Application of advances in endocytosis and membrane trafficking to drug delivery.
Ontology highlight
ABSTRACT:
SUBMITTER: Ju Y
PROVIDER: S-EPMC7853512 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.
| S-EPMC7419031 | biostudies-literature
Project description:Musculoskeletal disorders are a significant burden on the global economy and public health. Advanced drug delivery plays a key role in the musculoskeletal field and holds the promise of enhancing the repair of degenerated and injured musculoskeletal tissues. Ideally, drug delivery should have the ability to directly deliver therapeutic agents to the diseased/injured sites with a desirable drug level over a period of time. Here, we present a mini-review of the current state-of-the-art research associated with local drug delivery and its use for the treatment of musculoskeletal disorders. First, an overview of drug delivery strategies, with a focus on issues related to musculoskeletal pathology, potential therapeutic strategies, conventional and non-conventional drugs, and various delivery systems, is introduced. Then, we highlight recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering techniques), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications. STATEMENT OF SIGNIFICANCE: Three important aspects are highlighted in this manuscript: 1) The advanced musculoskeletal drug delivery is introduced from the aspects ranging from musculoskeletal disorders, potential therapeutic solutions, and various drug delivery systems. 2) The recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering technique), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery), are highlighted. 3) The challenges and perspectives of future research directions in the development of musculoskeletal local drug delivery are presented.
| S-EPMC6615977 | biostudies-literature
Project description:Purpose of reviewEmerging developments and research for drug delivery to the posterior segment offer a promising future for the treatment of vitreoretinal disease. As new technologies enter the market, clinicians should be aware of new indications and ongoing clinical trials.Recent findingsThis review summarizes the advantages and shortcomings of the most commonly used drug delivery methods, including vitreous dynamics, physician sustainability and patient preferences. Currently available, intravitreal, corticosteroid-release devices offer surgical and in-office management of retinal vascular disease and posterior uveitis. The suprachoroidal space offers a new anatomic location for the delivery of lower dose medications directly to the target tissue. Implantable drug reservoirs would potentially allow for less frequent intravitreal injections reducing treatment burdens and associated risks. Newer innovations in encapsulated cell technology offer promising results in early clinical trials.SummaryAlthough pars plana intravitreal injection remains the mainstay of therapy for many vitreoretinal diseases, targeted delivery and implantable eluting devices are rapidly demonstrating safety and efficacy. These therapeutic modalities offer promising options for the vitreoretinal therapeutic landscape.
| S-EPMC4575283 | biostudies-literature
Project description:Endocytosis is key to fibrinogen (Fg) uptake, trafficking of integrins (?IIb?3, ?v?3), and purinergic receptors (P2Y1, P2Y12), and thus normal platelet function. However, the molecular machinery required and possible trafficking routes are still ill-defined. To further identify elements of the platelet endocytic machinery, we examined the role of a vesicle-residing, soluble N-ethylmaleimide factor attachment protein receptor (v-SNARE) called cellubrevin/vesicle-associated membrane protein-3 (VAMP-3) in platelet function. Although not required for normal platelet exocytosis or hemostasis, VAMP-3-/- mice had less platelet-associated Fg, indicating a defect in Fg uptake/storage. Other granule markers were unaffected. Direct experiments, both in vitro and in vivo, showed that loss of VAMP-3 led to a robust defect in uptake/storage of Fg in platelets and cultured megakaryocytes. Uptake of the fluid-phase marker, dextran, was only modestly affected. Time-dependent uptake and endocytic trafficking of Fg and dextran were followed using 3-dimensional-structured illumination microscopy. Dextran uptake was rapid compared with Fg, but both cargoes progressed through Rab4+, Rab11+, and von Willebrand factor (VWF)+ compartments in wild-type platelets in a time-dependent manner. In VAMP-3-/- platelets, the 2 cargoes showed limited colocalization with Rab4, Rab11, or VWF. Loss of VAMP-3 also affected some acute platelet functions, causing enhanced spreading on Fg and fibronectin and faster clot retraction compared with wild-type. In addition, the rate of Janus kinase 2 phosphorylation, initiated through the thrombopoietin receptor (TPOR/Mpl) activation, was affected in VAMP-3-/- platelets. Collectively, our studies show that platelets are capable of a range of endocytosis steps, with VAMP-3 being pivotal in these processes.
| S-EPMC5746669 | biostudies-literature
Project description:BackgroundIntegrin-mediated cell adhesion and spreading is dramatically enhanced by activation of the small GTPase, R-Ras. Moreover, R-Ras localizes to the leading edge of migrating cells, and regulates membrane protrusion. The exact mechanisms by which R-Ras regulates integrin function are not fully known. Nor is much known about the spatiotemporal relationship between these two molecules, an understanding of which may provide insight into R-Ras regulation of integrins.ResultsGFP-R-Ras localized to the plasma membrane, most specifically in membrane ruffles, in Cos-7 cells. GFP-R-Ras was endocytosed from these ruffles, and trafficked via multiple pathways, one of which involved large, acidic vesicles that were positive for Rab11. Cells transfected with a dominant negative form of GFP-R-Ras did not form ruffles, had decreased cell spreading, and contained numerous, non-trafficking small vesicles. Conversely, cells transfected with the constitutively active form of GFP-R-Ras contained a greater number of ruffles and large vesicles compared to wild-type transfected cells. Ruffle formation was inhibited by knock-down of endogenous R-Ras with siRNA, suggesting that activated R-Ras is not just a component of, but also an architect of ruffle formation. Importantly, beta1-integrin co-localized with endogenous R-Ras in ruffles and endocytosed vesicles. Expression of dominant negative R-Ras or knock down of R-Ras by siRNA prevented integrin accumulation into ruffles, impaired endocytosis of beta1-integrin, and decreased beta1-integrin-mediated adhesion. Knock-down of R-Ras also perturbed the dynamics of another membrane-localized protein, GFP-VSVG, suggesting a more global role for R-Ras on membrane dynamics. However, while R-Ras co-internalized with integrins, it did not traffic with VSVG, which instead moved laterally out of ruffles within the plane of the membrane, suggesting multiple levels of regulation of and by R-Ras.ConclusionsOur results suggest that integrin function involves integrin trafficking via a cycle of membrane protrusion, ruffling, and endocytosis regulated by R-Ras, providing a novel mechanism by which integrins are linked to R-Ras through control of membrane dynamics.
| S-EPMC2830936 | biostudies-literature
Project description:Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier-integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery.
| S-EPMC5854505 | biostudies-literature
Project description:Modifying surfaces of nanoparticles (NPs) with polyethylene glycol (PEG), the so-called PEGylation, is the most commonly used method for reducing premature clearance of NPs from the circulation. However, several reports point out that PEGylation may negatively influence the performance of NPs as a drug carrier. Alternative surface modification strategies, including substitute polymers, conditional removal of PEG, and biomimetic surface modification, may provide solutions for the limitations of PEG.
| S-EPMC3288878 | biostudies-other
Project description:The effective delivery of drugs to the eye remains a challenge. The eye has a myriad of defense systems and physiological barriers that leaves ocular drug delivery systems with low bioavailability profiles. This is mainly due to poor permeability through the epithelia and rapid clearance from the eye following administration. However, recent advances in both polymeric drug delivery and biomedical nanotechnology have allowed for improvements to be made in the treatment of ocular conditions. The employment of biodegradable polymers in ocular formulations has led to improved retention time, greater bioavailability and controlled release through mucoadhesion to the epithelia in the eye, amongst other beneficial properties. Nanotechnology has been largely investigated for uses in the medical field, ranging from diagnosis of disease to treatment. The nanoscale of these developing drug delivery systems has helped to improve the penetration of drugs through the various ocular barriers, thus improving bioavailability. This review will highlight the physiological barriers encountered in the eye, current conventional treatment methods as well as how polymeric drug delivery and nanotechnology can be employed to optimize drug penetration to both the anterior and posterior segment of the eye.
| S-EPMC6722735 | biostudies-literature
Project description:A new era of science and technology has emerged in pharmaceutical research with focus on developing novel drug delivery systems for oral administration. Conventional dosage forms like tablets and capsules are associated with a low bioavailability, frequent application, side effects and hence patient noncompliance. By developing novel strategies for drug delivery, researchers embraced an alternative to traditional drug delivery systems. Out of those, fast dissolving drug delivery systems are very eminent among pediatrics and geriatrics. Orally disintegrating films are superior over fast dissolving tablets as the latter are assigned with the risk of suffocation. Due to their ability of bypassing the dissolution and the first pass effect after oral administration, self-emulsifying formulations have also become increasingly popular in improving oral bioavailability of hydrophobic drugs. Osmotic devices enable a controlled drug delivery independent upon gastrointestinal conditions using osmosis as driving force. The advances in nanotechnology and the variety of possible materials and formulation factors enable a targeted delivery and triggered release. Vesicular systems can be easily modified as required and provide a controlled and sustained drug delivery to a specific site. This work provides an insight of the novel approaches in drug delivery covering the critical comparison between traditional and novel "advanced-designed" systems.
| S-EPMC7305387 | biostudies-literature
Project description:Purpose of reviewOsteoarthritis is associated with severe joint pain, inflammation, and cartilage degeneration. Drugs injected directly into intra-articular joint space clear out rapidly providing only short-term benefit. Their transport into cartilage to reach cellular targets is hindered by the tissue's dense, negatively charged extracellular matrix. This has limited, despite strong preclinical data, the clinical translation of osteoarthritis drugs. Recent work has focused on developing intra-joint and intra-cartilage targeting drug delivery systems (DDS) to enable long-term therapeutic response, which is presented here.Recent findingsSynovial joint targeting hybrid systems utilizing combinations of hydrogels, liposomes, and particle-based carriers are in consideration for pain-inflammation relief. Cartilage penetrating DDS target intra-cartilage constituents like aggrecans, collagen II, and chondrocytes such that drugs can reach their cellular and intra-cellular targets, which can enable clinical translation of disease-modifying osteoarthritis drugs including gene therapy.SummaryRecent years have witnessed significant increase in both fundamental and clinical studies evaluating DDS for osteoarthritis. Steroid encapsulating polymeric microparticles for longer lasting pain relief were recently approved for clinical use. Electrically charged biomaterials for intra-cartilage targeting have shown promising disease-modifying response in preclinical models. Clinical trials evaluating safety of viral vectors are ongoing whose success can pave the way for gene therapy as osteoarthritis treatment.
| S-EPMC8101446 | biostudies-literature