Human endothelial cells are initiators and targets of the rejection response. Pre-operative modification of endothelial cells by small interfering RNA transfection could shape the nature of the host ...response post-transplantation. Ablation of endothelial cell class II major histocompatibility complex molecules by small interfering RNA targeting of class II transactivator can reduce the capacity of human endothelial cells to recruit and activate alloreactive T cells. Here, we report the development of small interfering RNA-releasing poly(amine-co-ester) nanoparticles, distinguished by their high content of a hydrophobic lactone. We show that a single transfection of small interfering RNA targeting class II transactivator attenuates major histocompatibility complex class II expression on endothelial cells for at least 4 to 6 weeks after transplantation into immunodeficient mouse hosts. Furthermore, silencing of major histocompatibility complex class II reduces allogeneic T-cell responses in vitro and in vivo. These data suggest that poly(amine-co-ester) nanoparticles, potentially administered during ex vivo normothermic machine perfusion of human organs, could be used to modify endothelial cells with a sustained effect after transplantation.The use of gene silencing techniques in the treatment of post-transplantation host rejection is not long lasting and can have systemic effects. Here, the authors utilize a nanocarrier for siRNA for treatment of arteries ex vivo prior to implantation subsequently attenuating immune reaction in vivo.
Non-viral vehicles hold therapeutic promise in advancing the delivery of a variety of cargos in vitro and in vivo, including small molecule drugs, biologics, and especially nucleic acids. However, ...their efficacy at the cellular level is limited by several delivery barriers, with endolysosomal degradation being most significant. The entrapment of vehicles and their cargo in the acidified endosome prevents access to the cytosol, nucleus, and other subcellular compartments. Understanding the factors that contribute to uptake and intracellular trafficking, especially endosomal entrapment and release, is key to overcoming delivery obstacles within cells. In this review, we summarize and compare experimental techniques for assessing the extent of endosomal escape of a variety of non-viral vehicles and describe proposed escape mechanisms for different classes of lipid-, polymer-, and peptide-based delivery agents. Based on this evaluation, we present forward-looking strategies utilizing information gained from mechanistic studies to inform the rational design of efficient delivery vehicles.
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•Endosomal escape of nanomedicines is a complex barrier to intracellular delivery that remains poorly understood.•There is a need for quantitative and high-throughput assays to evaluate intracellular delivery vehicle trafficking.•Uptake and intracellular trafficking mechanisms of nanocarriers are dependent on vehicle composition and delivery context.•Mechanistic knowledge of the intracellular fate of nanomedicines can be used to enhance delivery to target locations.
The central nervous system (CNS) poses a unique challenge for drug delivery. The blood–brain barrier significantly hinders the passage of systemically delivered therapeutics and the brain ...extracellular matrix limits the distribution and longevity of locally delivered agents. Polymeric nanoparticles represent a promising solution to these problems. Over the past 40years, substantial research efforts have demonstrated that polymeric nanoparticles can be engineered for effective systemic and local delivery of therapeutics to the CNS. Moreover, many of the polymers used in nanoparticle fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of this strategy. Here, we review the major advances in the development of polymeric nanoparticles for drug delivery to the CNS.
Polymeric vehicles for nucleic acid delivery Piotrowski-Daspit, Alexandra S.; Kauffman, Amy C.; Bracaglia, Laura G. ...
Advanced drug delivery reviews,
2020, 2020-00-00, 20200101, Volume:
156
Journal Article
Peer reviewed
Open access
Polymeric vehicles are versatile tools for therapeutic gene delivery. Many polymers—when assembled with nucleic acids into vehicles—can protect the cargo from degradation and clearance in vivo, and ...facilitate its transport into intracellular compartments. Design options in polymer synthesis yield a comprehensive range of molecules and resulting vehicle formulations. These properties can be manipulated to achieve stronger association with nucleic acid cargo and cells, improved endosomal escape, or sustained delivery depending on the application. Here, we describe current approaches for polymer use and related strategies for gene delivery in preclinical and clinical applications. Polymer vehicles delivering genetic material have already achieved significant therapeutic endpoints in vitro and in animal models. From our perspective, with preclincal assays that better mimic the in vivo environment, improved strategies for target specificity, and scalable techniques for polymer synthesis, the impact of this therapeutic approach will continue to expand.
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The majority of commercial sunblock preparations use organic or inorganic ultraviolet (UV) filters. Despite protecting against cutaneous phototoxicity, direct cellular exposure to UV filters has ...raised a variety of health concerns. Here, we show that the encapsulation of padimate O (PO)--a model UV filter--in bioadhesive nanoparticles (BNPs) prevents epidermal cellular exposure to UV filters while enhancing UV protection. BNPs are readily suspended in water, facilitate adherence to the stratum corneum without subsequent intra-epidermal or follicular penetration, and their interaction with skin is water resistant yet the particles can be removed via active towel drying. Although the sunblock based on BNPs contained less than 5 wt% of the UV-filter concentration found in commercial standards, the anti-UV effect was comparable when tested in two murine models. Moreover, the BNP-based sunblock significantly reduced double-stranded DNA breaks when compared with a commercial sunscreen formulation.
Vaginal instillation of small-interfering RNA (siRNA) using liposomes has led to silencing of endogenous genes in the genital tract and protection against challenge from infectious disease. Although ...siRNA lipoplexes are easily formulated, several of the most effective transfection agents available commercially may be toxic to the mucosal epithelia and none are able to provide controlled or sustained release. Here, we demonstrate an alternative approach using nanoparticles composed entirely of FDA-approved materials. To render these materials effective for gene silencing, we developed novel approaches to load them with high amounts of siRNA. A single dose of siRNA-loaded nanoparticles to the mouse female reproductive tract caused efficient and sustained gene silencing. Knockdown of gene expression was observed proximal (in the vaginal lumen) and distal (in the uterine horns) to the site of topical delivery. In addition, nanoparticles penetrated deep into the epithelial tissue. This is the first report demonstrating that biodegradable polymer nanoparticles are effective delivery vehicles for siRNA to the vaginal mucosa.
Intravaginal (ivag) delivery, which is a proven way to confer local protection against STDs contracted via the reproductive tract, is complicated by the mucus gel barrier, the hormone cycle, and the ...harsh mucosal environment that leads to low residence-time for administered agents. Polymer delivery vehicles may be useful in overcoming these barriers. In this study, we explored the fate of nanoparticles (NP) made from poly(lactide-co-glycolide) (PLGA) in the mouse reproductive tract after ivag delivery. The nanoparticles were modified to display avidin (Avid–NP) or 2
kDa PEG (PEG–NP) on their surface. Vaginal retention fractions for both muco-adhesive Avid–NP and stealthy PEG–NP were 5× higher than unmodified PLGA particles (NP). The amount of particles associated with mucus differed across formulations (Avid–NP
>
NP
>
PEG–NP). PEG–NP was found at higher concentration in the tissue than Avid–NP and NP up to 6
h after delivery, and particles were found within epithelial cells, the underlying submucosal stromal and fibroblast cells of the vaginal tissue. Our results demonstrate that surface properties of nanoparticles can impact their fates following ivag delivery. Moreover, we show that the muco-evasive PEG-modified nanoparticles are the most effective among the delivery vehicles tested for this application.
PLGA nanoparticles with surface coatings of PEG and carrying fluorescent Coumarin-6 dye efficiently avoided leakage after vaginal delivery, traversed through the mucus gel layer, and were efficiently taken up by the tissues of the mouse female reproductive tract. On average, PEG-modified nanoparticle formulations displayed higher tissue retention across all measured time points than unmodified or Avidin-modified PLGA nanoparticles. *Denotes statistical significance with p
<
0.042; †
denotes p
<
0.053.
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Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward ...approach of bypassing the blood–brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents—cellular, protein, nucleic acid, and nanoparticle-based small molecules—that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.
Controlled release systems are an effective means for local drug delivery. In local drug delivery, the major goal is to supply therapeutic levels of a drug agent at a physical site in the body for a ...prolonged period. A second goal is to reduce systemic toxicities, by avoiding the delivery of agents to non-target tissues remote from the site. Understanding the dynamics of drug transport in the vicinity of a local drug delivery device is helpful in achieving both of these goals. Here, we provide an overview of controlled release systems for local delivery and we review mathematical models of drug transport in tissue, which describe the local penetration of drugs into tissue and illustrate the factors - such as diffusion, convection, and elimination - that control drug dispersion and its ultimate fate. This review highlights the important role of controlled release science in development of reliable methods for local delivery, as well as the barriers to accomplishing effective delivery in the brain, blood vessels, mucosal epithelia, and the skin.
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