Advanced Therapeutics最新文献

Despite decades of intense research, glioma remains a disease for which no adequate clinical treatment exists. Given the ongoing therapeutic failures of conventional treatment approaches, nanomedicine may offer alternative options because it can increase the bioavailability of drugs and alter their pharmacokinetics. Here, a new type of synthetic protein nanoparticles (SPNPs) is reported that allow for effective loading and controlled release of the potent cancer drug, paclitaxel (PTX) – a drug that so far has been unsuccessful in glioma treatment due to hydrophobicity, low solubility, and associated delivery challenges. SPNPs are prepared by electrohydrodynamic (EHD) jetting of dilute solutions of PTX-loaded albumin made by high-pressure homogenization. After EHD jetting, PTX SPNPs possess a dry diameter of 165 ± 44 nm, hydrated diameter of 297 ± 102 nm, and a zeta potential of −19 ± 8 mV in water. For the SPNP formulation with a total PTX loading of 9.4%, the loading efficiency is 94%, and controlled release of PTX is observed over two weeks (6% burst release). PTX SPNPs are more potent (68% lethality) than free PTX (45% lethality using 0.2% dimethyl sulfoxide). PTX SPNPs in combination with IR show a significant survival benefit in glioma-bearing mouse models, avoid adverse liver toxicity, and maintain a normal brain architecture. Immunohistochemistry reveals a dramatic tumor size reduction including 40% long-term survivors without discernible signs of tumor. Using flexibly engineered SPNPs, this work outlines an efficient strategy for the delivery of hydrophobic drugs that are otherwise notoriously hard to deliver.

Colorectal cancer (CRC) stands out as one of the most prevalent gastrointestinal cancers. Current treatment strategies for CRC are significantly hindered by systemic toxicity and suboptimal therapeutic efficacy. This study aims to overcome these limitations by developing a robust tumor-targeting chemo-photothermal strategy, combining Bortezomib (BTZ) as a proteasome inhibitor, IR780 iodide as a near-infrared dye, and Photothermal Therapy (PTT) agent, with hyaluronic acid (HA) serving as the shell for tumor targeting, denoted as HA/PB@IR780. The investigations reveal the impressive tumor-targeting affinity of HA/PB@IR780, leading to a synergistic chemo-photothermal therapeutic effect both in vitro and in vivo. Additionally, this material demonstrates the capability for drug release triggered by low pH conditions. Moreover, HA/PB@IR780 induced the generation of reactive oxygen species (ROS), triggered cells apoptosis via the PERK-CHOP-Bcl-2 pathway, and induced Immunogenic Cell Death (ICD) in CT26 cells. Importantly, HA/PB@IR780 selectively targets tumor sites, mitigating systemic toxic side effects and significantly extending the survival of CT26 tumor-bearing mice. In conclusion, this designed tumor-targeting nanocarrier represents a promising and potentially effective platform for the precise treatment of CRC.

At present, there is no therapeutic approach available to reverse the progression of pathological fibrosis and ventricle chamber stiffening. This study is designed to explore the effects of latent transforming growth factor-beta-binding protein 2 (LTBP2) on cardiac fibrosis in hypertrophic cardiomyopathy and the underlying mechanisms. The key differential gene LTBP2 is identified by mRNA sequencing. Ang II-induced cells and mice are treated with LTBP2 si-RNA or knockdown adenovirus, respectively, and the indicators of cardiac function, oxidative stress, cardiac fibrosis, apoptosis, and remodeling are examined. The underlying mechanism is elucidated in vitro by oxidative stress and an agonist of nuclear factor-kappa B (NF-κB). LTBP2 is upregulated in the cardiac tissue of mice with Ang II-mediated HF. The knockdown of LTBP2 enhanced cardiac function, attenuated cardiac fibrosis, apoptosis, hypertrophy, and oxidative stress injury, and suppressed NF-κB expression. These results are validated in vitro. The effects of LTBP2 gene silencing are reversed by either NF-κB or oxidative stress agonists in vitro. Taken together, these findings suggest that LTBP2 knockdown alleviates HF by inhibiting cardiac fibrosis, apoptosis, and hypertrophy via attenuating NF-κB signaling pathway and oxidative stress. Thus, targeting LTBP2 may be a novel approach to the treatment of HF.

Doxofylline, a newer methylxanthine derivative, has garnered increasing attention for its distinct pharmacological properties and therapeutic advantages over traditional agents such as theophylline. This paper provides a comprehensive review of the pharmacological characteristics and clinical efficacy of doxofylline, elucidating why it represents a significant advancement in methylxanthine therapy. Moreover, attention is given to the economic considerations surrounding its utilization, particularly in low- and medium-income countries where access to healthcare resources is limited. The affordability, improved tolerability, and dosing convenience of doxofylline make it a promising candidate for addressing the substantial burden of asthma and COPD in resource-constrained settings.

Upon progression to the metastatic stage, prostate tumors commonly exhibit multi-drug resistance. Combining multiple treatment protocols can be beneficial in overcoming this resistance, which is often attributed to tumor heterogeneity. Recently, nano-photosensitizer-mediated photothermal therapy is shown to inhibit tumor growth through multiple pathways, including thermal ablation and activation of the antitumor immune response. In this study, gold nanoparticles (Au) are selected as the core photosensitizer. Then, the photothermal conversion of Au is augmented through dopamine coating, and the chemotherapy drug doxorubicin (DOX) is grafted to the dopamine coating. The release of DOX from DOX-loaded dopamine-modified gold nanoparticles (Au@PDA@DOX) occurred in response to an acidic environment. The combination of chemotherapy and thermal ablation better inhibits the growth, migration, and invasion of tumor cells and induced tumor cell apoptosis and necrosis in vitro. More importantly, thermal ablation induces the immunogenic death of prostate tumor cells (RM-1) cells. The transition of prostate tumors from a “cold” to a “hot” tumor with immunogenicity is observed. The combination effectively activates the antitumor immune response, inhibits tumor growth, and alleviated bone damage by tumors in vivo. It is indicated that Au@PDA@DOX nanoparticles will offer a novel treatment protocol for prostate tumor bone metastases.

The development of RNA and oligonucleotide-based therapeutics is a longstanding goal and is currently gaining significant attention. Several RNA-based drugs are approved for clinical use. Others are under investigation or in preclinical trials. This study have initiated the development of RNA drugs for localized use in the esophagus, utilizing the EsoCap System. This system's core component is a mucoadhesive film that carries the RNA drug and is precisely applied to the esophagus. Research into the stability and properties of naked and liposomal-encapsulated RNA on mucoadhesive polymer film reveals that RNAs remain stable in various conditions without degradation, RNA leakage, or liposome fusion observed. The liposome size also remains constant after application on the film, drying, and rehydration. These findings pave the way for RNA drug development for esophageal diseases and their administration via the EsoCap system.

Age-related macular degeneration (AMD) is a degenerative eye disease that primarily affects the macula. AMD is a leading cause of vision loss in individuals over the age of 65, particularly more common in Caucasians than in other racial groups. Cerium oxide nanoparticles (CNPs) have emerged as highly promising nanomaterials in the treatment of AMD due to their potent antioxidant properties. In pathological damages of AMD conditions, characterized by oxidative stress resulting from an overproduction of reactive oxygen species (ROS), CNPs possess significant promise for attenuating the pathogenic processes and advancing therapeutic interventions. Despite their potential clinical applications, the widespread use of CNPs is greatly hampered by limited water solubility, and concerns have arisen about their potential impact on normal ROS production in mitochondria. Here, the antioxidative activity of glycol chitosan-coated CNPs (namely, GCCNPs) and their behavior in mouse primary RPE (mRPE) cells are reported through an in vitro trafficking study. This findings demonstrate that GCCNPs effectively neutralize excessive ROS and prefer to exclusively accumulate in cytosol without any uptake in the nucleus and mitochondria of the mRPE cells. Moreover, GCCNPs demonstrated therapeutic effects by reducing the ROS level in a laser-induced choroidal neovascularization (CNV) AMD-like murine model.

The unpredictable oral bioavailability of established drugs like tacrolimus and sulfasalazine presents a significant clinical challenge. This variability can lead to either toxicity or insufficient therapeutic effect. It is known that alterations in drug transporters and metabolic enzymes influence drug bioavailability. Recent evidence suggests that the indirect metabolism by gut microbes could influence transporters and enzymes which can affect the bioavailability of oral drugs. In this study, the pharmacokinetics of tacrolimus and sulfasalazine are modeled under varying host colonic conditions induced by the bacteria E. coli Nissle 1917 and Bifidobacterium adolescentis. Insight is provided into the sensitivity of pharmacokinetics to the bacterial influence on expression of intestinal drug transporters and cytochrome p450 enzymes. Our findings demonstrate that bacterial modulation reduces tacrolimus peak blood concentration compared to healthy renal transplant patients. Conversely, bacterial presence leads to a two-fold increase in sulfasalazine's peak plasma concentration compared to healthy subjects. These results suggest that incorporating the gut bacteria's influence on colonic transporters and enzymes can improve the explanation of pharmacokinetic variability. This approach has the potential to refine pharmacokinetic models and ultimately address the challenge of variable oral drug bioavailability.

Bladder cancer (BC) is a prevalent urological tumor with high recurrence rates, requiring long-term monitoring. Although cystoscopy is the primary diagnostic method, its invasiveness and cost hinder routine screening and follow-up. This study aimed to develop a novel diagnostic tool utilizing newly developed on-chip heating dPCR platform, which features integrated and rapid temperature control capabilities, for non-invasive BC detection. The dPCR platform is improved by integrating a multi-color detection system, enabling precise quantification of mutant allelic fraction (MAF) of TERT promoter mutations with a limit of detection (LOD) of 0.29%. Diagnostic performance is enhanced by integrating the NRN1 methylation biomarker and employing machine learning to optimize biomarker weighting. Testing the model on urine samples from controls (n = 35) and BC patients (n = 41) yielded a sensitivity of 0.92, specificity of 0.94, and an AUC of 0.98, surpassing conventional cytology in sensitivity while maintaining comparable specificity. Furthermore, the model effectively differentiated between normal controls and different stages, achieving accuracies of 0.92, 0.71, and 0.79 for NC, stage I, and stage II+ respectively. These findings suggest the proposed dPCR assays could serve as a sensitive and non-invasive approach for BC detection in clinical practice.