RSC Pharmaceutics最新文献

Applying lipid nanoparticle (LNP) technology to ribonucleic acid (RNA) nanomedicines was integral to the success of mRNA vaccines against COVID-19. To expand the power of LNP technology, extrahepatic delivery systems have been developed using specific ligands that target the cells in question. However, recent increases in evidence support targeting without the need to attach specific ligands to nanocarriers. In this review, we focused on protein corona-mediated extrahepatic delivery of nanoparticles as an alternative to classic ligand-mediated active targeting. First, the interaction of LNPs with biological components and the impact that the physicochemical properties of LNPs exert on their biological fate are discussed. Then, we highlight a new system that targets activated hepatic stellate cells (aHSCs) as a successful model achieved through intensive optimization of LNPs based on an ionizable cationic lipid library. We also discuss cumulative evidence that support the ligand-free extrahepatic delivery of nanoparticles to a broad diversity of tissues, such as the spleen, lungs, brain, tumors, kidneys, placenta, pancreas, and bone marrow. In conclusion, we propose protein corona-mediated extrahepatic delivery as a new strategy of active targeting for RNA nanomedicines and inspire the future directions in this area.

Aerosolized lipid nanoparticles (LNPs) delivering mRNA are an attractive strategy for use in local, inhalable therapy to treat patients with lung diseases. However, a major barrier to delivering aerosolized mRNA LNPs is the shear forces encountered during aerosolization. These forces lead to significant morphology changes and subsequent decrease in efficacy of mRNA delivery. To best retain the physicochemical properties of mRNA LNPs during aerosolization, we took a formulation-based strategy to stabilize LNPs. We used a design-of-experiment (DOE) approach to comprehensively screen rationally chosen excipients at multiple concentrations. Excipients were carefully selected based on their use in clinically approved inhaled products or their ability to support lipid membrane properties. These excipients were added to the same mRNA LNP composition after formulation, were subsequently characterized, and used to transfect human lung cells at air–liquid interface. From this systematic screen, we identified that the addition of our lead candidate, poloxamer 188, best stabilizes LNP size throughout aerosolization and enhances mRNA expression after aerosolization. Additional morphological studies of the inclusion of poloxamer 188 in LNPs suggests that the excipient lowers aerosolization induced fusion or aggregation of particles without altering the internal structure. Our results indicate that poloxamer 188 can support aerosolized mRNA LNP delivery by maintaining LNP size and significantly enhancing therapeutic nucleic acid delivery to lung cells.

Patients with cancer have faced exhausting physical and mental obstacles as a result of traditional treatment methods including chemotherapy and radiation therapy. In cancer, drug repurposing—the use of already-approved medications for novel therapeutic indications—has become a game-changing tactic. This method greatly lowers development costs and durations by utilizing the wealth of safety and pharmacokinetic data available for licensed medications. Large-scale databases and advanced computer techniques enable it to logically find either combinations of traditional medications or selective “non-selective” target medications. Furthermore, repurposing cancer drugs can undergo a significant and profound change thanks to genome-editing technologies like CRISPR-dCas9. It is recognized that there is yet unrealized potential of these advanced methods in further applications. Understanding the pros and cons of these technologies can provide valuable insights for clinical practice and fundamental research projects. This research will explore various innovative methods, including artificial intelligence (AI) algorithms, supervised machine learning (ML), data resources for in silico, microbial clustered regularly interspaced short palindromic repeats-dCas9 (CRISPR-dCas9) based artificial transcription factors, and combination therapy. This comprehensive guide outlines various methods for repurposing drugs, addressing effects, trials, barriers, and potential solutions to aid clinicians and researchers in maximizing efficacy and efficiency.

Developing a non-invasive insulin delivery system is crucial for improving diabetes management and patient compliance. Transdermal drug delivery offers a promising alternative to direct injection. However, the strong barrier function of the stratum corneum and the limitations of solution-based formulations hinder the effective penetration of insulin into the skin. To enhance transdermal delivery of insulin, we developed a needle-free ionic liquid-in-oil (IL/O) patch by integrating an IL/O microemulsion with an acrylic pressure-sensitive adhesive. The patch formulation included choline oleate as the biocompatible surface-active IL, sorbitan monolaurate as the co-surfactant, choline propionate as the non-aqueous polar phase, isopropyl myristate as the oil phase, and DURO-TAK® 87-4098 as the adhesive matrix. The IL/O patch adhered stably to the skin and facilitated insulin transport via the intercellular route by increasing the fluidity of lipids in the stratum corneum. In vivo pharmacodynamics revealed that, compared with the subcutaneous injection (dosage of 10 IU kg⁻¹), the IL/O patch (dosage of 50 IU kg⁻¹) maintained stable blood glucose levels in diabetic mice for up to 72 h, indicating sustained insulin release. The patch demonstrated excellent biocompatibility and low toxicity, making it a promising non-invasive alternative for transdermal insulin delivery and a potential platform for peptide- and protein-based therapeutics.

Praziquantel (PZQ) is the first-line treatment for schistosomiasis, but its low aqueous solubility and extensive first-pass metabolism limit PZQ's bioavailability. Furthermore, the commercial formulation of PZQ includes the inactive (S)-PZQ enantiomer, which causes unwanted side effects and a bitter taste. This work aimed to evaluate the impact of chirality on PZQ's performance in amorphous solid dispersion (ASD) formulations prepared from both racemic and the active (R)-PZQ enantiomer, with additional studies on polymer type and processing method. ASDs of (R,S)-PZQ and (R)-PZQ at 30% drug loading were prepared with HPMCAS MF and HPMC E5 via solvent evaporation (SE) and hot-melt extrusion (HME). Release testing was conducted in aqueous media with different pH values and in biorelevant media simulating fasted- and fed-state conditions. Results demonstrated that ASDs significantly enhanced PZQ concentrations, with the amorphous solubility being up to 8-fold higher than that of the corresponding crystalline form. HPMCAS-based ASDs showed pH-dependent release, with poor release at gastric pH but achieving near-complete release with crystallization inhibition at intestinal pH conditions, while HPMC-based ASDs exhibited faster gastric release but reduced stability due to crystallization, which was confirmed by polarized light microscopy (PLM) and powder X-ray diffraction (PXRD). (R)-PZQ-HPMCAS ASDs outperformed (R,S)-PZQ-HPMCAS ASDs in simple media at pH 6.5 at high target concentration, which was attributed to a slightly higher amorphous solubility. However, both ASDs exhibited comparable release in fasted-state media due to bile salt-enhanced solubility. PZQ-ASDs showed crystallization when evaluated in FeSSIF-V2 and did not release well. Different processing methods minimally affected release profiles, highlighting HME's potential as a scalable, solvent-free method. These findings suggest that (R)-PZQ-HPMCAS is a promising alternative to commercial racemic PZQ formulations, potentially reducing side effects and improving patient compliance through allowing for a reduced pill burden.

The versatility afforded by emerging additive manufacturing technologies (e.g., 3D printing and precision drop-on-demand deposition) has enabled the rapid and agile production of personalized medicine. The on-demand customization capabilities of these technologies provide novel avenues for point-of-care or distributed pharmaceutical manufacturing and compounding applications. Quality by design principles were used to investigate the production of solid tablet dosage forms for narrow therapeutic index (warfarin), selective serotonin reuptake inhibitor (citalopram), and medical countermeasure (doxycycline) drugs. We examined critical material attributes, critical process parameters, and critical quality attributes for the semisolid extrusion of pharmaceutical tablet excipients and drop-on-demand active pharmaceutical ingredient (API) ink dosing. Detailed investigations optimized the API ink formulation – specifically fluid properties relative to the tablet semisolid excipient, excipient temperature and physical state (i.e., solid vs. liquid), and solidification time – allowing for API and excipient mixing and redistribution. Personalized drug dosages, adjusted doses, and tapered regimens were manufactured, demonstrating accurate API quantity and required production content uniformity, as specified by the U.S. Pharmacopeia. Atline API ink verification and inline drop counting control strategies were employed and confirmed by post-production quantification measurements to properly maintain tablet-to-tablet quality assurance.

Proteins and nucleic acid therapeutics represent a significant and growing share of the pharmaceutical landscape. The majority of biological and therapeutic applications of these biomolecules require access to the cytosol. Delivery of biologics directly to the cytosol is made difficult by the impermeability of the cell membrane. As a result, most delivery strategies have utilized endocytic uptake pathways to deliver biologics into the cell. However, endosomally entrapped cargo often faces limited escape efficiency and is prone to degradation within endo/lysosomal compartments. The emergence of delivery vehicles capable of bypassing endocytosis and directly traversing the cell membrane offers a promising approach to improve the cytosolic delivery efficiency of biomolecules. Here, we highlight recent developments in endocytosis-independent delivery systems for biologics and ways to accurately assess cytosolic delivery of biologics. Strategies employing covalent and non-covalent modification of biomolecules will be reviewed, along with strategies incorporating both covalent and supramolecular processes.

Blood cancers, including leukemia, lymphoma, and multiple myeloma, originate within the bone marrow, where the intricate microenvironment presents considerable challenges for conventional therapies such as chemotherapy, immunotherapy, radiotherapy, and hematopoietic stem cell transplantation. These approaches often suffer from poor specificity, low bioavailability, and systemic toxicity, resulting in suboptimal treatment outcomes. In response, significant advances in targeted drug delivery systems, including liposomes, pegylated formulations, and polymeric nanoparticles have been developed to enhance drug stability, prolong circulation time, and improve tumor accumulation while reducing off-target effects. This review provides a comprehensive overview of recent innovations in ligand-directed drug delivery systems for blood cancers. Emphasis is placed on systems functionalized with antibodies, peptides, aptamers, and proteins designed to overcome the barriers of the bone marrow niche and enable selective delivery to malignant cells. Notably, leukemia has emerged as a key model for evaluating these technologies, with promising preclinical and clinical results. However, despite technological progress, critical translational challenges remain. These include biological heterogeneity, variability in target receptor expression, immunogenicity of nanoparticles, and the complexity of scaling multifunctional delivery systems under clinical conditions. Furthermore, current in vitro and in vivo models fail to accurately recapitulate the bone marrow's dynamic physiology, underscoring the need for improved predictive systems. Future perspectives suggest the integration of personalized nanomedicine approaches that adapt to patient-specific genetic profiles and disease states. Additionally, artificial intelligence (AI) and big data analytics are expected to revolutionize delivery optimization, biomarker discovery, and therapy customization. Ultimately, interdisciplinary collaboration is required to bridge the gap between bench and bedside. By addressing current limitations and embracing innovation, the field moves closer to realizing safe, precise, and effective therapies for patients with hematologic malignancies.

A novel formulation (IL-NP) for the transdermal delivery of nucleic acid medicines was developed using biocompatible ionic liquid (IL). The formulation was created by mixing DNA in water with an IL in ethanol, followed by freeze-drying and dispersion in oil, producing uniformly sized particles. In vitro studies demonstrated the enhanced skin penetration of IL-NP, while mechanistic studies showed that the IL increased cell membrane fluidity to promote cellular uptake. In vivo experiments with tumor-bearing mice confirmed that transdermal administration of IL-NP achieved comparable antitumor effects as direct injection of DNA, without side effects. This formulation effectively overcomes barriers to both stratum corneum penetration and cellular uptake, providing a non-invasive alternative to injecting nucleic acid therapeutics.

The field of healthcare monitoring continuously strives to find new and better ways of improving healthcare access and advancing the accuracy and precision of diagnostic and treatment approaches. To add to its challenges, the modern and fast-paced lifestyle now presents the need for even more sensitive, specific, and rapid methods of continuous healthcare monitoring technology that can generate real-time information. The integration of cutting-edge nanotechnology in health care with its unique and versatile properties has brought a technological revolution in the way disease detection, management, and treatment are approached, finding applications from early-stage disease detection to real-time physiological parameter monitoring. The unique physical and chemical properties of nanoparticles provide a basic structural framework on which successive chemical and biological detection systems can be built. This characteristic of nanoparticles provided healthcare researchers with opportunities to create nanoparticle-based nanosensors, nanomedicine, bioimaging, point-of-care, and other such devices. Here we provide a comprehensive review of the development and advancement of nanosensors in healthcare monitoring, its types, applications, and future prospects, and highlight the development and challenges faced in the field. The review also sheds light on the all-encompassing nature of nanotechnology, in terms of compatibility with different existing streams of applied sciences in healthcare.