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Traditional bolus vaccines typically require multiple doses, which complicates the vaccination process and may cause missed shots, leading to sub-optimal immunity and reduced vaccine effectiveness. Herein, a gel-based long-acting vaccine system with self-adjuvant properties based on laponite was constructed to simplify vaccination procedures and improve vaccine effectiveness. Firstly, the gel system could recruit multiple types of immune cells to form immune niches. Secondly, it could achieve sustained delivery of antigens to lymph nodes by active transport and passive drainage. Then, the gel system triggered the formation of a large number of germinal centers, which elicited enhanced and durable humoral immune responses, as well as strong cellular immune responses. As a result, it eventually showed good prophylactic and therapeutic effects in a variety of tumor models including melanoma, colorectal cancer and peritoneal metastasis models. By further combining the immunoadjuvant CpG ODN and cytokine IL-12, the effect of the gel-vaccine could be further enhanced. In a murine peritoneal metastasis model of colorectal carcinoma, a single administration of the gel-vaccine resulted in complete tumor eradication in 8/9 mice. In summary, this study developed an immunologically active gel-vaccine system. And as a robust and versatile vaccine platform, by loading different antigens and adjuvants, this gel-vaccine system is expected to realize its better therapeutic potential., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The treatment landscape for opioid use disorder (OUD) faces challenges stemming from the limited efficacy of existing medications, poor adherence to prescribed regimens, and a heightened risk of fatal overdose post-treatment cessation. Therefore, there is a pressing need for innovative therapeutic strategies that enhance the effectiveness of interventions and the overall well-being of individuals with OUD. This study explored the therapeutic potential of nor-Levo-α-acetylmethadol (nor-LAAM) to treat OUD. We developed sustained release nor-LAAM-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles (MP) using a hydrophobic ion pairing (HIP) approach. The nor-LAAM-MP prepared using HIP with pamoic acid had high drug loading and exhibited minimal initial burst release and sustained release. The nor-LAAM-MP was further optimized for desirable particle size, drug loading, and release kinetics. The lead nor-LAAM-MP (F4) had a relatively high drug loading (11 wt%) and an average diameter (19 μm) and maintained a sustained drug release for 4 weeks. A single subcutaneous injection of nor-LAAM-MP (F4) provided detectable nor-LAAM levels in rabbit plasma for at least 15 days. We further evaluated the therapeutic efficacy of nor-LAAM-MP (F4) in a well-established fentanyl-addiction rat model, and revealed a marked reduction in fentanyl choice and withdrawal symptoms in fentanyl-dependent rats. These findings provide insights into further developing long-acting nor-LAAM-MP for treating OUD. It has the potential to offer a new effective medication to the existing sparse armamentarium of products available to treat OUD., Competing Interests: Declaration of competing interest The nor-LAAM-MP technology described in this publication has been filed as a patent application through Virginia Commonwealth University (VCU). Qingguo Xu, Matthew Banks, Diane Ingabire, Chaolong Qin, Tuo Meng, and Aji Alex Moothedathu Raynold are the co-inventors who are subject to certain rules and restrictions under VCU policy. The terms of this arrangement are being managed by VCU in accordance with its conflict-of-interest policies., (Copyright © 2023. Published by Elsevier B.V.)

Extracellular vesicles (EVs) are a population of small vesicles secreted by essentially all cell types, containing a wide variety of biological macromolecules. Due to their intrinsic capabilities for efficient intercellular communication, they are involved in various aspects of cellular functioning. In the past decade, EVs derived from stem cells attracted interest in the field of regenerative medicine. Owing to their regenerative properties, they have great potential for use in tissue repair, in particular for tissues with limited regenerative capabilities such as cartilage. The maintenance of articular cartilage is dependent on a precarious balance of many different components that can be disrupted by the onset of prevalent rheumatic diseases. However, while cartilage is a tissue with strong mechanical properties that can withstand movement and heavy loads for years, it is virtually incapable of repairing itself after damage has occurred. Stem cell-derived EVs (SC-EVs) transport regenerative components such as proteins and nucleic acids from their parental cells to recipient cells, thereby promoting cartilage healing. Many possible pathways through which SC-EVs execute their regenerative function have been reported, but likely there are still numerous other pathways that are still unknown. This review discusses various preclinical studies investigating intra-articular injections of free SC-EVs, which, while often promoting chondrogenesis and cartilage repair in vivo, showed a recurring limitation of the need for multiple administrations to achieve sufficient tissue regeneration. Potentially, this drawback can be overcome by making use of an EV delivery platform that is capable of sustainably releasing EVs over time. With their remarkable versatility and favourable chemical, biological and mechanical properties, hydrogels can facilitate this release profile by encapsulating EVs in their porous structure. Ideally, the optimal delivery platform can be formed in-situ, by means of an injectable hydrogel that can be administered directly into the affected joint. Relevant research fulfilling these criteria is discussed in detail, including the steps that still need to be taken before injectable hydrogels for sustained delivery of EVs can be applied in the context of cartilage regeneration in the clinic., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Oral delivery of peptides is a challenge due to their instability and their limited transport and absorption characteristics within the gastrointestinal tract. In this work, we used layering techniques in a fluidized bed dryer to create a configuration in which the active peptide, permeation enhancers, and polymers are coated to control the release of the peptide. Formulations were developed to disintegrate at pH values of 5.5 and 7.0. In addition, sustained-release or mucoadhesive polymers were coated to trigger release at a desired site in the gastrointestinal tract. Dissolution studies with a USP Type I (basket) apparatus confirmed the duration of release. Pharmacokinetic studies were performed in beagle dogs to evaluate bioavailability. A high-disintegration pH was found to be advantageous in enhancing bioavailability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We examine different approaches for the controlled release of L-lactate, which is a signaling molecule that participates in tissue remodeling and regeneration, such as cardiac and muscle tissue. Robust, flexible, and self-supported 3-layers films made of two spin-coated poly(lactic acid) (PLA) layers separated by an electropolymerized poly(3,4-ethylenedioxythiophene) (PEDOT) layer, are used as loading and delivery systems. Films with outer layers prepared using homochiral PLA and with nanoperforations of diameter 146 ± 70 experience more bulk erosion, which also contributes to the release of L-lactic acid, than those obtained using heterochiral PLA and with nanoperforations of diameter 66 ± 24. Moreover, the release of L-lactic acid as degradation product is accelerated by applying biphasic electrical pulses. The four approaches used for loading extra L-lactate in the 3-layered films were: incorporation of L-lactate at the intermediate PEDOT layer as primary dopant agent using (1) organic or (2) basic water solutions as reaction media; (3) substitution at the PEDOT layer of the ClO 4 - dopant by L-lactate using de-doping and re-doping processes; and (4) loading of L-lactate at the outer PLA layers during the spin-coating process. Electrical stimuli were applied considering biphasic voltage pulses and constant voltages (both negative and positive). Results indicate that the approach used to load the L-lactate has a very significant influence in the release regulation process, affecting the concentration of released L-lactate up to two orders of magnitude. Among the tested approaches, the one based on the utilization of the outer layers for loading, approach (4), can be proposed for situations requiring prolonged and sustained L-lactate release over time. The biocompatibility and suitability of the engineered films for cardiac tissue engineering has also been confirmed using cardiac cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Wild-type erythropoietin (EPO) is promising for neuroprotection, but its therapeutic use is limited because it causes a systemic rise in hematocrit. We have developed an EPO-R76E derivative that maintains neuroprotective function without effects on hematocrit, but this protein has a short half-life in vivo. Here, we compare the efficacy and carrier-induced inflammatory response of two polymeric microparticle (MP) EPO-R76E sustained release formulations based on conventional hydrolytically degradable poly(lactic-co-glycolic acid) (PLGA) and reactive oxygen species (ROS)-degradable poly(propylene sulfide) (PPS). Both MP types effectively loaded EPO-R76E and achieved sustained release, providing detectable levels of EPO-R76E at the injection site in the eye in vivo for at least 28 days. Testing in an in vitro oxidative stress assay and a mouse model of blast-induced indirect traumatic optic neuropathy (bITON) showed that PPS and PLGA MP-mediated delivery of EPO-R76E provided therapeutic protection. While unloaded PLGA MPs inherently increase levels of pro-inflammatory cytokines in the bITON model, drug-free PPS MPs have innate antioxidant properties that provide therapeutic benefit both in vitro and in vivo. Both PLGA and PPS MPs enabled sustained release of EPO-R76E, providing therapeutic benefits including reduction in inflammation and axon degeneration, and preservation of visual function as measured by electroretinogram. The PPS-based MP platform is especially promising for further development, as the delivery system provides inherent antioxidant benefits that can be harnessed to work in complement with EPO-R76E or other drugs for neuroprotection in the setting of traumatic eye injury., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The toll-like receptor 7 and 8 (TLR7/8) agonist Resiquimod (R848) has been recognized as a promising immunostimulator for the treatment of cutaneous cancers in multiple clinical trials. However, systemic administration of R848 often results in strong immune-related toxicities while having limited therapeutic effects to the tumor. In the present study, a prodrug-based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. R848 was conjugated to α-tocopherol to constitute an R848-Toco prodrug, followed by formulating with a tocopherol-modified hyaluronic acid (HA-Toco) as a polymeric nano-suspension. In vitro evaluation showed that the delivery system prolonged the release kinetics while maintaining TLR agonist activities. When administered subcutaneously, the nano-suspension formed a depot at the injection site, inducing localized immune responses without systemic expansion. This formulation also suppressed tumor growth and recruited immune cells to the tumor in a murine model of head and neck cancer. In a preclinical canine study of spontaneous mast cell tumors, the treatment led to a 67% response rate (three partial remissions and one complete remission)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

As one of the leading causes of central vision loss in elderly population, worldwide cases of age-related macular degeneration (AMD) have seen a dramatic increase over the past several years. Treatment regimens for AMD, especially with biological agents, are complicated due to anatomical and physiological barriers, as well as administration of high doses and frequent regimens. Some clinical examples include monthly intravitreal administration of anti-VEGF antibody ranibizumab (Lucentis®) from Genentech and aflibercept (Eylea®) from Regeneron Pharmaceuticals. Long-acting sustained intraocular drug delivery provides promising solutions, such as Vitrasert® from Bausch & Lomb, an intravitreal biodegradable polymeric implant made from poly(D,L-lactic co glycolic acid) (PLGA), and can be used as a guiding reference to formulate sustained delivery systems. In this review, we discuss the anatomy and physiology of the eye, barriers to delivery, pathology of AMD, opportunities for biological therapeutics, and future prospects of intraocular delivery strategies that are in development for treatment of AMD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Transcript therapies using chemically modified messenger RNAs (cmRNAs) are emerging as safe and promising alternatives for gene and recombinant protein therapies. However, their applications have been limited due to transient translation and relatively low stability of cmRNAs compared to DNA. Here we show that vacuum-dried cmRNA-loaded collagen sponges, termed transcript activated matrices (TAMs), can serve as depots for sustained delivery of cmRNA. TAMs provide steady state protein production for up to six days, and substantial residual expression until 11days post transfection. Another advantage of this technology was nearly 100% transfection efficiency as well as low toxicity in vitro. TAMs were stable for at least 6months at room temperature. Human BMP-2-encoding TAMs induced osteogenic differentiation of MC3T3-E1 cells in vitro and bone regeneration in a non-critical rat femoral bone defect model in vivo. In summary, TAMs are a promising tool for bone regeneration and potentially also for other applications in regenerative medicine and tissue engineering., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Increasing evidence has demonstrated special advantages of the nanomedicinal approach for the management of cardiovascular disease. We hypothesize that sustained delivery of rapamycin (RAP) may provide more desirable therapeutic effects than traditional oral administration by selectively inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. To evidence this assumption and develop an effective, safe, and translational nanotherapy for atherosclerosis, this study was designed to examine antiatherosclerotic efficacy of a RAP nanotherapy based on an acetalated β-cyclodextrin (Ac-bCD) material in apolipoprotein E-deficient (ApoE(-/-)) mice. First, biodegradable and biocompatible materials of Ac-bCDs were synthesized by kinetically controlled acetalation, giving rise to carrier materials that may not generate acidic byproducts after hydrolysis. Then RAP-loaded nanoparticles base on various Ac-bCDs were prepared by a nanoemulsion technique, which can sustain drug release for different periods of time, depending on the composition of Ac-bCDs. For a RAP/Ac-bCD180-derived nanotherapy (RAP-NP) that may continue RAP release for up to 20days in vitro, it afforded constant drug levels in both the blood and aortic tissue after subcutaneous injection, while orally administered free RAP showed typical peak-valley profiles with remarkably high peak concentrations. Therapeutic studies conducted in an experimental model of atherosclerosis established in ApoE(-/-) mice revealed that RAP-NP significantly reduced the formation of atherosclerotic lesions and dramatically enhanced the stability of plaques, which was more efficacious than orally delivered free RAP. Moreover, rupture-prone proinflammatory factors in both serum and aortas were significantly decreased after treatment. Whereas oral administration of RAP simultaneously inhibited mTORC1 and mTORC2 in the aorta, sustained delivery by RAP-NP selectively suppressed mTORC1, agreeing with in vitro results in smooth muscle cells. These findings demonstrated that antiatherosclerotic activity of RAP may be considerably improved by sustained release via the Ac-bCD material-derived nanocarrier, which was achieved through selectively inhibiting mTORC1., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Transarterial chemoembolization (TACE) is used to treat various types of hypervascular tumors such as hepatocellular carcinoma and renal cancer. However, embolization and blocking of blood vessels nourishing a tumor mass evokes an angiogenic response due to the secretion of vascular endothelial growth factor (VEGF), which results in the formation of new blood vessels and eventually limitation in therapeutic efficacy. The presented work investigates the feasibility of loading the clinically used embolic beads (DC Bead®) with Bevacizumab (BEV), an anti-VEGF antibody, and control its release kinetics via Layer-by-Layer (LbL) coating. This strategy has the aim to achieve high, localized and sustained concentrations of BEV at the tumor site and reduce drug exposure in the systemic circulation. High loading of BEV on lyophilized beads of about 76mg BEV/bead vial was achieved. LbL coating was carried out by depositing alternating layers of the biocompatible polymers alginate and poly-L-lysine. Coating was proven successful by monitoring the reversal of zeta potential after addition of each layer. Morphological changes of the bead surface before and after coating were illustrated using SEM imaging. Moreover, release profiles from different formulations were studied and results showed that optimizing the number of deposited layers effectively slows the release of BEV for three days. Activity of released BEV was studied in different 2D and 3D cell based assays. Released BEV fractions showed comparable activity to fresh BEV solution used as control after 3days. In conclusion, our results suggest the opportunity for loading anti-VEGF antibodies on commercially available embolic beads to increase the efficacy of TACE of hypervascular tumors., (Copyright © 2016 Elsevier B.V. All rights reserved.)