Erlotinib-Loaded Dendrimer Nanocomposites as a Targeted Lung Cancer Chemotherapy.

Lung cancer is the main cause of cancer-related mortality globally. Erlotinib is a tyrosine kinase inhibitor, affecting both cancerous cell proliferation and survival. The emergence of oncological nanotechnology has provided a novel drug delivery system for erlotinib. The aims of this current investigation were to formulate two different polyamidoamine (PAMAM) dendrimer generations-generation 4 (G4) and generation 5 (G5) PAMAM dendrimer-to study the impact of two different PAMAM dendrimer formulations on entrapment by drug loading and encapsulation efficiency tests; to assess various characterizations, including particle size distribution, polydispersity index, and zeta potential; and to evaluate in vitro drug release along with assessing in situ human lung adenocarcinoma cell culture. The results showed that the average particle size of G4 and G5 nanocomposites were 200 nm and 224.8 nm, with polydispersity index values of 0.05 and 0.300, zeta potential values of 11.54 and 4.26 mV of G4 and G5 PAMAM dendrimer, respectively. Comparative in situ study showed that cationic G4 erlotinib-loaded dendrimer was more selective and had higher antiproliferation activity against A549 lung cells compared to neutral G5 erlotinib-loaded dendrimers and erlotinib alone. These conclusions highlight the potential effect of cationic G4 dendrimer as a targeting-sustained-release carrier for erlotinib.

Visualizing the 4D Impact of Gold Nanoparticles on DNA.

The genotoxicity of AuNPs has sparked a scientific debate, with one perspective attributing it to direct DNA damage and another to oxidative damage through reactive oxygen species (ROS) activation. This controversy poses challenges for the widespread use of AuNPs in biomedical applications. To address this debate, we employed four-dimensional atomic force microscopy (4DAFM) to examine the ability of AuNPs to damage DNA in vitro in the absence of ROS. To further examine whether the size and chemical coupling of these AuNPs are properties that control their toxicity, we exposed individual DNA molecules to three different types of AuNPs: small (average diameter = 10 nm), large (average diameter = 22 nm), and large conjugated (average diameter = 39 nm) AuNPs. We found that all types of AuNPs caused rapid (within minutes) and direct damage to the DNA molecules without the involvement of ROS. This research holds significant promise for advancing nanomedicines in diverse areas like viral therapy (including COVID-19), cancer treatment, and biosensor development for detecting DNA damage or mutations by resolving the ongoing debate regarding the genotoxicity mechanism. Moreover, it actively contributes to the continuous endeavors aimed at fully harnessing the capabilities of AuNPs across diverse biomedical fields, promising transformative healthcare solutions.

Comparison of Tau and Amyloid-ß Targeted Immunotherapy Nanoparticles for Alzheimer's Disease.

Alzheimer's disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-ß plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-ß hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-ß, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-ß hypothesis, with Aß dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies.

MicroRNA-219 loaded chitosan nanoparticles for treatment of glioblastoma.

Recent evidence has implicated microRNA-219 (miR-219) in regulation of gene contributed in glioblastoma (GBM) pathogenesis. This study aimed to prepare miR-219 in chitosan (CS) nanoparticles (NPs), characterize and investigate their efficacy on human GBM cell line (U87 MG). NPs were prepared using ionic gelation method. The influence of process parameters on physicochemical characteristics of NPs was investigated. Apoptotic effect of miR-219 was examined on U87 MG cells. Formulated NPs showed particle size of 109 ± 2.18 nm, with poly dispersity index equal to 0.2 ± 0.05, and zeta potential of +20.5 ± 0.7 mV. Entrapment efficiency of miR-219 in loaded NP has reached 95%. The in vitro release study demonstrated sustained release pattern of miR-219 from CS-NPs. Gel retardation assay has confirmed the integrity of miR-219 after production process. The fabricated NPs reduced the survival of U87 MG cells to 78% after 24 h of post-transfection, and into 67.5% after 48 h. However, fibroblasts were not affected by the NPs, revealing their specificity for GBM cells. Given the tumour suppressing function of miR-219, and advantage of CS-NPs for gene delivery to the central nervous system, the presented NPs have a great potential for treatment of GBM.

Trastuzumab Targeted Neratinib Loaded Poly-Amidoamine Dendrimer Nanocapsules for Breast Cancer Therapy.

BACKGROUND: Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy. METHODS: TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake. RESULTS: The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer. CONCLUSION: In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.

Spatiotemporal PFQNM visualization of the effect of suicide dendriplexes on dividing HeLa cells.

Suicide gene delivery is significant in cancer therapy but has not been fully investigated on a cellular scale. Here, Peak Force Quantitative Nanomechanical atomic force microscopy (PFQNM-AFM) was applied to visualize the effect of herpes simplex virus thymidine kinase dendriplexes (G4AcFaHSTK) on the morphological and nanomechanical properties of individual live and dividing HeLa cells. Cells were then exposed to G4AcFaHSTK, followed by ganciclovir, and directly imaged by real-time PFQNM-AFM. Cell membrane liquefaction, cytoplasmic shrinkage, and cytoskeleton structure loss were observed during cell division. The average Young's modulus of the nuclear region increased with time as the cell continued from metaphase (6.29 kPa) to telophase (13.6 kPa) and then decreased (2.25 kPa) upon apoptosis. In contrast, cells exposed to either ganciclovir or G4AcFaHSTK alone have no changes. Thus, understanding the real-time effects of suicide dendriplexes on the cytoskeletal and nanomechanical behaviors of cancer cells may provide new methods for cancer treatment.

Solid and cystic papillary neoplasm of the pancreas in a 18-year-old female: a case report.

CONTEXT: Solid and cystic papillary neoplasm of the pancreas is an extremely rare neoplasm that mostly affects young females in the mean age of 25 years and accounts for about 0.2-2.7% of all pancreatic tumors. CASE REPORT: A 18-year-old female presented with progressively increasing mass in the left hypochondrium and epigastric regions and vague abdominal pain. There was no history of jaundice and vomiting. The mean diameter of the tumors was 17x24 cm. Preoperative core needle revealed solid and cystic papillary neoplasm. Distal pancreatectomy and splenectomy were performed. The patient did not receive adjuvant therapy and no tumor recurrence was detected in follow up. CONCLUSION: Solid and cystic papillary neoplasm may reach large dimensions with a benign behavior and is curable by surgical excision. Differential diagnosis from other tumors with aggressive behavior is therefore important.