Orally ingestible medication utilizing layered double hydroxide nanoparticles strengthened alginate and hyaluronic acid-based hydrogel bead for bowel disease management.

In the treatment of bowel diseases such as ulcerative colitis through oral administration, an effective drug delivery system targeting the colon is crucial for enhancing efficacy and minimizing side effects of therapeutic agents. This study focuses on the development of a novel nanocomposite hydrogel bead comprising a synergistic blend of biological macromolecules, namely sodium alginate (ALG) and hyaluronic acid (HA), reinforced with layered double hydroxide nanoparticles (LDHs) for the oral delivery of dual therapeutics. The synthesized hydrogel bead exhibits significantly enhanced gel strength and controllable release of methylprednisolone (MP) and curcumin (CUR), serving as an anti-inflammatory drug and a mucosal healing agent, compared to native ALG or ALG/HA hydrogel beads without LDHs. The physicochemical properties of the synthesized LDHs and hydrogel beads were characterized using various techniques, including scanning electron microscopy, zeta potential measurement, transmission electron microscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy. In vitro release studies of MP and CUR under simulated gastrointestinal tract (GIT) conditions demonstrate the superior controlled release property of the nanocomposite hydrogel bead, particularly in minimizing premature drug release in the upper GIT environment while sustaining release of over 82 % of drugs in the colonic environment. Thus, the modularly engineered carrier designed for oral colon targeting holds promise as a potential candidate for the treatment of ulcerative colitis.

Nanocarrier systems loaded with IR780, iron oxide nanoparticles and chlorambucil for cancer theragnostics.

Theragnostics has become a popular term nowadays, since it enables both diagnosis and therapy at the same time while only using one carrier platform. Therefore, formulating a nanocarrier system that could serve as theragnostic agent by using simple techniques would be an advantage during production. In this project, we aimed to develop a nanocarrier that can be loaded with the chemotherapeutic medication chlorambucil and magnetic resonance imaging agents (e.g., iron oxide nanoparticles and near-infrared fluorophore IR780) for theragnostics. Poly(lactic-co-glycolic acid) was combined with the aforementioned ingredients to generate poly(vinyl alcohol)-based nanoparticles (NPs) using the single emulsion technique. Then the NPs were coated with F127 and F127-folate by simple incubation for five days. The nanoparticles have the hydrodynamic size of approx. 250 nm with negative charge. Similar to chlorambucil and IR780, iron oxide loadings were observed for all three kinds of NPs. The release of chlorambucil was quicker at pH 5.4 than at pH 7.4 at 37 °C. The F127@NPs and F127-folate@NPs demonstrated much greater cell uptake and toxicity up to 72 h after incubation. Our in vitro results of F127@NPs and F127-folate@NPs have demonstrated the ability of these systems to serve as medication and imaging agent carriers for cancer treatment and diagnostics, respectively.

Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype-phenotype relationship is required to support newborn screening (NBS) and guide treatment. RESULTS: We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient's genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population. CONCLUSIONS: These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype-phenotype relationships and NBS.

Identifying therapeutic drug targets using bidirectional effect genes.

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10-8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.