Lipid nanoparticle encapsulated large peritoneal macrophages migrate to the lungs via the systemic circulation in a model of clodronate-mediated lung-resident macrophage depletion.

Rationale: A mature tissue resident macrophage (TRM) population residing in the peritoneal cavity has been known for its unique ability to migrate to peritoneally located injured tissues and impart wound healing properties. Here, we sought to expand on this unique ability of large peritoneal macrophages (LPMs) by investigating whether these GATA6+ LPMs could also intravasate into systemic circulation and migrate to extra-peritoneally located lungs upon ablating lung-resident alveolar macrophages (AMs) by intranasally administered clodronate liposomes in mice. Methods: C12-200 cationic lipidoid-based nanoparticles were employed to selectively deliver a small interfering RNA (siRNA)-targeting CD-45 labeled with a cyanine 5.5 (Cy5.5) dye to LPMs in vivo via intraperitoneal injection. We utilized a non-invasive optical technique called Diffuse In Vivo Flow Cytometry (DiFC) to then systemically track these LPMs in real time and paired it with more conventional techniques like flow cytometry and immunocytochemistry to initially confirm uptake of C12-200 encapsulated siRNA-Cy5.5 (siRNA-Cy5.5 (C12-200)) into LPMs, and further track them from the peritoneal cavity to the lungs in a mouse model of AM depletion incited by intranasally administered clodronate liposomes. Also, we stained for LPM-specific marker zinc-finger transcription factor GATA6 in harvested cells from biofluids like broncho-alveolar lavage as well as whole blood to probe for Cy5.5-labeled LPMs in the lungs as well as in systemic circulation. Results: siRNA-Cy5.5 (C12-200) was robustly taken up by LPMs. Upon depletion of lung-resident AMs, these siRNA-Cy5.5 (C12-200) labeled LPMs rapidly migrated to the lungs via systemic circulation within 12-24 h. DiFC results showed that these LPMs intravasated from the peritoneal cavity and utilized a systemic route of migration. Moreover, immunocytochemical staining of zinc-finger transcription factor GATA6 further confirmed results from DiFC and flow cytometry, confirming the presence of siRNA-Cy5.5 (C12-200)-labeled LPMs in the peritoneum, whole blood and BALF only upon clodronate-administration. Conclusion: Our results indicate for the very first time that selective tropism, migration, and infiltration of LPMs into extra-peritoneally located lungs was dependent on clodronate-mediated AM depletion. These results further open the possibility of therapeutically utilizing LPMs as delivery vehicles to carry nanoparticle-encapsulated oligonucleotide modalities to potentially address inflammatory diseases, infectious diseases and even cancer.

Platelet Membrane Nanocarriers Cascade Targeting Delivery System to Improve Myocardial Remodeling Post Myocardial Ischemia-Reperfusion Injury.

Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L-arginine and FTY720 to facilitate the cascade-targeted delivery of these substances to the myocardial injury site and enable the controlled release of L-arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia-reperfusion injury and late reperfusion inflammation. During the ischemia-reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L-arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti-apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi-targeted therapy and clinical translation for cardiac injury.

Potent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir.

The development of latency reversing agents that potently reactivate HIV without inducing global T cell activation would benefit the field of HIV reservoir research and could pave the way to a functional cure. Here, we explore the reactivation capacity of a lipid nanoparticle containing Tat mRNA (Tat-LNP) in CD4 T cells from people living with HIV undergoing antiretroviral therapy (ART). When combined with panobinostat, Tat-LNP induces latency reversal in a significantly higher proportion of latently infected cells compared to PMA/ionomycin (≈ 4-fold higher). We demonstrate that Tat-LNP does not alter the transcriptome of CD4 T cells, enabling the characterization of latently infected cells in their near-native state. Upon latency reversal, we identify transcriptomic differences between infected cells carrying an inducible provirus and non-infected cells (e.g. LINC02964, GZMA, CCL5). We confirm the transcriptomic differences at the protein level and provide evidence that the long non-coding RNA LINC02964 plays a role in active HIV infection. Furthermore, p24+ cells exhibit heightened PI3K/Akt signaling, along with downregulation of protein translation, suggesting that HIV-infected cells display distinct signatures facilitating their long-term persistence. Tat-LNP represents a valuable research tool for in vitro reservoir studies as it greatly facilitates the in-depth characterization of HIV reservoir cells' transcriptome and proteome profiles.

Aquasomal drug delivery system: A special emphasis on the formulation techniques and applications / Sistema de administración de fármacos Aquasomal: Especial énfasis en las técnicas de formulación y aplicaciones

Introducción: Aquasome es un sistema portador de nanopartículas autoensamblado con tres capas. El sistema se compone de un núcleo sólido nanocristalino interno recubierto de oligómero polihidroxilado. Adsorbidas en la capa recubierta se encuentran moléculas de fármacos o compuestos bioquímicamente activos. El autoensamblaje en este sentido se refiere a la formación independiente de moléculas en patrones organizados, de larga duración y con enlaces no covalentes. nueva tecnología de administración de fármacos. El artículo aborda principalmente los procesos de formulación utilizados para crear nanoestructuras autoensambladas y sus diversas aplicaciones posibles. Método: En la búsqueda bibliográfica se utilizaron varias bases de datos en línea, incluidas Science Direct, Medline, Web of Science, Google Scholar y Scopus. Se realizaron búsquedas en los conjuntos de datos en busca de entradas de estudios hasta julio de 2023. El documento de revisión aborda especialmente muchos elementos de la formación de aquasomas por parte de varios investigadores que emplean métodos/técnicas modificadas como la coprecipitación, la autoprecipitación, la pulverización catódica, etc. También ilustra una variedad de campos de terapia en los que se ha reconocido que el aquasoma tiene una gran influencia, como el oxígeno y el transporte de extractos. Resultados: El núcleo sólido es responsable de brindar estabilidad estructural, mientras que el recubrimiento oligomérico es crucial para proteger contra la deshidratación y estabilizar las moléculas bioactivas. Este vehículo de administración de fármacos biodegradable a escala nanométrica muestra una tendencia a acumularse en el hígado y los músculos. La no modificación de la adsorción del fármaco en la superficie del aquasoma facilita una respuesta farmacológica rápida al permitir el reconocimiento sin obstrucciones del receptor en el sitio de acción. (AU)

Introduction: Aquasome is a self-assembled nanoparticulate carrier system with three layers. The system is made up of a polyhydroxy oligomer-coated inner nanocrystalline solid core. Adsorbed on the coated layer are drug mole-cules or biochemically active compounds. Self-assembly in this sense refers to the independent formation of mole-cules into organised, long-lasting, and non-covalently bonded patterns.This paper gives an overview of aquasome formation, covering structural properties, formulation methodologies, and the benefits and drawbacks of this novel drug delivery technology. The article primarily addresses the formulation processes used to create self-assembled nanostructures and their various possible applications.Method: Several online databases, including Science Direct, Medline, Web of Science, Google Scholar and Scopus, were used in the literature search. The datasets were searched for entries of studies up to July, 2023. The review paper especially addresses many elements of aquasome formation by various researchers employing methods/modified techniques such as co-precipitation, self-precipitation, sputtering, and and so forth. It also illustrates a variety of fields of therapy in which aquasome has been recognised to have a major influence, such as oxygen and extract carrier.Results: The solid core is responsible for providing structural stability, while the oligomeric coating is crucial for safeguarding against dehydration and stabilising the bioactive molecules. This biodegradable drug delivery vehicle at the nanoscale level exhibits a tendency to accumulate in the liver and muscles. The non-modification of drug adsorption onto the aquasome surface facilitates prompt pharmacological response by allowing unobstructed re-ceptor recognition at the action site. (AU)

New SDS-Based Polyelectrolyte Multicore Nanocarriers for Paclitaxel Delivery-Synthesis, Characterization, and Activity against Breast Cancer Cells.

The low distribution of hydrophobic anticancer drugs in patients is one of the biggest limitations during conventional chemotherapy. SDS-based polyelectrolyte multicore nanocarriers (NCs) prepared according to the layer by layer (LbL) procedure can release paclitaxel (PTX), and selectively kill cancer cells. Our main objective was to verify the antitumor properties of PTX-loaded NCs and to examine whether the drug encapsulated in these NCs retained its cytotoxic properties. The cytotoxicity of the prepared nanosystems was tested on MCF-7 and MDA-MB-231 tumour cells and the non-cancerous HMEC-1 cell line in vitro. Confocal microscopy, spectrophotometry, spectrofluorimetry, flow cytometry, and RT PCR techniques were used to define the typical hallmarks of apoptosis. It was demonstrated that PTX encapsulated in the tested NCs exhibited similar cytotoxicity to the free drug, especially in the triple negative breast cancer model. Moreover, SDS/PLL/PTX and SDS/PLL/PGA/PTX significantly reduced DNA synthesis. In addition, PTX-loaded NCs triggered apoptosis and upregulated the transcription of Bax, AIF, cytochrome-c, and caspase-3 mRNA. Our data demonstrate that these novel polyelectrolyte multicore NCs coated with PLL or PLL/PGA are good candidates for delivering PTX. Our discoveries have prominent implications for the possible choice of newly synthesized, SDS-based polyelectrolyte multicore NCs in different anticancer therapeutic applications.

CD38-targeted and erythrocyte membrane camouflaged nanodrug delivery system for photothermal and chemotherapy in multiple myeloma.

Multiple myeloma (MM) is a malignant and incurable disease. Chemotherapy is currently the primary treatment option for MM. However, chemotherapeutic drugs can interrupt treatment because of serious side effects. Therefore, development of novel therapeutics for MM is essential. In this study, we designed and constructed an innovative nanoparticle-based drug delivery system, P-R@Ni3P-BTZ, and investigated its feasibility, effectiveness, and safety both in vitro and in vivo. P-R@Ni3P-BTZ is a nanocomposite that consists of two parts: (1) the drug carrier (Ni3P), which integrates photothermal therapy (PTT) with chemotherapy by loading bortezomib (BTZ); and (2) the shell (P-R), a CD38 targeting peptide P-modified red blood cell membrane nanovesicles. In vitro and in vivo, it was proven that P-R@Ni3P-BTZ exhibits remarkable antitumor effects by actively targeting CD38 + MM cells. P-R@Ni3P-BTZ significantly induces the accumulation of intracellular reactive oxygen species (ROS) and increases the apoptosis of MM cells, which underlies the primary mechanism of its antitumor effects. In addition, P-R@Ni3P exhibits good biocompatibility and biosafety, both in vitro and in vivo. Overall, P-R@Ni3P-BTZ is a specific and efficient MM therapeutic method.

Nanoparticles for cancer therapy: a review of influencing factors and evaluation methods for biosafety

Nanoparticles are widely used in the biomedical field for diagnostic and therapeutic purposes due to their small size, high carrier capacity, and ease of modification, which enable selective targeting and as contrast agents. Over the past decades, more and more nanoparticles have received regulatory approval to enter the clinic, more nanoparticles have shown potential for clinical translation, and humans have increasing access to them. However, nanoparticles have a high potential to cause unpredictable adverse effects on human organs, tissues, and cells due to their unique physicochemical properties and interactions with DNA, lipids, cells, tissues, proteins, and biological fluids. Currently, issues, such as nanoparticle side effects and toxicity, remain controversial, and these pitfalls must be fully considered prior to their application to body systems. Therefore, it is particularly urgent and important to assess the safety of nanoparticles acting in living organisms. In this paper, we review the important factors influencing the biosafety of nanoparticles in terms of their properties, and introduce common methods to summarize the biosafety evaluation of nanoparticles through in vitro and in body systems (AU)

Drug-Loaded Zwitterion-Based Nanomotors for the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) treatment requires a nanosystem for drug delivery that can effectively penetrate the blood-spinal cord barrier (BSCB). Herein, we designed poly(2-methacryloyloxyethyl phosphorylgallylcholine) (PMPC)/l-arginine (PMPC/A)-based nanomotors that can release nitric oxide (NO). The nanomotors were loaded with the inducible NO synthase inhibitor 1400W and nerve growth factor (NGF). PMPC with a zwitterionic structure not only provided good biocompatibility for the nanomotors but also facilitated their passage through the BSCB owing to the assistance of a large number of choline transporters on the BSCB. Additionally, the l-arginine loaded on the nanomotors was able to react with reactive oxygen species in the microenvironment of the injured nerve to produce NO, thereby conferring the ability of autonomic movement to the nanomotors, which facilitated the uptake of drugs by cells in damaged areas and penetration in pathological tissues. Moreover, in vivo animal experiments indicated that the PMPC/A/1400W/NGF nanomotors could effectively pass through the BSCB and restore the motion function of a rat SCI model by regulating its internal environment as well as the release of therapeutic drugs. Thus, the drug delivery system based on nanomotor technology offers a promising strategy for treating central nervous system diseases.

Uncovering the Fate and Risks of Intravenously Injected Prussian Blue Nanoparticles in mice by an Integrated Methodology of Toxicology, Pharmacokinetics, Proteomics, and Metabolomics.

BACKGROUND: Prussian blue (PB) nanoparticles (NPs) have been intensively investigated for medical applications, but an in-depth toxicological investigation of PB NPs has not been implemented. In the present study, a comprehensive investigation of the fate and risks of PB NPs after intravenous administration was carried out by using a mouse model and an integrated methodology of pharmacokinetics, toxicology, proteomics, and metabolomics. RESULTS: General toxicological studies demonstrated that intravenous administration of PB NPs at 5 or 10 mg/kg could not induce obvious toxicity in mice, while mice treated with a relatively high dose of PB NPs at 20 mg/kg exhibited loss of appetite and weight decrease in the first two days postinjection. Pharmacokinetic studies revealed that intravenously administered PB NPs (20 mg/kg) underwent fast clearance from blood, highly accumulated in the liver and lungs of mice, and finally cleared from tissues. By further integrated proteomics and metabolomics analysis, we found that protein expression and metabolite levels changed significantly in the liver and lungs of mice due to the high accumulation of PB NPs, leading to slight inflammatory responses and intracellular oxidative stress. CONCLUSIONS: Collectively, our integrated experimental data imply that the high accumulation of PB NPs may cause potential risks to the liver and lungs of mice, which will provide detailed references and guidance for further clinical application of PB NPs in the future.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Insight into the mechanism behind oral bioavailability-enhancement by nanosuspensions through combined dissolution/permeation studies.

As numerous new drug candidates are poorly water soluble, enabling formulations are needed to increase their bioavailability for oral administration. Nanoparticles are a conceptually simple, yet resource consuming strategy for increasing drug dissolution rate, as predicting in vivo oral absorption using in vitro dissolution remains difficult. The objective of this study was to obtain insight into nanoparticle characteristics and performance utilizing an in vitro combined dissolution/permeation setup. Two examples of poorly soluble drugs were examined (cinnarizine and fenofibrate). Nanosuspensions were produced by top-down wet bead milling using dual asymmetric centrifugation, obtaining particle diameters of approx. 300 nm. DSC and XRPD studies indicated that nanocrystals of both drugs were present with retained crystallinity, however with some disturbances. Equilibrium solubility studies showed no significant increase in drug solubility over the nanoparticles, as compared to the raw APIs. Combined dissolution/permeation experiments revealed significantly increased dissolution rates for both compounds compared to the raw APIs. However, there were substantial differences between the dissolution curves of the nanoparticles as fenofibrate exhibited supersaturation followed by precipitation, whereas cinnarizine did not exhibit any supersaturation, but instead a shift towards faster dissolution rate. Permeation rates were found significantly increased for both nanosuspensions when compared to the raw APIs, indicating a direct implication that formulation strategies are needed, be it stabilization of supersaturation by precipitation inhibition and/or dissolution rate enhancement. This study indicates that in vitro dissolution/permeation studies can be employed to better understand the oral absorption enhancement of nanocrystal formulations.

Near-Infrared Phototheranostic Iron Pyrite Nanocrystals Simultaneously Induce Dual Cell Death Pathways via Enhanced Fenton Reactions in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered more aggressive with a poorer prognosis than other breast cancer subtypes. Through systemic bioinformatic analyses, we established the ferroptosis potential index (FPI) based on the expression profile of ferroptosis regulatory genes and found that TNBC has a higher FPI than non-TNBC in human BC cell lines and tumor tissues. To exploit this finding for potential patient stratification, we developed biologically amenable phototheranostic iron pyrite FeS2 nanocrystals (NCs) that efficiently harness near-infrared (NIR) light, as in photovoltaics, for multispectral optoacoustic tomography (MSOT) and photothermal ablation with a high photothermal conversion efficiency (PCE) of 63.1%. Upon NIR irradiation that thermodynamically enhances Fenton reactions, dual death pathways of apoptosis and ferroptosis are simultaneously triggered in TNBC cells, comprehensively limiting primary and metastatic TNBC by regulating p53, FoxO, and HIF-1 signaling pathways and attenuating a series of metabolic processes, including glutathione and amino acids. As a unitary phototheranostic agent with a safe toxicological profile, the nanocrystal represents an effective way to circumvent the lack of therapeutic targets and the propensity of multisite metastatic progression in TNBC in a streamlined workflow of cancer management with an integrated image-guided intervention.

Chemoprevention of bilirubin encephalopathy with a nanoceutical agent.

BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Mechanistic modelling of targeted pulmonary delivery of dactinomycin iron oxide-loaded nanoparticles for lung cancer therapy.

With the increase in respiratory conditions including lung cancer post covid-19 pandemic, drug-loaded nanoparticulate dry powder inhalers (DPIs) can facilitate targeted lung delivery as a patient-friendly, non-invasive method. The aim of this work was to synthesise and optimise iron oxide nanoparticles (IONPs) containing dactinomycin as a model drug, using Quality by Design principles. Chitosan and sodium alginate were investigated as polymeric coatings. The mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), burst-effect (BE), entrapment-efficiency and the emitted-dose (ED) were investigated in initial screening studies and outcomes used to set up a Design of Experiments. Results revealed that chitosan IONPs were superior to that of sodium alginate in delivering DPI with optimal properties [ED (89.9%), FPF (59.7%), MMAD (1.59 µm) and BE (12.7%)]. Design space for targeted IONPs included formulations containing 2.1-2.5% dactinomycin and 0.5-0.9% chitosan. Differential scanning calorimetry and X-ray diffraction and SEM-EDS analysis revealed effective formation of IONPs, and TEM images revealed the production of spherical IONPs with particle size of 4.4 ± 0.77 nm. This work overcame the light sensitivity of dactinomycin to potentially target the high molecular weight drugs to the lungs, with controlled delivery based on a reduced burst effect.

Celecoxib nanocrystal-loaded dissolving microneedles with highly efficient for osteoarthritis treatment.

Osteoarthritis (OA) is a prevalent degenerative disease that has a significant impact on patients' lives. Celecoxib (CXB) is now primarily used to treat OA with oral dosing. CXB's limited water solubility, on the other hand, restricts its therapeutic application. We developed a delivery system of dissolving microneedles (DMNs) loaded with CXB-nanocrystals (CXB-NCs) for the treatment of OA. Oral administration's inefficiency and injectable administration's poor compliance might be solved using DMNs. Furthermore, carrier-free NCs may dramatically increase the dissolution of drugs with poorly water-solubility, as well as the drug load of DMNs. Antisolvent precipitation was used to make CXB-NCs. CXB-NC@DMNs were prepared by mixing CXB-NCs with hyaluronic acid (HA) that had high mechanical qualities and could permeate the skin efficiently in vitro. The therapeutic effect of oral CXB-NCs was substantially better than that of the same dose of oral CXB in an in vivo pharmacodynamic trial, demonstrating that the preparation of CXB into NCs might greatly increase CXB bioavailability. Furthermore, we discovered that DMNs loaded with low-dose CXB-NCs had similar or even better efficacy than the oral CXB-NCs group. The findings suggested that CXB-NC@DMNs may be a very efficient and promising drug delivery strategy in the treatment of OA.

Resveratrol Nanoparticles Suppresses Migration and Invasion of Renal Cell Carcinoma Cells by Inhibiting Matrix Metalloproteinase 2 Expression and Extracellular Signal-Regulated Kinase Pathway.

The aim of this study was to examine the impact of Resveratrol nanoparticles on migration/invasion capacity of renal cell carcinoma (RCC) cells and its mechanism. Human RCC cells were exposed to dimethyl sulfoxide or gradient concentrations of Resveratrol nanoparticles respectively, and U0126 were also added in some experiments. We examined renal cell viability by MTT assay, and wound healing test and Transwell assays were used detect invasion and migration capability of RCC cells. We used Western blotting assay to analyze the protein levels in extracellular signal-regulated kinase (ERK) signaling. We also detected the enzymatic capacity of matrix metalloproteinase 2 (MMP-2) in cells by gelatin enzymatic profiling. Resveratrol nanoparticles treatment significantly suppressed cell viability to migrate and invade RCC cells in a dose-dependent manner. Also, notably were reduced MMP-2 activity and expression, and elevated TIMP-2 level were observed in RCC cells exposed with Resveratrol nanoparticles. Further, Resveratrol nanoparticles treatment significantly decreased only the expression of p-ERK1/2, but not p-p38 and p-JNK. Moreover, U0126, which is the ERK inhibitor, exerted similar role as Resveratrol nanoparticles did. Of note was that, combined use of U0126 and Resveratrol nanoparticles displayed a more intense suppression of MMP-2 activity and expression, and also the viability to migrate and invade the RCC cells, compared with Resveratrol nanoparticles treatment alone. The Resveratrol nanoparticles inhibited RCC cells migration and invasion by regulating MMP2 expression and ERK pathways.

One step closer to cancer nanomedicine.

High-throughput tool uncovers links between cell signaling and nanomaterial uptake.

Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery.

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3, which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.

A novel nitidine chloride nanoparticle overcomes the stemness of CD133+EPCAM+ Huh7 hepatocellular carcinoma cells for liver cancer therapy.

BACKGROUND: Stemness of CD133+EPCAM+ hepatocellular carcinoma cells ensures cancer resistance to apoptosis,which is a challenge to current liver cancer treatments. In this study, we evaluated the tumorcidal activity of a novel nanoparticle of nitidine chloride (TPGS-FA/NC, TPGS-FA: folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate, NC: nitidine chloride), against human hepatocellular carcinoma (HCC) cell line Huh7 growth in vitro and in vivo. METHODS: Huh7 cells were treated with TPGS-FA/NC. Cell proliferation was assessed using MTT and colony assays. The expression of cell markers and signaling proteins was detected using western blot analyses. A sphere culture technique was used to enrich cancer stem cells (CSC) in Huh7 cells. TPGS-FA/NC (7.5, 15, 30, 60, 120 µg/mL) dose-dependently inhibited the proliferation of HCC cells, which associated with a reduction in AQP3 and STAT3 expression. Importantly,TPGS-FA/NC (10, 20, and 40 µg/mL) significantly reduced the EpCAM+/CD133+cell numbers, suppressed the sphere formation. The in vivo antitumor efficacy of TPGS-FA/NC was proved in Huh7 cell xenograft model in BALB/c nude mice, which were administered TPGS-FA/NC(4 mg· kg - 1· d - 1, ig) for 2 weeks. RESULTS: TPGS-FA/NC dose-dependently suppressed the AQP3/STAT3/CD133 axis in Huh7 cells. In Huh7 xenograft bearing nude mice, TPGS-FA/NC administration markedly inhibited Huh7 xenograft tumor growth . CONCLUSIONS: TPGS-FA/NC inhibit HCC tumor growth through multiple mechanisms, and it may be a promising candidate drug for the clinical therapy of hepatocellular carcinoma.