Journal of Drug Targeting最新文献

3-D multi-faceted, nano-globular PAMAM dendritic skeleton is a highly significant polymer that offers applications in biomedical, industrial, environmental and agricultural fields. This is mainly due to its enhanced properties, including adjustable surface functionalities, biocompatibility, non-toxicity, high uniformity and reduced cytotoxicity, as well as its numerous internal cavities. This trait inspires further exploration and advancements in tailoring approaches. The implementation of deliberate strategic modifications in the morphological characteristics of PAMAM is crucial through chemical and biological interventions, in addition to its therapeutic advancements. Thus, the production of peripheral groups remains a prominent and highly advanced technique in molecular fabrication, aimed at boosting the potential of PAMAM conjugates. Currently, there exist numerous dendritic-hybrid materials, despite the widespread use of PAMAM-conjugated frameworks as drug delivery systems, which are well regarded for their efficacy in enhancing potency through the incorporation of surface functions. This paper provides a comprehensive review of recent progress in the design and assembly of various components of PAMAM conjugates, focusing on their unique formulations. The review encompasses synthetic methodologies, a thorough evaluation of their applicability, and an analysis of their potential functions in the context of Drug Delivery Systems (DDS) in the current period.

Recent advancements in multifunctional nanomaterials for cancer therapy have highlighted porphyrin-based metal-organic frameworks (MOFs) as promising candidates due to their unique properties and versatile applications. This overview focuses on the use of porphyrin-based MOFs for combined photodynamic therapy (PDT) and photothermal therapy (PTT) in cancer treatment. Porphyrin-based MOFs offer high porosity, tuneable structures, and excellent stability, making them ideal for drug delivery and therapeutic applications. The incorporation of porphyrin molecules into the MOF framework enhances light absorption and energy transfer, leading to improved photodynamic and photothermal effects. Additionally, the porosity of MOFs allows for the encapsulation of therapeutic agents, further enhancing efficacy. In PDT, porphyrin-based MOFs generate reactive oxygen species (ROS) upon light activation, destroying cancer cells. The photothermal properties enable the conversion of light energy into heat, resulting in localised hyperthermia and tumour ablation. The combination of PDT and PTT in a single platform offers synergistic effects, leading to better therapeutic outcomes, reduced side effects, and improved selectivity. This dual-modal treatment strategy provides precise spatiotemporal control over the treatment process, paving the way for next-generation therapeutics with enhanced efficacy and reduced side effects. Further research and optimisation are needed for clinical applications.

Drug targeting can be achieved by coupling drugs or their carriers to affinity molecules, mostly antibodies (Abs), which recognise specific protein targets. However, most proteins are not expressed in an exclusive configuration but as various isoforms. Hence, selected targeting molecules may fail to target with enough efficiency in clinical trials, which is overlooked. We illustrate this by targeting intercellular adhesion molecule 1 (ICAM-1), a cell-surface protein overexpressed in many pathologies. Most ICAM-1 targeting studies used Ab R6.5, which binds ICAM-1 domain 2 (D2). Yet, literature and our data show that D2 is frequently absent among ICAM-1 isoforms. We thus produced a battery of five new Abs (B4, B6, B11, C12 and G2) and tested their ability to recognise both full-length and -D2 ICAM-1. In solution, all Abs recognised both ICAM-1 forms (from 5.3 × 10¹¹ to 4.2 × 10¹² sum intensity/well). Coating them on nanocarriers (NCs) rendered G2 specific against -D2 ICAM-1 (4.2 × 10⁶ NCs/well) while other Abs kept their dual recognition (from 6.4 × 10⁶ to 2.2 × 10⁷ NCs/well). All Abs induced NC intracellular uptake in respective cells (from 42% to 85%) and displayed good cross-species reactivity (from 4.4 × 10¹¹ to 2.6 × 10¹² sum intensity/well). These Abs represent valuable tools to target ICAM-1 and illustrate a new targeting paradigm that may improve classical strategies.

Glioblastoma multiforme (GBM), the most aggressive form of brain cancer, poses substantial challenges to effective treatment due to its complex and infiltrative nature, making it difficult to manage. Photodynamic therapy (PDT) and sonodynamic therapy (SDT), have emerged as promising individual treatment options against GBM due to their least-invasive approach. However, both PDT and SDT have drawbacks that require careful consideration. A combination therapy using light and sound waves has gained attention, offering new avenues to overcome challenges from individual therapies. Sono-photodynamic therapy (SPDT) has been used against various tumours. Researchers are considering SPDT as a favourable alternative to the conventional therapies for GBM. SPDT offers complementary mechanisms of action, including the production of ROS, disruption of cellular structures, and induction of apoptosis, leading to enhanced tumour cell death. This review gives an insight about PDT/SDT and their limitations in GBM treatment and the need for combination therapy. We try to unveil the process of SPDT and explore the mechanism behind improved SPDT-meditated cell death in GBM cells by focusing on the ROS-mediated cell response occurring as a result of SPDT and discussing current modifications in the existing sensitisers for their optimal use in SPDT for GBM therapy.

ABSTRACT Alzheimer's disease (AD), which is marked by gradual neuronal decline and subsequent loss of cognitive functions and memory, poses significant treatment challenges. The present study involved the development, in vitro, and in vivo evaluation of a novel intranasal mucoadhesive in-situ gel of vinpocetine (VIN) with the aim to target the brain. An innovative gel formulation composed of poloxamer 407, HPMC E15 LV, and citric acid as a solubilizer was developed by 2³ Factorial Design. The developed optimal formulation exhibited favorable rheological properties as it displayed ideal gelation time (31.6 ± 1.52 sec), optimum gelling temperature (32 ± 1.0 °C), enhanced mucoadhesive strength (6622 ± 2.64 dynes/cm²), prolonged adhesion (7.22 ± 0.57 hrs) compared with the baseline formulation (F18), and improved drug release in 12 hrs (39.59 ± 1.6%). In vivo, pharmacokinetics revealed a significant increase in C_max (∼2-fold) and AUC_0-t (∼2-fold) in the brain with the in-situ intranasal gel compared to the oral route. In the rat model of AD, in-situ intranasal gel demonstrated significantly greater efficacy (p < 0.001) than oral administration in alleviating AD symptoms as evidenced by behavioral and histological studies. Thus, VIN in-situ gel can be safe and noninvasive for nose-to-brain drug delivery.

Atherosclerosis (AS) is a chronic systemic inflammatory disease, where early diagnosis and theranostics strategy for AS are crucial for improving outcomes. However, conventional diagnostic techniques are limited in identifying early AS lesions, failing to stop the progression of AS in time. Nano-delivery systems have shown significant potential in AS diagnosis and treatment, offering distinct advantages in plaque identification and enhancing drugs concentration at lesion sites, thereby advancing new-generation theranostics strategy. This review discusses the application of nano-delivery systems based on imaging technology in AS diagnosis, and we further explore recent advancements in combining different imaging technologies with emerging theranostics strategy. In addition, we also discuss the challenges faced by nano-delivery systems for AS diagnosis and theranostics in clinical translation, such as nanoparticle targeting efficiency, cytotoxicity and long-term accumulation, immune clearance and inaccurate disease modelling. Finally, we also provide prospects on nano-delivery systems based on diagnostic and therapeutic strategies.

Drug-induced photosensitivity is a potential adverse event of many drugs and chemicals used across a wide range of specialties in clinical medicine. In the present study, we investigated the feasibility of predicting the photosensitising effects of drugs and chemical compounds via state-of-the-art artificial intelligence-based workflows. A dataset of 2200 drugs was used to train three distinct models (logistic regression, XGBoost and a deep learning model (Chemprop)) to predict photosensitising attributes. Labels were obtained from a list of previously published photosensitisers by string matching and manual validation. External evaluation of the different models was performed using the tox21 dataset. ROC-AUC ranged between 0.8939 (Chemprop) and 0.9525 (XGBoost) during training, while in the test partition it ranged between 0.7785 (Chemprop) and 0.7927 (XGBoost). Analysis of the top 200 compounds of each model resulted in 55 overlapping molecules in the external validation set. Prediction scores in fluoroquinolones within this subset corresponded well with culprit substructures such as fluorinated aryl halides suspected of mediating photosensitising effects. All three models appeared capable of predicting photosensitising effects of chemical compounds. However, compared to the simpler model, the complex models appeared to be more confident in their predictions as exhibited by their distribution of prediction scores.

Vision loss and blindness are significant issues in both developed and developing countries. There are a wide variety of aetiologies that can cause vision loss, which are outlined in this review. Although treatment has significantly improved over time for some conditions, nearly half of all people with vision impairment are left untreated. Gene delivery is an emerging field that may assist with the treatment of some of these difficult to manage forms of vision loss. Here we review how a component of nanotechnology-based, non-viral gene delivery systems are being applied to help resolve vision impairment. This review focuses on the use of lipid and polymer nanoparticles, and quantum dots as gene delivery vectors to the eye. Finally, we also highlight some emerging technologies that may be useful in this discipline.

Effective drug delivery to the central nervous system (CNS) remains a challenge due to the blood-brain barrier (BBB). Macromolecules such as proteins and peptides are unable to cross BBB and have poor therapeutic efficacy due to little or no drug distribution. A promising alternative is the conjugation of a drug to a shuttle molecule that can reach the CNS via receptor-mediated transcytosis (RMT). Several receptors have been described for RMT, such as low-density lipoprotein receptor-related protein 1 (LRP1). We used phage display technology combined with an in vitro BBB model to identify LRP1 ligands. A single domain antibody (dAb) library was used to enrich for species that selectively bind to immobilised LRP1 ligand. We obtained a novel nanobody, dAb D11, that selectively binds to LRP1 receptor and mediates in vitro internalisation of phage particles in brain endothelial cells, with a dissociation constant Kd of 183.1 ± 85.8 nM. The high permeability of D11 was demonstrated by an in vivo biodistribution assay in mice. We discovered D11, the first LRP1 binding dAb with BBB permeability. Our findings will contribute to the development of RMT-based drugs for the treatment of CNS diseases.

The side effects of chemotherapy drugs have prompted the development of targeted therapies. Distinctive abundance of lipid peroxidation (LPO) in tumor cells represents a potential target for drug delivery. However, LPO - based targeted ligands remain under - exploited. In this work, the targeting of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), was investigated within a mesoporous silica nanocarrier loaded with doxorubicin (DOX) and connected with 4-NH₂-TEMPO obtaining DOX/MSN-TEMPO. A cellular uptake assay showed a faster uptake of DOX/MSN-TEMPO than blank group on Hela, L929 and 4T1 cells, revealing TEMPO's active targeting ability for tumor cells. After observing this phenomenon, the fabrication of a basic copolymer module carrying cyanine5.5 (Cy5.5) and TEMPO was reported. In vivo experiments were conducted on mouse MCF-7 tumor models, displaying selective aggregation of nano micelles at the tumor site and thereby verifying the broad applicability of TEMPO. Based on the large amounts of LPO leads to the presence of numerous free radicals, while TEMPO, as a free radical capture agent, further targets tumor cells. These findings verify the targeting ability of TEMPO for most tumor cells and collectively underscore the potential of TEMPO and analogous capture agents as innovative targeted ligands for drug delivery.