Journal of Drug Targeting最新文献

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.

The cytosolic delivery of therapeutic proteins represents a promising strategy for addressing diseases caused by protein dysfunction. Despite significant advances, efficient delivery remains challenging due to barriers such as cell membrane impermeability, endosomal sequestration and protein instability. This review summarises recent progress in protein delivery systems, including physical, chemical and biological approaches, with a particular focus on strategies that enhance endosomal escape and targeting specificity. We further discuss the clinical translatability of these approaches and propose future directions for improving delivery efficiency and safety, ultimately unlocking the therapeutic potential of intracellular proteins.

A knowledge of the difference of spatio-temporal behaviour of nanomedicine in different type of tumour models is important to develop well-targeted nanomedicine for tumour. In this study, intratumoral accumulation of the model nanomedicine, gadolinium-conjugated dextran (Gd-Dex), was examined with magnetic resonance imaging in two tumour models; mouse sarcoma S180 and radiation-induced mouse fibrosarcoma RIF-1. From time-course of the distribution images, the plasma-to-tumour interstitial tissue transfer constant (K^trans) and fractional plasma volume (V_p) were calculated and mapped. Gd-Dex preferentially distributed to the marginal region of S180 tumours immediately after its injection, and then started to accumulate in some parts of the central region. K^trans and V_p values were large in the marginal region, while only K^trans was large in some parts of the central region. In contrast, the distribution of Gd-Dex in RIF-1 tumours was fairly homogeneous, and may have resulted from the homogeneous distributions of K^trans and V_p. The amounts of Gd-Dex that accumulated in entire tumours in both tumour models correlated with the volume of tumours; however, accumulation in large S180 tumours deviated from the correlation in the early phase. The differences in the manner and pharmacokinetics of nanomedicine among tumour models may affect the accumulation of the medicine.

Ischaemic stroke is a central nervous system disease with high morbidity, recurrence and mortality rates. Thrombolytic and neuroprotective therapies are the main therapeutic strategies for ischaemic stroke, however, the poor delivery efficiency of thrombolytic and neuroprotective drugs to the brain limits their clinical application. So far, the development of nanomedicine has brought opportunities for the above challenges, which can not only realise the effective accumulation of drugs in the target site, but also improve the pharmacokinetic behaviour of the drugs. Among the most rapidly developing nanoparticles, micelles gradually emerging as an effective strategy for ischaemic stroke treatment due to their own unique advantages. This review provided an overview of targeted and response-release micelles based on the physicochemical properties of the ischaemic stroke microenvironment, summarised the targeting strategies for delivering micellar formulations to the thrombus, blood-brain barrier, and brain parenchyma, and finally described the potentials and challenges of polymeric micelles in the treatment of ischaemic stroke.

Nanotechnology has significantly impacted drug discovery and development over the past three decades, offering novel insights and expanded treatment options. Key to this field is nanoparticles, ranging from 1 to 100 nanometres, with unique properties distinct from larger materials. Selenium nanoparticles (SeNPs) are particularly promising due to their low toxicity and selective cytotoxicity against cancer cells. They have shown efficacy in reducing various cancers types and mitigating conditions like diabetic nephropathy and neurological disorders, such as Alzheimer's disease. This review highlights SeNPs' role in enhancing drug delivery systems, improving the absorption of water-soluble compounds, proteins, peptides, vaccines, and other biological therapies. By modifying nanoparticle surfaces with targeting ligands, drug delivery can achieve precise site-specific delivery, increasing effectiveness. SeNPs can be synthesised through physical, chemical, and biological methods, each offering advantages in stability, size, and application potential. Additionally, SeNPs enhance immune responses and reduce oxidative stress, validating their role in biotherapy and nanomedicine. Their ability to target macrophages and regulate polarisation underscores their potential in antimicrobial therapies. Recent advancements, such as mannosylated SeNPs for targeted delivery, exemplify innovative nanotechnology applications in medicine. Overall, SeNPs represent a promising frontier in nanomedicine, offering new avenues for treating and managing various diseases.

We report the development of an immunotherapeutic molecule, a Humanized immunotoxin, for treating hCG-expressing advanced-stage cancers. PiPP, a high-affinity anti-hCG monoclonal antibody, is used in the immunotoxin for 'homing' hCG-positive cancer cells. The deimmunized (DI) form of α-Sarcin, a fungal-origin toxin that lacks functional T-cell epitopes, is used in the design to ensure minimal immunogenicity of the immunotoxin for repetitive use in humans. A single-chain variable fragment (scFv) of PiPP was constructed by linking the Humanized VH and VL regions of the antibody. The scFv part of the antibody was further linked to the toxin α-Sarcin (DI) at the gene level and expressed as a recombinant protein in E. coli. The immunotoxin was purified from the bacterial cell lysate and analysed for binding and cytotoxicity to hCG-secreting colorectal and pancreatic cancer cells. The results showed that the scFv(PiPP)-Sarcin immunotoxin was able to bind to colorectal and pancreatic cancer cells and killed approximately 85% of the cells. In vivo testing of the immunotoxin produced results similar to those of in vitro testing against colorectal adenocarcinoma-induced tumours. This immunotoxin could be a promising immunotherapeutic agent for treating colorectal, pancreatic and other terminal-stage hCG-expressing cancers.

Decade-long efforts in medicinal biotechnology have enabled large-scale in-vitro production of optimised therapeutic RNA constructs for stable in-vivo delivery and modify the expression of disease-related genes. The success of lipid nanoparticle-formulated mRNA vaccines against Severe acute respiratory syndrome Coronavirus-2 (SARS-Cov2) has opened a new era of RNA therapeutics and non-viral drug delivery systems. The major limiting factor in the clinical translation of RNA-based drugs is the availability of suitable delivery vehicles that can protect RNA payloads from degradation, offer controlled release, and pose minimal inherent toxicity. Unwanted immune response, payload size constraints, genome integration, and non-specific tissue targeting limit the application of conventional viral drug-delivery vehicles. This review summarises current research on nano-sized drug carriers, including lipid nanoparticles, polymer-based formulations, cationic nanoemulsion, and cell-penetrating peptides, for targeted therapeutic RNA delivery. Further, this paper highlights the biomimetic approaches (i.e. mimicking naturally occurring bio-compositions, molecular designs, and systems), including virus-like particles (VLPs), exosomes, and selective endogenous eNcapsidation (SEND) technology being explored as safer and more efficient alternatives.