Palmar-plantar erythrodysesthesia (PPE), also known as hand and foot syndrome, is a condition characterized by inflammation-mediated damage to the skin on the palms and soles of the hands and feet. PPE limits the successful therapeutic applications of anticancer drugs. However, identifying this toxicity during preclinical studies is challenging due to the lack of accurate in vitro and in vivo animal-based models. Therefore, there is a need for reliable models that would allow the detection of this toxicity early during the drug development process. Herein, we describe the use of an in vitro skin explant assay to assess traditional DXR, Doxil reference listed drug (RLD) and two generic PEGylated liposomal DXR formulations for their abilities to cause inflammation and skin damage. We demonstrate that the results obtained with the in vitro skin explant assay model for traditional DXR and Doxil correlate with the clinical data.

Apolipoprotein-based, synthetic high-density lipoprotein (sHDL) nanodiscs have been extensively studied as a potential therapeutic agent for cardiovascular disease due to their ability to promote reverse cholesterol transport. Recently, polymer-based nanodiscs have been made possible with the development of novel polymeric materials such as styrene-maleic anhydride copolymer (SMA). While the polymer-based nanodiscs resemble the discoidal structure of sHDLs, their functional similarity with sHDL has not been investigated. In the present study, we compared the SMA-based and peptide-based sHDL nanodiscs focusing on their cholesterol mobilization effects. Results showed that SMA-based nanoparticles presented similar particle size and in vitro cholesterol efflux effect to those of sHDL nanodiscs. However, SMA nanodiscs induced less cholesterol mobilization in vivo, possibly due to insufficient cholesterol esterification by lecithin:cholesterol acyltransferase.

Dental and orthopedic implants have become routine medical technologies for tooth replacement and bone fixation. Despite significant progress in implantology, achieving sufficient osseointegration remains a challenge, often leading to implant failure over the long term. Nanotechnology offers the potential to mimic the natural patterns of living tissues, providing a promising platform for tissue engineering and implant surface design. Among the various methods for developing nanostructures, High-Regular Laser-Induced Periodic Surface Structures (HR-LIPSS) techniques stand out for their ability to fabricate highly ordered nanostructures with excellent long-range repeatability and production efficiency. In this study, we utilized an innovative technical approach to generate traditional laser-induced superficial LIPSS nanostructures, followed by detailed surface analysis using classical microscopy and physicochemical methods. Our findings demonstrate for the first time that nanostructured LIPSS surfaces can significantly enhance cell adhesion and proliferation while providing an optimal environment for cell metabolism. Given the high reproducibility, low cost, and potential of HR-LIPSS techniques to support cell growth and differentiation, this novel technology has the potential to impact both the industrial development of new implants and clinical outcomes after implantation.

In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform. NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy.

Atherosclerotic carotid stenosis (ACS) is a recognized risk factor for ischemic stroke. Currently, the gold diagnostic standard is Doppler ultrasound, the results of which do not provide certainty whether a given person should be qualified for surgery or not, because in some patients, carotid artery stenosis, for example at the level of 70 %, does not cause ischemic stroke in others yes. Therefore, there is a need for new methods that will clearly indicate the marker qualifying the patient for surgery. In this article we used Fourier Transform InfraRed Attenuated Total Reflectance (FTIR-ATR) spectra of serum collected from healthy and patients suffering from ACS, which had surgery were analyzed by machine learning and Principal Component Analysis (PCA) to determine chemical differences and spectroscopy marker of ACS. PCA demonstrated clearly differentiation between serum collected from healthy and non-healthy patients. Obtained results showed that in serum collected from ACS patients, higher absorbances of PO stretching symmetric, CH and CH symmetric and asymmetric and amide I vibrations were noticed than in control group. Moreover, lack of peak at 1106 cm was observed in spectrum of serum from non-control group. As a result of spectral shifts analysis was found that the most important role in distinguishing between healthy and unhealthy patients is played by FTIR ranges caused by vibrations of PO phospholipids, amides III, II and CO lipid vibrations. Continuing, peaks at 1636 cm and 2963 cm were proposed as a potential spectroscopy markers of ACS. Finally, accuracy of obtained results higher than 90 % suggested, that FTIR-ATR can be used as an additional diagnostic tool in ACS qualifying for surgery.

The low oral bioavailability of puerarin (Pur) affects its efficacy. Preparation of puerarin cubic liquid crystal nanoparticles (Pur-Cub) enhances the protective effect of Pur against ischemic stroke (IS) by increasing its bioavailability. The average particle size, PDI, and zeta potential of Pur-Cub were 274.70 ± 16.20 nm, 0.24 ± 0.05 and -25.30 ± 2.34 mV, respectively. Polarized light microscopy (PLM) and Small angle X-ray diffraction (SAXS) identified Pur-Cub as a cubic phase (Pn3m). The in vitro release of Pur-Cub was fast and then slow, in accordance with the biphasic kinetic equation. Pur-Cub increased the penetration of Pur in the intestine (mainly the duodenum) and significantly improved the bioavailability of Pur in the blood (304.16 %) and its distribution in the brain (1.69-fold) compared to Pur suspension. Pur-Cub narrowed down cerebral infarcts and significantly reduced levels of TNF-α, IL-1β, and IL-6 in a rat model of middle cerebral artery occlusion (MCAO).

The use of chemically modified nanocomposites for atherosclerotic plaques can open up new opportunities for studying their effect on changing the structure of the plaque itself. It was shown on the model of the greater omentum of two groups of experimental animals (rats n = 30), which were implanted with Fe@C NPs nanocomposites of 10-30 Nm size into the omentum area. Group 1 (n = 15) consisted of animals that were implanted with chemically modified Fe@C NPs nanocomposites and control group 2 (n = 15) was with non-modified Fe@C NPs nanocomposites. After 1, 2 and 3 weeks we conducted the morphological study of changes in the structure of the omentum using two dyes (Nile Blue and Sudan III), which are specific for adipose tissue. Chemically modified nanocomposites have demonstrated, in contrast to non-modified nanoparticles, to cause morphological changes in the structure of the greater omentum accompanied by the probable release of a similar antiatherogenic factor.

The pharmacokinetics in patients dosed with the nanoparticle-based MRI contrast agent SN132D is explained by a size dependent clearance mechanism and this behavior was modeled numerically. Blood samples from 14 patients were analyzed for silicon (a component of the nanoparticle) by ICP-OES. The pharmacokinetic model has only one free parameter and relies on a measured size distribution of the contrast agent and well-established properties of the renal and cardiovascular systems. The model fits well (R = 0.9910) with experimental data from samples taken from ten minutes to two weeks after start of infusion. These results support that the cut-off diameter for human renal filtration is 5.5 nm. The agreement between experiment and model implies that there is little or no plasma protein binding to the nanoparticles.

Selective in vivo immune cell manipulation offers a promising strategy for cancer vaccines. In this context, spatiotemporal control over recruitment of specific cells, and their direct exposure to appropriate immunoadjuvants and antigens are key to effective cancer vaccines. We present an implantable 3D-printed cancer vaccine platform called the 'NanoLymph' that enables spatiotemporally-controlled recruitment and manipulation of immune cells in a subcutaneous site. Leveraging two reservoirs each for continuous immunoadjuvant release or antigen presentation, the NanoLymph attracts dendritic cells (DCs) on site and exposes them to tumor-associated antigens. Upon local antigen-specific activation, DCs are mobilized to initiate a systemic immune response. NanoLymph releasing granulocyte-macrophage colony-stimulating factor and CpG-oligodeoxynucleotides with irradiated whole cell tumor lysate inhibited tumor growth of B16F10 murine melanoma in a prophylactic and therapeutic vaccine setting. Overall, this study presents the NanoLymph as a versatile cancer vaccine development platform with replenishable and controlled local release of antigens and immunoadjuvants.

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation.

The overexpression of inflammatory factors is closely related to the pathogenesis of acute kidney injury (AKI). Additionally, the overproduction of reactive oxygen species (ROS) further exacerbates the inflammatory response. In light of this, monotherapies focused solely on inflammation have proven to be suboptimal. Therefore, this study successfully developed a nanoparticle (SC@Se/GA) that possesses anti-inflammatory and antioxidant properties. The SC@Se/GA has a smaller size, better stability, and kidney-targeting. In vivo experiments showed that the GPx enzyme activity of SC@Se/GA increases by almost 50 % more than SC@Se alone, indicating its efficient ability to scavenge ROS. In the meantime, SC@Se/GA has a longer renal retention period (>24 h) than free drug GA, which can dramatically lower the levels of inflammatory factors TNF-α and IL-6. In summary, SC@Se/GA, through its synergistic anti-inflammatory and antioxidant effects, markedly alleviates CDDP-induced renal injury and restores renal function, providing a new effective strategy for treating AKI.

Given the profound multiple myeloma (MM) heterogeneity in clonal proliferation of malignant plasma cells (PCs) and anti-MM therapeutic potential of nanotherapies, it is inevitable to develop treatment plan for patients with MM. Two composite nanoparticles (NPs), AsS/FeO (4:1) and AsS/FeO (1:1) demonstrated effective anti-MM activity in in vitro, ex vivo, and in vivo in xenograft mouse model. Composite NPs triggered activation of p-ERK1/2/p-JNK, and downregulation of c-Myc, p-PI3K, p-4E-BP1; G/M cell cycle arrest with increase in cyclin B1, histones H2AX/H3, activation of p-ATR, p-Chk1/p-Chk2, p-H2AX/p-H3; and caspase- and mitochondria-dependent apoptosis induction. NPs attenuated the stem cell-like side population in MM cells, both alone and in the presence of stroma. For a higher clinical response rate, AsS/FeO (4:1) observed synergism with dexamethasone and melphalan, while AsS/FeO (1:1) showed synergistic effects in combination with bortezomib, lenalidomide and pomalidomide anti-MM agents, providing the framework for further clinical evaluation of composite NPs in MM.

In this study, a platform was fabricated by combining a cationic lipid, 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) with mesenchymal stem cell membrane (MSCM) to produce a positively charged hybrid vesicle. The prepared hybrid vesicle was used to condense BIRC5 CRISPR/Cas9 plasmid for survivin (BIRC5) gene editing. The Sgc8-c aptamer (against protein tyrosine kinase 7) was then attached to the surface of the prepared NPs through electrostatic interactions. In this regard, melanoma cancer cells (B16F0 cell line) overexpressing PTK7 receptor could be targeted. Investigations were conducted on this system to evaluate its transfection efficiency, cellular toxicity, and therapeutic performance in preclinical stage using B16F0 tumor bearing C57BL/6 J mice. The results verified the superiority of the Hybrid/ BIRC5 compared to Liposome/ BIRC5 in terms of cellular toxicity and transfection efficiency. The cells exposure to Hybrid/BIRC5 significantly enhanced cytotoxicity. Moreover, Apt-Hybrid/BIRC5 showed higher anti-proliferation activity toward PTK7-positive B16F0 cancer cells than that of the PKT7-negative CHO cell line. The active tumor targeting nanoparticles increased the cytotoxicity through down-regulation of BIRC5 expression as confirmed by Western blot analysis. In preclinical stage, Apt-Hybrid/BIRC5 showed remarkable tumor growth suppression toward B16F0 tumorized mice. Thus, our study suggested that genome editing for BIRC5 through the CRISPR/Cas9 system could provide a potentially safe approach for melanoma cancer therapy and has great potential for clinical translation.

Actinic cheilitis (AC) is a lip disorder, with no standard treatment. Imiquimod (IMIQ) is an immunomodulator that treat precancerous lesions; however, its commercial form causes severe adverse effects. This study aimed to assess IMQ release from a chitosan hydrogel containing 0.05 % nanoencapsulated (NANO) imiquimod (IMIQ-0.05 %-NANO) and its efficacy in AC treatment. The hydrogels were prepared by incorporating chitosan into polymeric nanocapsules (NCimiq) loaded with IMQ, produced using the interfacial deposition of preformed polymer method. IMQ release was evaluated using automated Franz Cells. A triple-blind randomized controlled trial (49 subjects) compared the efficacy of: IMIQ-0.05 %-NANO, 5 % free imiquimod (IMIQ-5 %), 0.05 % free imiquimod (IMIQ-0.05 %), and placebo hydrogel. The IMIQ-NANO-0.05 % and IMIQ-5 % groups exhibited significantly higher rates of clinical improvement (p < 0.05); however, the IMIQ-5 % group experienced more adverse effects (92.3 % of subjects) compared to other groups (p < 0.05). In conclusion, in the studied sample, IMIQ-NANO-0.05 % was a safe and effective option to treat AC.

Gold nanorods (GNR) produce heat upon irradiation with near-infrared light, enabling a tumor-targeted photothermal therapy. In this study, we prepared GNR coated with sulfated hyaluronic acid (sHA) with a binding affinity for CD44 via electrostatic interactions to deliver GNR to tumors efficiently and stably, and evaluated their usefulness for photothermal therapy. Cationic GNR modified with trimethylammonium groups electrostatically interacted with native HA or sHA with varying degrees of sulfation to form complexes. While GNR/HA was unstable in saline, GNR/sHA maintained the absorbance peak in the near-infrared region, particularly for GNR/sHA with higher degrees of sulfation. GNR/sHA exhibited an intense photothermal effect upon irradiation with near-infrared light. Furthermore, in vitro and in vivo studies revealed that GNR coated with sHA containing approximately 1.2 sulfated groups per HA unit could accumulate in CD44-positive tumors via an HA-specific pathway. These findings indicate the effectiveness of GNR/sHA as a tumor-targeted photothermal therapeutic agent.

Maintenance therapy (MT) for ovarian cancer (OC) is crucial for preventing disease relapse. Curcumol shows effective anti-OC ability and low-toxicity to the normal ovarian epithelial cells, however, its bioavailability is low. Herein, micellar loaded curcumol (MC) was prepared and the anti-tumor ability of MC were performed on OC cells. The results indicated that the IC values of MC in two kinds of OC cells were 37.69 ± 2.43 and 28.54 ± 1.58 μg/mL, respectively. Mechanistically, curcumol could interact with the AKT site, inhibiting the phosphorylation of FOXO3a, which promoted FOXO3a nuclear locating and recruited it to the PERK promoter, activating the ERS induced apoptosis pathway. Moreover, MC inhibited the growth of SKOV3 cells on tumor-bearing nude mice and the DiR-labeled MC could quickly accumulate in the tumor region. MC provides great feasibility to achieve efficient MT for OC based on the nanoplatforms of active ingredients from natural products.

Glioblastoma (GBM) is a central nervous system cancer with high incidence and poor survival rates. Enhancing drug penetration of the blood-brain barrier (BBB) and targeting efficacy is crucial for improving treatment outcomes. In this study, we developed a redox-sensitive targeted nano-delivery system (HCA-A2) for temozolomide (TMZ) and β-lapachone (β-Lapa). This system used hyaluronic acid (HA) as the hydrophilic group, arachidonic acid (CA) as the hydrophobic group, and angiopep-2 (A2) as the targeting group. Control systems included non-redox sensitive (HDA-A2) and non-targeting (HCA) versions. In vitro, HCA-TMZ-Lapa micelles released 100 % of their payload in a simulated tumor microenvironment within 24 h, compared to 43.97 % under normal conditions. HCA-A2 micelles, internalized via clathrin-mediated endocytosis, showed stronger cytotoxicity and better BBB penetration and cellular uptake than controls. In vivo studies demonstrated superior tumor growth inhibition with HCA-A2 micelles, indicating their potential for GBM treatment.

Nucleic acid biomarker detection has great importance in the diagnosis of disease, the monitoring of disease progression and the classification of patients according to treatment decision making. Nucleic acid biomarkers found in the blood of patients have generated a lot of interest due to the possibility of being detected non-invasively which makes them ideal for monitoring and screening tests and particularly amenable to point-of-care (POC) or self-testing. A major challenge to POC molecular diagnostics is the need to enrich the target to optimise detection. In this work, we describe a microfabricated device for the enrichment of short dsDNA target sequences, which is especially valuable for potential detection methods, as it improves the probability of effectively detecting the target in downstream analyses. The device integrated a heating element and a temperature sensor with a microfluidic chamber to carry out the denaturation of the dsDNA combined with blocking-probes to enrich the target. This procedure was validated by fluorescence resonance energy transfer (FRET) technique, labelling DNA with a fluorophore and a quencher. As proof of concept, a 23-mer long dsDNA sequence corresponding to the L858R mutation of the EGFR gene was used. The qualitative results obtained determined that the most optimal blocking rate was obtained with the incorporation of 11/12-mer blocking-probes at a total concentration of 6 μM. This device is a powerful DNA preparation tool, which is an indispensable initial step for subsequent detection of sequences via nucleic acid hybridisation methods.

Orthopaedic medicine often treats intervertebral disc degeneration (IVDD), which is caused by nucleus pulposus (NP) tissue damage and mechanical stress. Bioactive glasses (BGs), widely used for bone regeneration, can incorporate therapeutic ions into their network. Manganese (Mn) activates human osteoblast integrins, proliferation, and spreading. The CMnBGNPs-NPMSCs are carboxymethyl cellulose hydrogels functionalized with MnBGsNPs and NP-derived mesenchymal stem cells to treat IVDD. To ensure stability and biocompatibility of CMnBGNPs-NPMSCs were characterized for rheological properties like gelation time and swelling ratio. Gene expression analysis of PAX1, FOXF1, CA12, HBB, and OVOS2 via qRT-PCR further assessed the hydrogel's characteristics. Rat models with induced IVDD had hydrogel-MSC composite injected into their intervertebral discs for in vivo studies. Histological examination, immunohistochemical staining for inflammation and disc regeneration markers, and disc height assessments assessed therapeutic efficacy. CMnBGNPs-NPMSCs show promising results for IVDD treatment, offering a novel therapeutic strategy with clinical implications for degenerative disc diseases.