Journal of Drug Targeting最新文献

Small-molecule compounds exhibit distinct pharmacological properties and clinical effectiveness. Over the past decade, advances in covalent drug discovery have led to successful small-molecule drugs, such as EGFR, BTK, and KRAS (G12C) inhibitors, for cancer therapy. Researchers are paying more attention to refining drug screening methods aiming for high throughput, fast speed, high specificity, and accuracy. Therefore, the discovery and development of small-molecule drugs has been facilitated by significantly reducing screening time and financial resources, and increasing promising lead compounds compared with traditional methods. This review aims to introduce classical and emerging methods for screening small-molecule compounds in targeted cancer therapy. It includes classification, principles, advantages, disadvantages, and successful applications, serving as valuable references for subsequent researchers.

Drug efflux transporters, especially those belonging to the ATP-binding cassette (ABC) transporter superfamily, play a crucial role in various drug resistance issues, including multidrug resistance (MDR) in cancer and treatment-resistant depression (TRD) in individuals with major depressive disorder. Key transporters in this context include P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). This study aimed to investigate the modulatory effects of polyoxyethylene (20) sorbitan monolaurate (Tween 20) on these efflux transporters in vitro and to evaluate its potential for overcoming drug resistance in two models: an in vitro cancer MDR model and an in vivo TRD model. The findings indicated that 0.001% Tween 20 significantly inhibited the efflux actions of all three transporters. Additionally, 0.005% Tween 20 effectively reversed resistance to paclitaxel, vincristine, doxorubicin, and mitoxantrone in various cancer MDR cell lines. In the in vivo depression-like behaviour model, 0.01% Tween 20 markedly enhanced the antidepressant and anxiolytic effects of fluoxetine. Given its strong inhibitory effects on P-gp, MRP1, and BCRP, along with its capacity to reverse drug resistance both in vitro and in vivo, Tween 20 is a compelling candidate for tackling transporter-mediated drug resistance.

Drug addiction, particularly to opioids like morphine, remains a pressing global health issue. Curcumin, a natural flavonoid, holds promise for treating neurological disorders, yet faces challenges, such as poor solubility and limited bioavailability across the blood-brain barrier. Solid lipid nanoparticles offer a solution, facilitating drug delivery to the brain. Using the Box-Behnken design, nanoparticles were optimised, yielding particles sized 152 nm, with a polydispersity index of 0.254, and an encapsulation efficiency of 70.74%. These nanoparticles enhance curcumin concentration and retention in brain tissue. Behavioural experiments using the conditioned place preference (CPP) test confirmed curcumin's impact on morphine addiction and its modulation of c-Fos gene expression. Pharmacological network analysis identified potential mechanisms of action, highlighting common targets in calcium and serotonin pathways. Docking simulations showed curcumin's affinity for proteins like 5HT1A, MAO-A, and TRPV1, relevant to addiction pathways. This research underscores the potential of curcumin-loaded solid lipid nanoparticles as a therapeutic approach for combating opioid addiction and neurological disorders.

Glioblastoma multiforme (GBM) is a widespread and life-threatening kind of brain cancer, which has a high mortality rate. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, irreversibly adheres to a conserved cysteine residue of two enzymes BTK and BMX, inhibiting their kinase activities, which leads to suppression of the growth of glioma cells. This study synthesised PLGA-PEG-folate (PPF) polymer and subsequently encapsulated ibrutinib within PPF nanoparticles (IBT-PPF-NPs). H NMR spectra confirmed the synthesis of PPF polymer. The efficiency of IBT-PPF-NPs was 97 ± 2.26% with 8.8 ± 0.2% drug loading. The particle size was 208 ± 4.8 nm. The IC₅₀ value of free ibrutinib, IB-PPF-NPs and ibrutinib encapsulated in PLGA NPs (IB-P-NPs) was 10.2, 7.6 and 10.13 µM in C6 cell lines, whereas in U-87 MG cells was 24.4, 16 and 25.2 µM, respectively. The cellular uptake of FITC-PPF-NPs increased from 47.6% to 90.3% in C6 cells and from 55% to 97.3% in U-87 MG cells compared to FITC-P-NPs. The in vivo results indicate a significant reduction in tumour size in treatment groups in comparison to control groups, while the group that received the intratumoural injection of IB-PPF-NPs exhibited a greater reduction. The folate-targeting agent enhances the nanoparticles' effectiveness by promoting their uptake through the endocytosis pathway.

Phloretin exhibits strong antioxidant and anti-aging properties by inhibiting mitochondrial oxidation of glutamate, succinic acid, and ascorbic acid. However, its clinical application is limited by poor aqueous solubility and low oral bioavailability. To enhance its bioavailability and efficacy, we incorporated phloretin into nano-micelles (phloretin-MM) using the thin film dispersion method. Characterization revealed that the optimal formulation had TPGS and Pluronic F68 in a 4:1 ratio as the excipients, which resulted in spherical micelles with an average particle size of 33.28 nm and an encapsulation efficiency of 71.2 ± 0.48%. The in vitro release profile showed that the phloretin-MM showed significantly higher cumulative release rates than free phloretin across various pH conditions, while the pharmaceutical analysis in rats indicated that phloretin-MM significantly improved the oral bioavailability of phloretin (about 5 folds) in circulation. Additionally, through the analysis of the staining of zebrafish under light microscopy and the average gray value, it can be concluded that phloretin has anti-aging drug effect, and phloretin-MM is better than free phloretin. These findings suggest that TPGS/Pluronic F68-modified phloretin-MM could serve as an excellent nano-drug carrier system, potentially enhancing the solubility, bioavailability, and anti-aging effects of phloretin for broader clinical applications.

Osteoporosis is a common metabolic bone disorder that requires new treatment strategies. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a proven osteogenic agent in diabetes-linked bone loss. However, poor solubility, low oral bioavailability and inadequate bone-targeting limit its use in osteoporosis. We have successfully developed the bone-targeted liposomes of linagliptin using an aspartic acid conjugate, that is poly (aspartic acid-co-lactide)-1,2-dipalmitoyl-sn-glycero-3-phospho ethanolamine (PAL-DPPE), which was prior synthesised and identified using FTIR and NMR. Liposomes were evaluated for particle size, encapsulation efficacy, drug loading and release study in addition to in vitro hydroxyapatite binding ability. To determine the anti-osteoporosis effect of liposomes, in vivo testing was performed in glucocorticoid-induced osteoporosis model in mice. Bone targeted liposomes of linagliptin having particle size of 281.7 nm and hydroxyapatite affinity of 89% significantly improved the bone architecture parameters and bone mineral density in micro-computed tomography analysis. Further, these liposomes positively modulated sclerostin, bone morphogenetic protein-2, receptor activator of nuclear factor kappa beta/osteoprotegerin ratio and other bone turnover biomarkers. The findings demonstrate that aspartic acid conjugate (PAL-DPPE)-based bone-targeted liposomes of linagliptin hold promise for the treatment of osteoporosis. Moreover, the possible mechanistic pathways involved here is Wnt and AMPK pathway.

Arsenic trioxide (ATO), the active ingredient in Chinese arsenic, effectively inhibits hepatocellular carcinoma (HCC) cell growth, but its clinical application is limited by the lack of a targeted delivery system. Phosphatidylinositol proteoglycan 3 (GPC3) is specifically expressed in HCC, and CPP44 is a cell-penetrating peptide that targets HCC cells. Here, we developed a liposome incorporating ATO with dual surface modifications of anti-GPC3 antibody and CPP44. The system was firstly enriched and localised at the liver tumour site through passive targeting by EPR and active targeting by specific binding of anti-GPC3 antibody to GPC3 protein. CPP44 then facilitated ATO penetration into HCC cells. Specifically, we first employed computational modelling to demonstrate that the covalently-coupled antibody maintained its binding ability to the GPC3 antigen. Subsequent experimental assays revealed that Dl-ATO-Lp exhibited higher cell uptake rate and stronger tumour cell killing effect. In an HCC mouse model, Dl-ATO-Lp achieved effective tumour targeting, with a tumour inhibition rate of 63.43%. This dual-ligand liposome system enhances the targeted delivery and therapeutic efficacy of ATO, offering a promising direction for solid tumour therapy and advancing the clinical application of ATO.

Endoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analysed the contribution of the three major ER stress pathways-IRE1, ATF6, and PERK-in lung cancer pathogenesis via modulation of tumour microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.

Open wounds are prone to bacterial infiltration mostly resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), which affects healing of open wounds. Topical linezolid nano-dispersion using essential oils as nanoemulgel can increase solubility of drug and bypass side-effects like GI-irritation of oral administration. Pseudo-ternary phase diagram was built to optimise nanoemulsion. Surfactant/co-surfactant mixture (3:1), deionised water and Oil_mix (4:1) with drug were vortexed and then ultrasonicated. 1% carbopol gel of optimised nanoemulsion was prepared and characterised, exposed to antimicrobial study, cytocompatibility study using HEK293 cell-line, and in vivo wound healing study using rat excision model. Histological study was performed to confirm growth of stratum corneum. Optimised formulation has particle size (244.6 ± 178.66 nm), polydispersity index (25%), entrapment efficiency (92.3 ± 3.38%) and in vitro drug release (87.58 ± 4.16%) best fitted in Korsmeyer-Peppas kinetics model. Nanoemulgel F6 (0.2%w/w) was found with viscosity of 5345 ± 6 cP constituting a very excellent antimicrobial effect against MRSA. HEK293 cells had shown good cytocompatibility with formulation. The wound contraction rate was 99.66 ± 0.57% at day 15 on daily application of nanoemulgel and stratum corneum was almost fully regenerated. The developed nanoemulgel has potential antimicrobial efficacy and can promote wound healing.

There are 275,000 new cases of oral cancer (OC) per year, making it the sixth most common cancer in the world. Severe adverse effects, including loss of function, deformity, and systemic toxicity, are familiar with traditional therapies such as radiation, chemotherapy, and surgery; due to their unique properties, nanoparticles (NPs) have emerged as a superior alternative over chemo/radiotherapy and surgery due to their targeting capability, bioavailability, compatibility, and high solubility. Due to their unique properties, metallic NPs have garnered significant attention in OC control. In addition to the fact that metal NPs may be harmful to human cells, the reactive chemicals used to make them pose the same risk, which limits their use in medicine. Green synthesis (GS) is a novel strategy that uses biological materials like yeast, bacteria, fungi, and plant extracts. Compared to more traditional chemical synthesis processes, these are more environmentally benign and manageable for living organisms. This article summarises the GS of NPs made of metals and metal oxides and their anticancer effects on OC. The method's potential benefits and drawbacks in advancing metallic NPs' GS and shaping OC therapy's future were also discussed.