State-of-the-Art Review on Inhalable Lipid and Polymer Nanocarriers: Design and Development Perspectives.

Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era of nucleic acid therapeutics and personalized medicine for the local treatment of severe lung diseases. However, the success of any inhalation therapy is driven by a delicate interplay of factors, such as the physiochemical profile of the payload, formulation, inhalation device, aerodynamic properties, and interaction with the lung fluids. The development of drug delivery systems tailored to the needs of this administration route is central to its success and to revolutionize the treatment of respiratory diseases. With this review, we aim to provide an up-to-date overview of advances in the development of nanoparticulate carriers for drug delivery to the lung tissue, with special regard concerning lipid and polymer-based nanocarriers (NCs). Starting from the biological barriers that the anatomical structure of the lung imposes, and that need to be overcome, the current strategies to achieve efficient lung delivery and the best support for the success of NCs for inhalation are highlighted.

Fabrication of mesoporous silica nanoparticles for targeted delivery of sunitinib to ovarian cancer cells.

Introduction: Mesoporous silica nanoparticles (MSNPs) are considered innovative multifunctional structures for targeted drug delivery owing to their outstanding physicochemical characteristics. Methods: MSNPs were fabricated using the sol-gel method, and polyethylene glycol-600 (PEG600) was used for MSNPs modification. Subsequently, sunitinib (SUN) was loaded into the MSNPs, MSNP-PEG and MSNP-PEG/SUN were grafted with mucin 16 (MUC16) aptamers. The nanosystems (NSs) were characterized using FT-IR, TEM, SEM, DLS, XRD, BJH, and BET. Furthermore, the biological impacts of MSNPs were evaluated on the ovarian cancer cells by MTT assay and flow cytometry analysis. Results: The results revealed that the MSNPs have a spherical shape with an average dimension, pore size, and surface area of 56.10 nm, 2.488 nm, and 148.08 m2g-1, respectively. The cell viability results showed higher toxicity of targeted MSNPs in MUC16 overexpressing OVCAR-3 cells as compared to the SK-OV-3 cells; that was further confirmed by the cellular uptake results. The cell cycle analysis exhibited that the induction of sub-G1 phase arrest mostly occurred in MSNP-PEG/SUN-MUC16 treated OVCAR-3 cells and MSNP-PEG/SUN treated SK-OV-3 cells. DAPI staining showed apoptosis induction upon exposure to targeted MSNP in MUC16 positive OVCAR-3 cells. Conclusion: According to our results, the engineered NSs could be considered an effective multifunctional targeted drug delivery platform for the mucin 16 overexpressing cells.

Targeted Delivery of Sunitinib by MUC-1 Aptamer-Capped Magnetic Mesoporous Silica Nanoparticles.

Magnetic mesoporous silica nanoparticles (MMSNPs) are being widely investigated as multifunctional novel drug delivery systems (DDSs) and play an important role in targeted therapy. Here, magnetic cores were synthesized using the thermal decomposition method. Further, to improve the biocompatibility and pharmacokinetic behavior, mesoporous silica was synthesized using the sol-gel process to coat the magnetic cores. Subsequently, sunitinib (SUN) was loaded into the MMSNPs, and the particles were armed with amine-modified mucin 1 (MUC-1) aptamers. The MMSNPs were characterized using FT-IR, TEM, SEM, electrophoresis gel, DLS, and EDX. MTT assay, flow cytometry analysis, ROS assessment, and mitochondrial membrane potential analysis evaluated the nanoparticles' biological impacts. The physicochemical analysis revealed that the engineered MMSNPs have a smooth surface and spherical shape with an average size of 97.6 nm. The biological in vitro analysis confirmed the highest impacts of the targeted MMSNPs in MUC-1 overexpressing cells (OVCAR-3) compared to the MUC-1 negative MDA-MB-231 cells. In conclusion, the synthesized MMSNP-SUN-MUC-1 nanosystem serves as a unique multifunctional targeted delivery system to combat the MUC-1 overexpressing ovarian cancer cells.

The synergy between miR-486-5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells.

Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486-5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486-5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486-5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486-5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486-5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486-5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC.

Piperacillin Encapsulation in Nanoliposomes Using Modified Freeze-Drying of a Monophase Solution Method: Preparation, Characterization and In Vitro Antibacterial Activity.

Piperacillin (Pip) is a broad spectrum ß-lactam against most Gram-positive and Gram-negative aerobic and anaerobic bacteria. However, bacterial resistance restricts its benefits for the treatment of infectious diseases. Recently, nanoliposomal systems have been investigated as encouraging strategies to address this issue owing to their immense potential. We aimed to encapsulate Pip in liposomal nanoparticles and study their antibacterial activities in vitro against Pseudomonas aeruginosa (P. aeruginosa). Different liposomes were prepared based on the freeze-drying of a monophase solution method. Then, they were characterized in terms of size, zeta potential, polydispersity-index, and morphology. For further analysis, spectra of ATR-FTIR and XRD were taken for liposomal Pip. Encapsulation efficiency (EE) was determined via agar diffusion assay. Also, minimum inhibitory concentrations (MICs) were investigated by the standard broth macro-dilution method. The liposomes were from 100.9 to 444.13 nm with z-potential of - 30.70 to - 10.57 mV. EE of the selected formulation was 53.1%. TEM results showed that the liposomes were nanosized and almost spherical. ATR-FTIR results confirmed the full encapsulation of Pip in nanoliposomes. The X-ray pattern indicated that the liposomal Pip was amorphous. The MIC (10.6 µg/ml) of the nanoliposomal Pip against P. aeruginosa was one-half of the MIC (21.25 µg/ml) of free Pip for the same organisms. Considering four aspects (nanosized liposomes, no need for sterilization, suitable EE and enhanced antibacterial effects), this preparation method seems promising and may be used to overcome the bacterial resistance relative to Pip.

Targeting of high mobility group A2 by small interfering RNA-loaded nanoliposome-induced apoptosis and migration inhibition in gastrointestinal cancer cells.

BACKGROUND: Considering the complex nature of gastrointestinal cancer, different methods including surgery, radiotherapy, and chemotherapy are considered for the treatment. Novel strategies including silencing of oncogenes using safe delivery systems could be considered as a novel approach in colorectal cancer treatment. The aim of this study was to investigate the silencing effect of high mobility group A2 (HMGA2) small interfering RNA (siRNA)-loaded nanoliposomes on gastrointestinal cancers. METHODS: The siRNA-lipoplexes were prepared using dioleoyl trimethylammonium propane (DOTAP)/cholesterol (Chol)/1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) through the freeze-drying of a monophase solution method. The size, polydispersity index (PDI), and zeta-potential of nanoliposomes were determined using Zetasizer analyzer. The morphology of the nanoliposomes was determined by transmission electron microscopy (TEM). The agarose gel-retardation assay was carried out to confirm the loading of siRNAs into liposome. The silencing of the HMGA2 in cancer cells was evaluated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of liposomes on cell cytotoxicity was studied by MTT assay. The inhibitory effect of siRNA-loaded liposomes was evaluated by a wound-healing assay. The apoptosis induction was investigated via the annexin V/propidium iodide assay. RESULTS: The size, PDI, and zeta-potential of the prepared liposomes were found to be 350 nm, 0.67, and 86.3 mV, respectively. They were spherical in shape and could efficiently associate with siRNA. The results of gene silencing showed that the optimum condition of HMGA2 silencing was 80 pmol HMGA2 and 24 hours after treatment in each cancer cell lines. MTT assays indicated that silencing of HMGA2 in optimal condition could reduce the viability of the cancer cells more than 60% in the three cell lines. The result of the apoptosis assay showed more than 50% of the cell deaths related to the apoptosis in all three cell lines. The gene expression evaluation confirmed that apoptosis was induced via the intrinsic pathway inducing both caspase-3 and -9 expressions. Also, the reduction in Bcl2 expression confirmed the activation apoptosis pathway in the treated cancer cells. The wound-healing assay showed the suppression of cancer cell migration after treatment with the prepared nanoliposomes. CONCLUSION: The results of this study showed the HMGA2 siRNA-loaded nanoliposomes could be effective in the treatment of gastrointestinal cancers.