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International Journal of Nanomedicine 2023Nucleic acids have emerged as promising therapeutic agents for many diseases because of their potential in modulating gene expression. However, the delivery of nucleic... (Review)
Review
Nucleic acids have emerged as promising therapeutic agents for many diseases because of their potential in modulating gene expression. However, the delivery of nucleic acids remains a significant challenge in gene therapy. Although viral vectors have shown high transfection efficiency, concerns regarding teratogenicity or carcinogenicity have been raised. Non-viral vehicles, including cationic polymers, liposomes, and inorganic materials possess advantages in terms of safety, ease of preparation, and low cost. Nevertheless, they also face limitations related to immunogenicity, quick clearance in vivo, and lack of targeting specificity. On the other hand, bioinspired strategies have shown increasing potential in the field of drug delivery, yet there is a lack of comprehensive reviews summarizing the rapid development of bioinspired nanoparticles based on the cell membrane camouflage to construct the nucleic acids vehicles. Herein, we enumerated the current difficulties in nucleic acid delivery with various non-viral vehicles and provided an overview of bioinspired strategies for nucleic acid delivery.
Topics: Nucleic Acids; Transfection; Nanoparticles; Liposomes; Cell Membrane
PubMed: 38164266
DOI: 10.2147/IJN.S433737 -
European Journal of Pharmaceutical... Aug 2023Fused deposition modeling (FDM) and selective laser sintering (SLS) are two of the most employed additive manufacturing (AM) techniques within the pharmaceutical...
Fused deposition modeling (FDM) and selective laser sintering (SLS) are two of the most employed additive manufacturing (AM) techniques within the pharmaceutical research field. Despite the numerous advantages of different AM methods, their respective drawbacks have yet to be fully addressed, and therefore combinatorial systems are starting to emerge. In the present study, hybrid systems comprising SLS inserts and a two-compartment FDM shell are developed to achieve controlled release of the model drug theophylline. Via the use of SLS a partial amorphization of the drug is demonstrated, which can be advantageous in the case of poorly soluble drugs, and it is shown that sintering parameters can regulate the dosage and release kinetics of the drug from the inserts. Furthermore, via different combinations of inserts within the FDM-printed shell, various drug release patterns, such as a two-step or prolonged release, can be achieved. The study serves as a proof of concept, highlighting the advantages of combining two AM techniques, both to overcome their respective shortcomings and to develop modular and highly tunable drug delivery devices.
Topics: Pharmaceutical Preparations; Drug Liberation; Drug Delivery Systems; Theophylline; Printing, Three-Dimensional; Technology, Pharmaceutical; Dosage Forms; Tablets
PubMed: 37277047
DOI: 10.1016/j.ejps.2023.106486 -
Cell Reports. Medicine Nov 2023Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation...
Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%-100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different T1/T2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design.
Topics: Animals; Mice; Liposomes; Th1 Cells; Emulsions; Adjuvants, Immunologic; Malaria Vaccines; Malaria
PubMed: 37913775
DOI: 10.1016/j.xcrm.2023.101245 -
International Journal of Nanomedicine 2024Natural products have proven to have significant curative effects and are increasingly considered as potential candidates for clinical prevention, diagnosis, and... (Review)
Review
Natural products have proven to have significant curative effects and are increasingly considered as potential candidates for clinical prevention, diagnosis, and treatment. Compared with synthetic drugs, natural products not only have diverse structures but also exhibit a range of biological activities against different disease states and molecular targets, making them attractive for development in the field of medicine. Despite advancements in the use of natural products for clinical purposes, there remain obstacles that hinder their full potential. These challenges include issues such as limited solubility and stability when administered orally, as well as short durations of effectiveness. To address these concerns, nano-drug delivery systems have emerged as a promising solution to overcome the barriers faced in the clinical application of natural products. These systems offer notable advantages, such as a large specific surface area, enhanced targeting capabilities, and the ability to achieve sustained and controlled release. Extensive in vitro and in vivo studies have provided further evidence supporting the efficacy and safety of nanoparticle-based systems in delivering natural products in preclinical disease models. This review describes the limitations of natural product applications and the current status of natural products combined with nanotechnology. The latest advances in nano-drug delivery systems for delivery of natural products are considered from three aspects: connecting targeting warheads, self-assembly, and co-delivery. Finally, the challenges faced in the clinical translation of nano-drugs are discussed.
Topics: Nanoparticle Drug Delivery System; Biological Products; Nanoparticles; Nanotechnology; Solubility
PubMed: 38260243
DOI: 10.2147/IJN.S443692 -
Proceedings of the National Academy of... Dec 2023Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid,...
Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated. We hypothesize that the three CIL-LNPs react differently to pH changes and hence study the structure of CIL/chol bulk phases in water. Using synchrotron X-ray scattering a sequence of ordered CIL/chol mesophases with lowering pH values are observed. These phases show isotropic inverse micellar, cubic Fd3m inverse micellar, inverse hexagonal [Formula: see text] and bicontinuous cubic Pn3m symmetry. If polyadenylic acid, as mRNA surrogate, is added to CIL/chol, excess lipid coexists with a condensed nucleic acid lipid [Formula: see text] phase. The next-neighbor distance in the excess phase shows a discontinuity at the Fd3m inverse micellar to inverse hexagonal [Formula: see text] transition occurring at pH 6 with distinctly larger spacing and hydration for DD vs. MC3 and KC2. In mRNA LNPs, DD showed larger internal spacing, as well as retarded onset and reduced level of DD-LNP-mediated eGFP expression in vitro compared to MC3 and KC2. Our data suggest that the pH-driven Fd3m-[Formula: see text] transition in bulk phases is a hallmark of CIL-specific differences in mRNA LNP efficacy.
Topics: Animals; Mice; Liposomes; Nanoparticles; Micelles; Hydrogen-Ion Concentration; RNA, Messenger; RNA, Small Interfering
PubMed: 38055742
DOI: 10.1073/pnas.2310491120 -
European Journal of Pharmaceutics and... Sep 2023The development of biocompatible delivery systems is a necessity for medical and topical applications. Herein, the development of a new bigel for topical application is...
The development of biocompatible delivery systems is a necessity for medical and topical applications. Herein, the development of a new bigel for topical application is described. It is composed of 40% colloidal lipid hydrogel and 60% olive oil and beeswax oleogel. Its characterization and the potential of the bigel as a drug carrier through the skin was evaluated in vitro using fluorescence microscopy and two phases of the bigel were labeled with two fluorescent probes: sodium fluorescein (hydrophilic phase) and Nile red (lipophilic phase). The structure of the bigel showed two phases with fluorescence microscopy in which the hydrogel phase was incorporated into a continuous oleogel matrix. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) presented a combination of vibrations characteristic of the different molecules forming the bigel, and Differential Scanning Calorimetry (DSC) showed different transitions attributed to beeswax lipids. Small-angle and wide-angle X-ray scattering (SAXS and WAXS) indicated a predominant lamellar structure with orthorhombic lateral packing that could be related to the arrangement of beeswax crystals. Bigel enables deeper penetration of hydrophilic and lipophilic probes into deeper layers, making it a promising candidate for effective topical carriers in medical and dermatological applications.
Topics: Scattering, Small Angle; X-Ray Diffraction; Skin; Hydrogels
PubMed: 37433416
DOI: 10.1016/j.ejpb.2023.07.004 -
International Journal of Nanomedicine 2023Tissue engineering scaffolds are porous and can be loaded with growth factors to promote osteogenesis and bone repair, which can solve the problem of clinical bone...
BACKGROUND
Tissue engineering scaffolds are porous and can be loaded with growth factors to promote osteogenesis and bone repair, which can solve the problem of clinical bone defects. The direct loading of growth factors on scaffolds is hindered by the disadvantages of low loading capacities, and uncontrollable burst release. Zeolitic imidazolate framework-8 (ZIF-8) has osteoinductive activity and drug-loading potential and can be loaded with growth factors to achieve sustained release. In this study, we aimed to establish a sustained release system of composite scaffolds loaded with growth factors to achieve the goal of slow controlled release and effective bone repair.
METHODS
ZIF‑8 nanoparticles loaded with bone morphogenetic protein-2 (BMP-2) were incorporated into poly-(lactide-co-glycolide)/mesoporous bioactive glass (PLGA/MBG) porous scaffolds by a 3D-printing method. The surface morphology, chemical properties and BMP-2 release of the prepared scaffold were investigated. The osteoblast adhesion, proliferation, spreading, and osteogenic differentiation in vitro and the bone repair ability in vivo of the PLGA/MBG/ZIF-8/BMP-2 (PMZB) scaffold were evaluated, and compared with those of PLGA/MBG (PM) and PLGA/MBG/ZIF-8 (PMZ) scaffolds.
RESULTS
The results showed that the PMZB scaffold exhibited a slow and continuous BMP-2 release pattern, enhanced osteoblast adhesion, proliferation, spreading and osteogenic differentiation in vitro, and promoted new bone formation and bone repair in vivo.
CONCLUSION
The PLGA/MBG/ZIF-8/BMP-2 porous scaffold could continuously and slowly release BMP-2, enhance osteogenic activity, and promote new bone formation and bone repair at bone defects. The PMZB scaffold can be used as a bone graft material to repair bone defect at non-weight-bearing sites.
Topics: Delayed-Action Preparations; Osteogenesis; Nanoparticles; Osteoblasts; Plastic Surgery Procedures
PubMed: 37701821
DOI: 10.2147/IJN.S423985 -
Pharmacological Research Mar 2024The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the... (Review)
Review
The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.
Topics: Drug Delivery Systems; Biological Products; Nanoparticle Drug Delivery System; Biological Availability
PubMed: 38341055
DOI: 10.1016/j.phrs.2024.107100 -
Drug Delivery Dec 2023Functionalized drug delivery systems have been investigated to improve the targetability and intracellular translocation of therapeutic drugs. We developed high...
Functionalized drug delivery systems have been investigated to improve the targetability and intracellular translocation of therapeutic drugs. We developed high functionality and quality lipids that met unique requirements, focusing on the quality of functional lipids for the preparation of targeted nanoparticles using microfluidic devices. While searching for a lipid with high solubility and dispersibility in solvents, which is one of the requirements, we noted that KK-(EK)-lipid imparts nonspecific cellular association to polyethylene glycol (PEG)-modified (PEGylated) liposomes, such as cell-penetrating peptides (CPPs). We investigated whether KK-(EK)-lipid, which has a near-neutral charge, is a novel CPP-modified lipid that enhances the intracellular translocation of nanoparticles. However, the cellular association mechanism of KK-(EK)-lipid is unknown. Therefore, we synthesized (EK)-lipid derivatives based on the sequence of KK-(EK)-lipid and determined the sequence sites involved in cellular association. In addition, KK-(EK)-lipid was applied to extracellular vesicles (EVs) and mRNA encapsulated lipid nanoparticles (mRNA-LNPs). KK-(EK)-lipid-modified EVs and mRNA-LNPs showed higher cellular association and in vitro protein expression, respectively, compared to unmodified ones. We elucidated KK-(EK)-lipid to have potential for applicability in the intracellular delivery of liposomes, EVs, and mRNA-LNPs.
Topics: Liposomes; Drug Delivery Systems; Nanoparticles; Cell-Penetrating Peptides; Lipids; RNA, Messenger
PubMed: 36964673
DOI: 10.1080/10717544.2023.2191891 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2024In the past, the administration of medicines for children mainly involved changes to adult dosage forms, such as crushing tablets or opening capsules. However, these... (Review)
Review
In the past, the administration of medicines for children mainly involved changes to adult dosage forms, such as crushing tablets or opening capsules. However, these methods often led to inconsistent dosing, resulting in under- or overdosing. To address this problem and promote adherence, numerous initiatives, and regulatory frameworks have been developed to develop more child-friendly dosage forms. In recent years, multiparticulate dosage forms such as mini-tablets, pellets, and granules have gained popularity. However, a major challenge that persists is effectively masking the bitter taste of drugs in such formulations. This review therefore provides a brief overview of the current state of the art in taste masking techniques, with a particular focus on taste masking by film coating. Methods for evaluating the effectiveness of taste masking are also discussed and commented on. Another important issue that arises frequently in this area is achieving sufficient dissolution of poorly water-soluble drugs. Since the simultaneous combination of sufficient dissolution and taste masking is particularly challenging, the second objective of this review is to provide a critical summary of studies dealing with multiparticulate formulations that are tackling both of these issues.
Topics: Taste; Solubility; Humans; Drug Compounding; Pharmaceutical Preparations; Dosage Forms; Chemistry, Pharmaceutical; Tablets; Administration, Oral; Child; Excipients; Drug Liberation
PubMed: 38815202
DOI: 10.2478/acph-2024-0015