RSC Pharmaceutics最新文献

The size distribution of an inhaled pharmaceutical aerosol generated by a nebulizer is a critical parameter influencing the deposition and therapeutic effect of the medication. Relative humidity (RH) can alter size distribution by promoting particle growth through condensation, depending on the hygroscopicity of the formulation. In this study, we evaluate the effect of RH on mannitol, trehalose, salbutamol, and tobramycin aerosols using the Comparative Hygroscopic Aerosol Particle Sizing (CHAPS) technique under varying RH conditions, ranging from ambient to physiological levels. The results demonstrate that RH significantly influences the aerosol particle size, with particle growth becoming more pronounced as RH exceeds 95%. The findings confirm that understanding the relationship between geometric radial growth factors (rGFs) from single droplet size measurements and the aerodynamic rGF is essential for more accurate prediction of plume size distribution, especially at lower RH levels. We also demonstrate consistency between the size distributions measured by CHAPS and a Next Generation Impactor (NGI), with CHAPS providing higher resolution in size and time and data on actuation-by-actuation variability in size distribution and aerosol dose.

Over the past decade, roughly 10% of new FDA-approved drugs targeted central nervous system (CNS) disorders, while it has been estimated that 98% of small-molecule drugs and nearly all large-molecule therapeutics are unable to cross the blood–brain barrier (BBB). There is a clear need for novel therapeutic modalities that promote receptor-mediated transcytosis modulation and efficiently deliver drugs to the brain. Here, we show that poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) polymersomes functionalised with a transferrin receptor (TfR)-targeted peptide can effectively deliver a glioblastoma small drug therapeutic (3,6-bis(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)xanthone; XGAc) through a two-dimensional model of the BBB and that the transport is dependent on the avidity of the nanoformulation. By adjusting the density of targeting peptides on polymersomes, we present a novel strategy to enhance the efficiency of BBB receptor-mediated transcytosis. These findings highlight the promise of precision-tuned polymersomes in overcoming the BBB and advancing treatments for glioblastoma and other brain diseases.

The rise in activity and multi-faceted impact of infectious agents such as human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented increase in morbidity and mortality around the globe. The spread of infectious diseases at an alarming rate has led to accelerated research on vaccine therapeutics, which can be further exemplified with COVID (coronavirus disease) vaccine development as a global emergency. This review aims to provide insights into vaccine development, components, manufacturing processes, types/platforms and strategies to improve their efficacy. The development of vaccines comprises four stages: (1) exploratory and preclinical, (2) clinical, (3) approval and (4) manufacturing and post-marketing surveillance. Vaccine formulations comprise antigens, adjuvants, preservatives, stabilizers, antibiotics, diluents and trace components. Vaccine manufacturing is a multi-step process involving antigen generation, release, purification, addition of other ingredients (e.g., adjuvants, preservatives, stabilizers, etc.), quality control testing and filling. Conventional vaccine platforms include live attenuated, inactivated/killed, toxoid, polysaccharide and polysaccharide conjugate, synthetic peptide and virus-like particles. Advanced technologies include viral vectors, bacterial vectors, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) vaccines. These platforms provide rapid development of vaccines at a relatively low cost compared to conventional counterparts. Several approaches have been adopted for improving vaccine efficacy such as the inclusion of adjuvants and delivery of vaccines via mucosal and transcutaneous routes. Efficient uptake of vaccine antigens by microfold cells (found in the epithelium covering mucosa-associated lymphoid tissues) with subsequent transfer to the underlying antigen-presenting cells provides an efficient vaccine delivery route. In the case of the transcutaneous route, abundant antigen presenting cells found in the skin layer (e.g., Langerhans) ensure efficient vaccine delivery and induction of potent immune responses. Additionally, both these routes can overcome limitations associated with traditionally employed parenteral routes, such as risk of disease transmission in unhygienic conditions and reuse of contaminated needles, production of biohazardous waste, requirement of trained personnel for administration, invasiveness and poor patient compliance. Identification of conserved pathogenic sequences using advanced genetic engineering methods, machine learning, and artificial intelligence can help in developing efficient vaccines. Moreover, global partnerships, funding and provision of resources from the World Health Organization (WHO) can ensure vaccine development, testing and research activities for developing countries.

Technological advancements in the formulation and delivery strategies of potent chemotherapeutic agents have been exploited to direct a site-specific drug delivery for the local treatment of tumours. Of these, new generations of nanoparticles are engineered to control the release of therapeutic agents, but they still possess off-target and overall systemic delivery. Injectable hydrogels have unique physico-chemical properties enabling their use as carriers to ensure site-specific targeting. Based on such observations, nanoparticle-loaded hydrogels represent an optimal candidate to both make use of controlled release chemotherapeutic agents (nanoparticles) and local delivery agents (hydrogels) using minimally invasive procedures to reach the target site. Here, we explore the interaction of drug-polymer conjugated nanoparticles with an alginate-based hydrogel network to confine and release a highly cytotoxic compound (hydroxyl-FK866). Specifically, chitosan coating was used to covalently link poly(lactic-co-glycolic acid) nanoparticles to oxidised alginate: confinement and interaction of nanoparticles within alginate-based hydrogels were evaluated using atomic force microscopy measurements, confirming the nanoparticle/hydrogel interaction. Deployment of composite injectable hydrogels in 3D printing was finally investigated. Rheological characterisation and printability tests were performed to assess the printability of alginate-based drug delivery systems to match site-specific geometrical requirements. Then, alginate hydrogels loaded with nanoparticles were ionically crosslinked to match the properties of soft tissues (e.g. breast tissue). The efficacy of 3D printed hydrogels loaded with a known dose of hydroxyl-FK866 was tested using human breast cancer MDA-MB-231 cells. Results confirmed the expected cytotoxicity, showing approx. 52% toxicity of the hydrogel loaded, after 48 hours of incubation, whereas lower viability (approx. 36%) was measured in cells treated with free nanoparticles (control).

The optimum delivery of very poorly soluble drug compounds is challenging, especially if targeting of disease sites is required. Delivery to the lung is hampered by a range of physiological issues, and inhalation may be the most appropriate route. When breathing is compromised by infection or poor lung capacity, nebulisation may enable therapeutics to be carried deep into the respiratory tract. Here we report the development of nebulised aqueous formulations of two highly water-insoluble drugs with demonstrated anti-SARS-CoV-2 activity and evaluate their pulmonary delivery using in vitro models that include the breathing patterns of children and COVID-19 infected adults.

Triple negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat, due to its aggressiveness, high heterogeneity and lack of targeted therapies. Efforts have been made to elucidate the mechanisms by which TNBC cells become drug-resistant, aiming to identify new molecular targets for the development of effective treatments. Here, we have generated a TNBC 3D multi-cellular spheroid model using MDA-MB-231 cells and assessed the efficacy of drug delivery formulations based on docetaxel (DTX)-loaded micellar-like nanoparticles (MLNP) compared with free DTX. We assessed the viability and the induction of apoptosis in the treated spheroids using established apoptosis and necrosis biomarkers: annexin-V, PI, Sytox and caspase 3 and 7 activity by flow cytometry. Given the efficacy results of the MLNPs and free DTX, the expression of selected genes related to resistance in breast cancer cells was assessed by RT-qPCR (real-time polymerase chain reaction) as well as western blot and immunofluorescence of the drug resistance protein (ABCG2/BCRP) in both 3D and 2D cell culture models of MDA-MB-231 cells. The results from these assays indicate that the TNBC 3D multi-cellular spheroids exhibit an intrinsic multi-drug resistance (MDR) through the up-regulation of ABCG2/BCRP gene and protein, compared to monolayers of the same cell line. Moreover, the results also demonstrate that the MLNPs had the best efficacy against TNBC 3D spheroids whereas the free drug was less efficacious. This suggests that the MLNPs were able to overcome the MDR of the TNBC 3D cell culture model when compared to free DTX.

A tool compound is a reagent that is a selective small-molecule modulator of a protein's activity. It enables researchers to investigate the mechanistic and phenotypic aspects of the molecular target through various experimental approaches, such as biochemical analyses, cell-based assays, or animal investigations. The field of life science research stands to gain significant advantages from the development of research tools that are both more accessible and aesthetically engaging, thereby facilitating the process of hypothesis formation. Target identification and efficacy prediction require novel methodologies due to the declining frequency of new medication approvals and the rising expense of drug development. In this review, we emphasize that chemical probe data collection offers researchers a comprehensive compilation of tool chemicals and also discusses the collection of currently available tool chemicals and highlights limitations in our capacity to target specific biochemical processes through pharmacological means selectively.

Tracking nanoparticles’ location is imperative for understanding cellular interactions, pharmacokinetics, and biodistribution. DiD is a lipophilic dye commonly used to label nanoparticles for trafficking studies. Herein, we show that DiD micelles form in polymer NP solutions during synthesis and can lead to false positive results in downstream assays. Potential methods to remove these micelles are also described.

The deadly parasite disease known as visceral leishmaniasis (VL) is caused by the protozoa of Leishmania donovani. Artesunate (ART) has been reported to act against VL. However, its medical use is limited owing to the fact that it belongs to BCS class II. Thus, the aim of the present work was to prepare ART-loaded bilosomes (ART-BIL) to mitigate the drawbacks associated with ART. Box–Behnken design was used to optimize ART-BIL prepared by the ethanol injection method. ART-BIL were characterized for vesicle size, entrapment efficiency, FTIR, DSC, TEM, in vitro drug release, in silico molecular docking, in vitro antileishmanial activity against Leishmania donovani, and in vivo pharmacokinetic assessment. The optimized spherical ART-BIL was found to have a vesicle size of 186.7 ± 15.0 nm and an entrapment efficiency of 95.36 ± 2.5%. Spherical, non-aggregated vesicles demonstrated a biphasic drug release profile with a remarkable increase in the dissolution rate of artesunate compared to an artesunate dispersion. In silico molecular docking studies revealed the antileishmanial potential of artesunate and chenodeoxycholic acid by binding them to glyceraldehyde 3-phosphate dehydrogenase (G3PDH). Further, in vitro antileishmanial studies showed a significant enhancement in the antileishmanial potential of artesunate while in vivo pharmacokinetic studies demonstrated 1.39 and 1.47 fold increases in the C_max and AUC of ART when formulated into bilosomes. ART-loaded bilosomes could be a promising drug delivery system for the treatment of visceral leishmaniasis.

Subcutaneous injection is a widely used route of drug administration, but biopredictive in vitro tools for predicting in vivo bioavailability are not widely established. One such system, the subcutaneous injection site simulator (SCISSOR), incorporates hyaluronic acid (HA) as a model of the subcutaneous extracellular matrix (ECM), which dictates the diffusion of test compounds. However, the native ECM found is markedly more complex. Here for the first time, we compared the permeation of macromolecules with different physicochemical properties (molecular weight and charge) and model biological molecules across the HA hydrogel (used in SCISSOR) and an animal-derived basement membrane extract (BME), an ECM. We coated tissue culture inserts with these matrices as a simple experimental set up to test the permeation. The results show that the two matrices displayed similarities and some notable differences in their performance as barriers for macromolecules of different properties, suggesting that a simple experimental setup utilising biologically derived ECM may act as an inexpensive and accessible tool to predict the in vivo performance of biotherapeutics for SC administration.