hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have shown significant potential as nanocarriers in multiple brain injury models.
-acetyl cysteine (NAC) is a clinically used antioxidant and anti-inflammatory agent which has shown significant potency when delivered in a targeted manner. Here we present a mitochondrial targeting hydroxyl PAMAM dendrimer-drug construct (TPP-D-NAC) with triphenyl-phosphonium (TPP) for mitochondrial targeting and NAC for targeted delivery to mitochondria in injured glia. Co-localization and mitochondrial content of mitochondria-targeted and unmodified dendrimer were assessed in microglia and macrophages
via immunohistochemistry and fluorescence quantification. Therapeutic improvements of TPP-D-NAC over dendrimer-NAC conjugate (D-NAC) and free NAC were evaluated
in microglia under oxidative stress challenge.
neuroinflammation targeting was confirmed in a rabbit model of TBI.
TPP-conjugated dendrimer co-localized significantly more with mitochondria than unmodified dendrimer without altering overall levels of cellular internalization. This targeting capability translated to significant improvements in the attenuation of oxidative stress by TPP-D-NAC compared to D-NAC and free NAC. Upon systemic administration in a rabbit TBI model, TPP-conjugated dendrimer co-localized specifically with mitochondria in activated microglia and macrophages in the white matter of the ipsilateral/injured hemisphere, confirming its BBB penetration and glial targeting capabilities.
D-NAC has shown promising efficacy in many animal models of neurodegeneration, and this work provides evidence that modification for mitochondrial targeting can further enhance its therapeutic efficacy, particularly in diseases where oxidative stress-induced glial cell death plays a significant role in disease progression.
Abstract Dendrimers are an emerging group of nanostructured, polymeric biomaterials that have potential as non-viral vehicles for delivering drugs and genetic material to intracellular targets. They ...have a high charge density with tunable surface functional groups, which can alter the local environment and influence cellular interactions. This can have a significant impact on the intracellular trafficking of dendrimer-based nanodevices. With the help of flow cytometry, fluorescence microscopy, and by using specific inhibitors, the influence of surface functionality on their uptake in A549 lung epithelial cells, and subsequent intracellular distribution was investigated. In this paper, we have shown that even though all the dendrimers are taken up by fluid-phase endocytosis, significant differences in uptake mechanisms exist. Anionic dendrimers appear to be mainly taken up by caveolae mediated endocytosis in A549 lung epithelial cells, while cationic and neutral dendrimers appear to be taken in by a non-clathrin, non-caveolae mediated mechanism that may be by electrostatic interactions or other non-specific fluid-phase endocytosis. These findings open up new possibilities of targeting therapeutic agents to specific cell organelles based on surface charge.
Neurotherapeutics for the treatment of central nervous system (CNS) disorders must overcome challenges relating to the blood-brain barrier (BBB), brain tissue penetration, and the targeting of ...specific cells. Neuroinflammation mediated by activated microglia is a major hallmark of several neurological disorders, making these cells a desirable therapeutic target. Building on the promise of hydroxyl-terminated generation four polyamidoamine (PAMAM) dendrimers (D4-OH) for penetrating the injured BBB and targeting activated glia, we explored if conjugation of targeting ligands would enhance and modify brain and organ uptake. Since mannose receptors cluster of differentiation (CD) 206 are typically over-expressed on injured microglia, we conjugated mannose to the surface of multifunctional D4-OH using highly efficient, atom-economical, and orthogonal Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry and evaluated the effect of mannose conjugation on the specific cell uptake of targeted and non-targeted dendrimers both in vitro and in vivo. In vitro results indicate that the conjugation of mannose as a targeting ligand significantly changes the mechanism of dendrimer internalization, giving mannosylated dendrimer a preference for mannose receptor-mediated endocytosis as opposed to non-specific fluid phase endocytosis. We further investigated the brain uptake and biodistribution of targeted and non-targeted fluorescently labeled dendrimers in a maternal intrauterine inflammation-induced cerebral palsy (CP) rabbit model using quantification methods based on fluorescence spectroscopy and confocal microscopy. We found that the conjugation of mannose modified the distribution of D4-OH throughout the body in this neonatal rabbit CP model without lowering the amount of dendrimer delivered to injured glia in the brain, even though significantly higher glial uptake was not observed in this model. Mannose conjugation to the dendrimer modifies the dendrimer's interaction with cells, but does not minimize its inherent inflammation-targeting abilities.
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•Trifunctional PAMAM dendrimer was constructed using CuAAC click chemistry.•Both mannose and Cy5 were conjugated to the dendrimer surface.•Dendrimer with mannose utilizes mannose receptor-mediated endocytosis.•Mannosylated dendrimer resides in mannose receptor positive cells in vivo.•Mannose conjugation did not reduce uptake of dendrimer in the brain.
Treatment of Central Nervous System (CNS) disorders still remains a major clinical challenge. The Blood–Brain Barrier (BBB), known as the major hindrance, greatly limits therapeutics penetration into ...the brain. Moreover, even though some therapeutics can cross BBB based on their intrinsic properties or via the use of proper nanoscale delivery vehicles, their therapeutic efficacy is still often limited without the specific uptake of drugs by the cancer or disease-associated cells. As more studies have started to elucidate the pathological roles of major cells in the CNS (for example, microglia, neurons, and astrocytes) for different disorders, nanomedicines that can enable targeting of specific cells in these diseases may provide great potential to boost efficacy. In this review, we aim to briefly cover the pathological roles of endothelial cells, microglia, tumor-associated microglia/macrophage, neurons, astrocytes, and glioma in CNS disorders and to highlight the recent advances in nanomedicines that can target specific disease-associated cells. Furthermore, we summarized some strategies employed in nanomedicine to achieve specific cell targeting or to enhance the drug neuroprotective effects in the CNS. The specific targeting at the cellular level by nanotherapy can be a more precise and effective means not only to enhance the drug availability but also to reduce side effects.
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Glioblastoma is among the most aggressive forms of cancers, with a median survival of just 15–20 months for patients despite maximum clinical intervention. The majority of conventional anti-cancer ...therapies fail due to associated off-site toxicities which can be addressed by developing target-specific drug delivery systems. Advances in nanotechnology have provided targeted systems to overcome drug delivery barriers associated with brain and other types of cancers. Dendrimers have emerged as promising vehicles for targeted drug and gene delivery. Dendrimer-mediated targeting strategies can be further enhanced through the addition of targeting ligands to enable receptor-specific interactions. Here, we explore the sugar moieties as ligands conjugated to hydroxyl-terminated polyamidoamine dendrimers to leverage altered metabolism in cancer and immune targeting. Using a highly facile click chemistry approach, we modified the surface of dendrimers with glucose, mannose, or galactose moieties in a well-defined manner, to target upregulated sugar transporters in the context of glioblastoma. We show that glucose modification significantly enhanced targeting of tumor-associated macrophages (TAMs) and microglia by increasing brain penetration and cellular internalization, while galactose modification shifts targeting away from TAMs towards galectins on glioblastoma tumor cells. Mannose modification did not alter TAMs and microglia targeting of these dendrimers, but did alter their kinetics of accumulation within the GBM tumor. The whole body biodistribution was largely similar between the systems. These results demonstrate that dendrimers are versatile delivery vehicles that can be modified to tailor their targeting for the treatment of glioblastoma and other cancers.
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•Systemic targeting of TAMs can provide promising immunotherapeutic options for GBM.•Hydroxyl PAMAM dendrimers target TAMs from systemic administration.•Glycosylation of PAMAM-OH significantly improves TAMs targeting and specificity.•These dendrimers are promising platform for enhanced anti-cancer drug delivery.
Small interfering RNAs (siRNAs) are potent weapons for gene silencing, with an opportunity to correct defective genes and stop the production of undesirable proteins, with many applications in ...central nervous system (CNS) disorders. However, successful delivery of siRNAs to the brain parenchyma faces obstacles such as the blood–brain barrier (BBB), brain tissue penetration, and targeting of specific cells. In addition, siRNAs are unstable under physiological conditions and are susceptible to protein binding and enzymatic degradation, necessitating a higher dosage to remain effective. To address these issues and advance siRNA delivery, we report the development of covalently conjugated hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer–siRNA conjugates, demonstrated with a siRNA against GFP (siGFP) conjugate (D-siGFP) utilizing glutathione-sensitive linkers. This allows for precise nucleic acid loading, protects the payload from premature degradation, delivers the siRNA cargo into cells, and achieves significant GFP knockdown in vitro (∼40%) and in vivo (∼30%). Compared to commercially available delivery systems such as RNAi Max and Lipofectamine, D-siGFP retains the potency of the siRNA in vitro. In addition, the dendrimer-siGFP conjugate significantly enhances the half-life of siRNA in the presence of plasma and endonucleases and maintains the passive targeting ability of PAMAM dendrimers to reactive microglia. When administered intratumorally to orthotopic glioblastoma multiform tumors (GBM) in CX3CR-1GFP mice, D-siGFP localizes in tumor-associated macrophages (TAMs) within the tumor parenchyma, minimizing off-target effects in other cell populations. The facile conjugation strategy for dendrimer–siRNA conjugates presented here offers a promising approach for targeted, systemic intracellular delivery of siRNA, serving as a potential bridge for the clinical translation of RNAi therapies.
Dendrimers are members of a versatile, fourth new class of polymer architecture (i.e. dendritic polymers after traditional linear, crosslinked and branched types)
1. Typically, dendrimers are used as ...well-defined scaffolding or nanocontainers to conjugate, complex or encapsulate therapeutic drugs or imaging moieties. As a delivery vector, the dendrimer conjugate linker or spacer chemistry plays a crucial part in determining optimum drug delivery to disease sites by conserving active drug efficacy while influencing appropriate release patterns. This review focuses on several crucial issues related to those dendrimer features, namely the role of dendrimers as nanoscaffolding and nanocontainers, crucial principles that might be invoked for improving dendrimer cytotoxicity properties, understanding dendrimer cellular transport mechanisms and the exciting role of dendrimers as high-contrast MRI imaging agents. The review concludes with a brief survey of translational efforts from research and development phases to clinical trials that are actively emerging.
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Vision impairment and loss due to posterior segment ocular disorders, including age-related macular degeneration and diabetic retinopathy, are a rapidly growing cause of disability ...globally. Current treatments consist primarily of intravitreal injections aimed at preventing disease progression and characterized by high cost and repeated clinic visits. Nanotechnology provides a promising platform for drug delivery to the eye, with potential to overcome anatomical and physiological barriers to provide safe, effective, and sustained treatment modalities. However, there are few nanomedicines approved for posterior segment disorders, and fewer that target specific cells or that are compatible with systemic administration. Targeting cell types that mediate these disorders via systemic administration may unlock transformative opportunities for nanomedicine and significantly improve patient access, acceptability, and outcomes. We highlight the development of hydroxyl polyamidoamine dendrimer-based therapeutics that demonstrate ligand-free cell targeting via systemic administration and are under clinical investigation for treatment of wet age-related macular degeneration.
Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial ...dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.
To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc
) is upregulated in Mecp2-null glia when compared to WT, the role of Xc
in the uptake of NAC and L-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan.
We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc
was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc
for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival.
These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.
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