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Purpose: Liver cancer is associated significantly with morbidity and mortality. The combination of low-intensity ultrasound with nanomedicine delivery systems holds promise as an alternative for the treatment for liver cancer. This study focuses on the utilization of folic acid (FA) modified nanoparticles, which are loaded with fluorescent dye DiR and liquid fluorocarbon (PFP). These nanoparticles have the potential to enhance liver cancer targeting under ultrasound stimulation and future applications in vivo., Methods: The pharmacokinetics and tissue distribution of folic acid-modified Crebanine polyethylene glycol-polylactic acid copolymer nanoparticles (FA-Cre@PEG-PLGA NPs) were investigated. The pharmacokinetic parameters, liver targeting, and in vivo distribution were assessed. Additionally, the inhibitory impacts of FA-Cre@PEG-PLGA NPs in combination with ultrasonic irradiation on the proliferation and acute toxicity of H22 cells of mouse hepatoma were investigated in vitro. The tumor targeting and anti-tumor efficacy of FA-Cre@PEG-PLGA NPs were assessed utilizing a small animal in vivo imaging system and an in situ hepatocellular carcinoma transplantation model, respectively., Results: The pharmacokinetic studies and tissue distribution tests demonstrated that FA-Cre@PEG-PLGA NPs conspicuously prolonged the half-life and retention time of the drug in rats, and the liver targeting effect was pronounced. Additionally, the in vivo acute toxicity test indicated that FA-Cre@PEG-PLGA NPs had minimal adverse reactions and could fulfill the aim of attenuating the drug. The outcomes of the animal experiments further substantiated that FA-Cre@PEG-PLGA NPs had a longer retention time at the tumor site, a superior anti-tumor effect, and less damage to liver and kidney tissue., Conclusion: The integration of FA-Cre@PEG-PLGA NPs with ultrasound irradiation demonstrated exceptional safety and potent anti-tumor efficacy in vivo, presenting a promising therapeutic strategy for the treatment of liver cancer through the combination of ultrasound technology with a nanomedicine delivery system., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cheng et al.)

Background: This study investigates the influence of various formulation parameters on the characteristics of hinokitiol-loaded phytosomes and evaluates their anticancer potential against breast cancer cells., Materials and Methods: Phytosomal nanoparticles were prepared and characterized for size, zeta potential, and entrapment efficiency. Morphological analysis was conducted using optical microscopy and transmission electron microscopy (TEM). The solubility of hinokitiol at different pH levels was determined, and the in vitro release profile of the optimized phytosomes was assessed. Cytotoxicity assays were performed to evaluate the anticancer efficacy against breast cancer cell lines, and apoptosis induction was examined using Annexin V/propidium iodide staining. Cell cycle analysis was conducted to assess the impact on cell cycle progression., Results: The optimized phytosomes demonstrated a size range of 138.4 ± 7.7 to 763.7 ± 15.4 nm, with zeta potentials ranging from -10.2 ± 0.28 to -53.2 ± 1.06 mV and entrapment efficiencies between 29.161 ± 1.163% and 92.77 ± 7.01%. Morphological characterization confirmed uniformity and spherical morphology. Hinokitiol solubility increased with pH, and the release from the optimized phytosomes exhibited sustained patterns. The formulated phytosomes showed superior cytotoxicity, with lower IC50 values compared to pure hinokitiol. Treatment induced significant apoptosis and cell cycle arrest at the G2/M and S phases., Conclusion: Hinokitiol-loaded phytosomes demonstrate promising anticancer efficacy against breast cancer cells, highlighting their potential as targeted therapeutic agents for breast cancer therapy., Competing Interests: The authors declare no conflict of interest., (© 2024 Ahmed et al.)

Long double-stranded (ds)RNA, a potent stimulator of type I interferon and the innate immune response. In the present study, we demonstrated, for the first time, the efficacy of cationic polystyrene latex nanostructures (clNPs) as a dsRNA carrier, improving cellular delivery and robustly potentiating the immunostimulatory capacity of dsRNA in the ovarian cancer cell line SKOV3. The clNPs complexed with an in vitro transcribed dsRNA molecule, were bound by SKOV3 cells, and had increased cellular association compared to uncomplexed clNPs. clNPs complexed with dsRNA induced a more robust innate immune response compared to dsRNA alone. Transcript expression of two interferon-stimulated genes, were increased 47- and 108-fold over dsRNA and induced a significant antiviral state against vesicular-stomatitis virus, resulting in a 3.3-fold improvement on the efficacy of dsRNA. These data highlight the potential of polystyrene latex nanostructures as dsRNA carriers for anticancer immunotherapies, improving the uptake and efficacy of the nucleic acid., (© 2024 The Author(s). Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, is encapsulated. Therefore, this work used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease (IBD). The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into nontargeted cells. This work successfully establishes a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles is further investigated on lipopolysaccharide (LPS) stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a, and IL-23 release after 24 h. Additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstrate promising results with significant immune response suppression in stimulated monocytes after 2 and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Background: Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine., Methods: CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined., Results: Initially, UV-vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 µg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC 50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 μg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial-mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis)., Conclusion: The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wu et al.)

Aim: The study aimed to develop enzyme-degradable nanoparticles comprising polyphosphates and metal cations providing sustained release of the antibacterial drug ethacridine (ETH)., Methods: Calcium polyphosphate (Ca-PP), zinc polyphosphate (Zn-PP) and iron polyphosphate nanoparticles (Fe-PP NPs) were prepared by co-precipitation of sodium polyphosphate with cations and ETH. Developed nanocarriers were characterized regarding particle size, PDI, zeta potential, encapsulation efficiency and drug loading. Toxicological profile of nanocarriers was assessed via hemolysis assay and cell viability on human blood erythrocytes and HEK-293 cells, respectively. The enzymatic degradation of NPs was evaluated in presence of alkaline phosphatase (ALP) monitoring the release of monophosphate, shift in zeta potential and particle size as well as drug release. The antibacterial efficacy against Escherichia coli was determined via microdilution assay., Results: NPs were obtained in a size range between 300 - 480 nm displaying negative zeta potential values. Encapsulation efficiency was in the range of 83.73 %- 95.99 %. Hemolysis assay underlined sufficient compatibility of NPs with blood cells, whereas drug and NPs showed a concentration dependent effect on HEK-293 cells viability. Ca- and Zn-PP NPs exhibited remarkable changes in zeta potential, particle size, monophosphate and drug release upon incubation with ALP, compared to Fe-PP NPs showing only minor differences. The released ETH from Ca- and Zn-PP nanocarriers retained the antibacterial activity against E. coli, whereas no antibacterial effect was observed with Fe-PP NPs., Conclusion: Polyphosphate nanoparticles cross-linked with divalent cations and ETH hold promise for sustained drug delivery triggered by ALP for parental administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Excessive amounts of reactive oxygen species (ROS) cause various biological damages and are involved in many diseases, such as cancer, inflammatory and thrombotic complications, and neurodegenerative diseases. Thus, ROS-responsive polymers with inherent ROS scavenging activity and biodegradability are extremely needed for the efficient treatment of ROS-related diseases. Here, this work fabricates the amphiphilic diblock copolymer PEG-b-PBC via ring-opening polymerization (ROP) of phenylboronic acid ester conjugated cyclic carbonate monomer. The copolymer easily forms micelles (BCM) and scavenges ROS rapidly. BCM not only releases the delivered drug but degrades to produce the small molecules p-hydroxybenzyl alcohol (HBA) with anti-inflammatory capability in the presence of H 2 O 2 . BCM can reduce the oxidative stress of human umbilical vein endothelial cells (HUVEC) and the levels of inflammatory factors secreted by macrophages, showing antioxidative and anti-inflammatory activity. Finally, BCM exerts a significant capability to reduce the complications of inflammation and thrombosis in vivo. The biodegradable aliphatic poly(carbonate)s have the potential to be used for drug delivery systems (DDS) for diseases induced by reactive oxygen species., (© 2023 Wiley‐VCH GmbH.)

Herein, a drug-loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL-LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL-101(Fe)-NH 2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross-linking with intratumoral Ca 2+ . Benefiting from the tumor retention ability, the fast-formed drug depository will continuously release DOX and Fe ions through the ATP-triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non-aggregated nanoparticles is able to convert the lactic acid to H 2 O 2 , which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX-induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long-term chemotherapy, and oxidation therapy, DOX@MIL-LOX@AL can execute high-performance antitumor chemotherapy and immune activation with only one subcutaneous administration., (© 2023 Wiley‐VCH GmbH.)

Transdermal drug administration has grown in popularity in the pharmaceutical research community due to its potential to improve drug bioavailability, compliance among patients, and therapeutic effectiveness. To overcome the substantial barrier posed by the stratum corneum (SC) and promote drug absorption within the skin, various physical penetration augmentation approaches have been devised. This review article delves into popular physical penetration augmentation techniques, which include sonophoresis, iontophoresis, magnetophoresis, thermophoresis, needle-free injection, and microneedles (MNs) Sonophoresis is a technique that uses low-frequency ultrasonic waves to break the skin's barrier characteristics, therefore improving drug transport and distribution. In contrast, iontophoresis uses an applied electric current to push charged molecules of drugs inside the skin, effectively enhancing medication absorption. Magnetophoresis uses magnetic fields to drive drug carriers into the dermis, a technology that has shown promise in aiding targeted medication delivery. Thermophoresis is the regulated heating of the skin in order to improve drug absorption, particularly with thermally sensitive drug carriers. Needle-free injection technologies, such as jet injectors (JIs) and microprojection arrays, offer another option by producing temporary small pore sizes in the skin, facilitating painless and effective drug delivery. MNs are a painless, minimally invasive method, easy to self-administration, as well as high drug bioavailability. This study focuses on the underlying processes, current breakthroughs, and limitations connected with all of these approaches, with an emphasis on their applicability in diverse therapeutic areas. Finally, a thorough knowledge of these physical enhancement approaches and their incorporation into pharmaceutical research has the potential to revolutionize drug delivery, providing more efficient and secure treatment choices for a wide range of health-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Augmentation of the activity of Food and Drug Administration-approved antibiotics by an adjuvant or antibiotic carrier is considered one of the promising strategies to fight against antibiotic-resistant bacteria. This study reports the development of sulfonium-cross-linked hyaluronic acid (HA)-based polymer (HA-SS-HA) as an inherent antimicrobial agent and antibiotic carrier. The HA-SS-HA polymer offers the potential for encapsulating various classes of antibiotics and accomplishing a stimuli-responsive release profile in the presence of hyaluronidase produced by bacterial cells within their extracellular environment. Systematic antibacterial studies reveal that the HA-SS-HA-encapsulated antibiotics (vancomycin, amoxicillin, and tetracycline) restore its activity against the antibiotic-resistant bacterial cells methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), and Pseudomonas aeruginosa. The HA-SS-HA gel shows robust efficacy in eradicating the mature biofilm of Staphylococcus aureus (S. aureus). The membrane-disrupting activity reveals that HA-SS-HA can also counteract the antibiotic resistance mechanism of the bacterial cells. The in vivo studies reveal excellent wound-healing activity of HA-SS-HA in albino laboratory-bred (BALB/c) mice. The outcome of additional antibacterial studies reveals that antibiotics-encapsulated HA-SS-HA hydrogel can effectively combat Gram-negative, Gram-positive, and antibiotic-resistant bacterial strains. Therefore, revitalizing the activity of commercial antibiotics by HA-SS-HA can be considered a valuable and economically effective strategy to fight against antibiotic-resistant bacteria., (© 2023 Wiley-VCH GmbH.)

The main objective of the experiment is to develop and evaluate hydrogel-bearing nanostructured lipid carriers (NLCs) loaded with ketoconazole (KTZ) for the effective treatment of candidiasis. The eugenol was used as a liquid lipid (excipient) for the development of KTZ-loaded NLCs and was explored for anti-fungal effect. The production of NLCs involves high energy processes to generate spherical, uniform particles, having a higher percentage of entrapment efficiency (%EE) for KTZ with 89.83 ± 2.31 %. The data from differential scanning calorimeter (DSC), powder x-ray diffraction (PXRD), and attenuated total reflectance (ATR) demonstrated the KTZ dispersion in NLCs. The NLCs loaded hydrogel possessed optimum spreadability and exhibited shear thinning behavior, indicating the ease of application of the final formulation. The 6.41-fold higher transdermal flux (Jss) was governed for KTZ from KTZ-NLC than coarse-KTZ, which explains the usefulness of NLCs. The KTZ-NLCs exhibited significant 2.58 and 6.35-fold higher retention in the stratum corneum and viable epidermis of the skin. The cell cytotoxicity studies using human dermal fibroblast cell (HDFS) lines depicted the usefulness of NLCs in reducing cell toxicities for KTZ. The KTZ-NLCs were found to inhibit planktonic growth and hyphal transition and showed a larger zone of inhibition against C. albicans strains with a MIC-50 value of 0.39 μg/mL. The antibiofilm activity of KTZ-NLCs at lower concentrations, in contrast to plain KTZ, explained the interaction of developed NLCs with fungal membranes. The overall results depicted the effectiveness of the loading KTZ in the lipid matrix to achieve antifungal activity against C. albicans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Nanodiamonds (ND) hold great potential for diverse applications due to their biocompatibility, non-toxicity, and versatile functionalization. Direct visualization of ND by means of non-invasive imaging techniques will open new venues for labeling and tracking, offering unprecedented and unambiguous detection of labeled cells or nanodiamond-based drug carrier systems. The structural defects in diamonds, such as vacancies, can have paramagnetic properties and potentially act as contrast agents in magnetic resonance imaging (MRI). The smallest nanoscale diamond particles, detonation ND, are reported to effectively reduce longitudinal relaxation time T 1 and provide signal enhancement in MRI. Using in vivo, chicken embryos, direct visualization of ND is demonstrated as a bright signal with high contrast to noise ratio. At 24 h following intravascular application marked signal enhancement is noticed in the liver and the kidneys, suggesting uptake by the phagocytic cells of the reticuloendothelial system (RES), and in vivo labeling of these cells. This is confirmed by visualization of nanodiamond-labeled macrophages as positive (bright) signal, in vitro. Macrophage cell labeling is not associated with significant increase in pro-inflammatory cytokines or marked cytotoxicity. These results indicate nanodiamond as a novel gadolinium-free contrast-enhancing agent with potential for cell labeling and tracking and over periods of time., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Peripheral nerve injury (PNI) is a common clinical challenge, requiring timely and orderly initiation of synergistic anti-inflammatory and reparative therapy. Although the existing cascade drug delivery system can realize sequential drug release through regulation of the chemical structure of drug carriers, it is difficult to adjust the release kinetics of each drug based on the patient's condition. Therefore, there is an urgent need to develop a cascade drug delivery system that can dynamically adjust drug release and realize personalized treatment. Herein, we developed a responsive cascade drug delivery scaffold (RCDDS) which can adapt to the therapeutic time window, in which Vitamin B12 is used in early controllable release to suppress inflammation and nerve growth factor promotes regeneration by cascade loading. The RCDDS exhibited the ability to modulate the drug release kinetics by hierarchically opening polymer chains triggered by ultrasound, enabling real-time adjustment of the anti-inflammatory and neuroregenerative therapeutic time window depending on the patient's status. In the rat sciatic nerve injury model, the RCDDS group was able to achieve neural repair effects comparable to the autograft group in terms of tissue structure and motor function recovery. The development of the RCDDS provides a useful route toward an intelligent cascade drug delivery system for personalized therapy.

Biomaterials such as nanohydroxyapatite and gelatin are widely explored to improve damaged joint architecture associated with rheumatoid arthritis (RA). Besides joint damage, RA is associated with inflammation of joints and cartilage, which potentiates the need for both bone nucleation and therapeutic intervention. For such purpose, a modified nanoprecipitation method is used herein to fabricate tofacitinib (Tofa)-loaded nanohydroxyapatite (nHA) embedded gelatin (GLT) nanoparticles (NPs) (Tofa-nHA-GLT NPs). The quality by design (QbD) approach is chosen to assess the key parameters that determine the efficiency of the NPs, and are further optimized via Box-Behnken design of experiment. The particle size, polydispersity, zeta potential, and encapsulation efficiency (EE) of the prepared NPs are found to be 269 nm, 0.18, -20.5 mV, and 90.7%, respectively. Furthermore, the NPs have improved stability, skin permeability, and a sustained drug release pattern at pH 6.5 (arthritic joint pH). Moreover, rhodamine-B loaded nHA-GLT NPs demonstrates considerably higher cellular uptake by the murine-derived macrophages than free rhodamine-B solution. In vitro, cell-based experiments confirm the good cell biocompatibility with insignificant toxicity. Thus, QbD-based approach has successfully led to the development of Tofa-nHA-GLT NPs with the potential to target inflamed arthritic joint., (© 2023 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.)

Triamcinolone acetonide (TA), a medium-potency synthetic glucocorticoid, is primarily employed to treat posterior ocular diseases using vitreous injection. This study aimed to design novel ocular nanoformulation drug delivery systems using PLGA carriers to overcome the ocular drug delivery barrier and facilitate effective delivery into the ocular tissues after topical administration. The surface of the PLGA nanodelivery system was made hydrophilic (2-HP-β-CD) through an emulsified solvent volatilization method, followed by system characterization. The mechanism of cellular uptake across the corneal epithelial cell barrier used rhodamine B (Rh-B) to prepare fluorescent probes for delivery systems. The triamcinolone acetonide (TA)-loaded nanodelivery system was validated by in vitro release behavior, isolated corneal permeability, and in vivo atrial hydrodynamics. The results indicated that the fluorescent probes, viz., the Rh-B-(2-HP-β-CD)/PLGA NPs and the drug-loaded TA-(2-HP-β-CD)/PLGA NPs, were within 200 nm in size. Moreover, the system was homogeneous and stable. The in vitro transport mechanism across the epithelial barrier showed that the uptake of nanoparticles was time-dependent and that NPs were actively transported across the epithelial barrier. The in vitro release behavior of the TA-loaded nanodelivery systems revealed that (2-HP-β-CD)/PLGA nanoparticles could prolong the drug release time to up to three times longer than the suspensions. The isolated corneal permeability demonstrated that TA-(2-HP-β-CD)/PLGA NPs could extend the precorneal retention time and boost corneal permeability. Thus, they increased the cumulative release per unit area 7.99-fold at 8 h compared to the suspension. The pharmacokinetics within the aqueous humor showed that (2-HP-β-CD)/PLGA nanoparticles could elevate the bioavailability of the drug, and its C max was 51.91 times higher than that of the triamcinolone acetonide aqueous solution. Therefore, (2-HP-β-CD)/PLGA NPs can potentially elevate transmembrane uptake, promote corneal permeability, and improve the bioavailability of drugs inside the aqueous humor. This study provides a foundation for future research on transocular barrier nanoformulations for non-invasive drug delivery.

The acidic pH of tumor tissue has been used to trigger drug release from nanoparticles. However, dynamic interactions between tumor pH and vascularity present challenges to optimize therapy to particular microenvironment conditions. Despite recent development of pH-sensitive nanomaterials that can accurately quantify drug release from nanoparticles, tailoring release to maximize tumor response remains elusive. This study hypothesizes that a computational modeling-based platform that simulates the heterogeneously vascularized tumor microenvironment can enable evaluation of the complex intra-tumoral dynamics involving nanoparticle transport and pH-dependent drug release, and predict optimal nanoparticle parameters to maximize the response. To this end, SPNCD nanoparticles comprising superparamagnetic cores of iron oxide (Fe 3 O 4 ) and a poly(lactide- co -glycolide acid) shell loaded with doxorubicin (DOX) were fabricated. Drug release was measured in vitro as a function of pH. A 2D model of vascularized tumor growth was calibrated to experimental data and used to evaluate SPNCD effect as a function of drug release rate and tissue vascular heterogeneity. Simulations show that pH-dependent drug release from SPNCD delays tumor regrowth more than DOX alone across all levels of vascular heterogeneity, and that SPNCD significantly inhibit tumor radius over time compared to systemic DOX. The minimum tumor radius forecast by the model was comparable to previous in vivo SPNCD inhibition data. Sensitivity analyses of the SPNCD pH-dependent drug release rate indicate that slower rates are more inhibitory than faster rates. We conclude that an integrated computational and experimental approach enables tailoring drug release by pH-responsive nanomaterials to maximize the tumor response.

Neuroprotection is one of the core treatment strategies for brain injuries including traumatic brain injury (TBI). NR2B9c is a promising neuroprotective peptide but its clinical translation is limited because of poor brain penetrability. Exosomes are naturally occurring nanovesicles having therapeutic potential for TBI as well as an efficient drug delivery carrier to the brain. Here, we engineered exosomes with neuron targeting peptide rabies virus glycoprotein (RVG29) via bio-orthogonal click chemistry technique and loaded it with NR2B9c, developing RVG-Exo NR2B9c . RVG29 conjugated exosome had higher neuron targeting efficiency compared to naïve exosomes both in vivo and in vitro. RVG-Exo NR2B9c had great cytoprotective effect against oxygen glucose deprived Neuro2a cells. Intravenous administration of RVG-Exo NR2B9c significantly improved behavioral outcomes and reduced the lesion volume after TBI injury in a mice controlled cortical impact model. Due to their multifunctionality and significant efficacy, we anticipate that RVG-Exo NR2B9c have the potential to be translated both as therapeutic agent as well as cargo delivery system to the brain for the treatment of TBI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: The primary objective of the research was to develop a cubosomal in situ gel encapsulated with Triamcinolone acetonide (TCA) in order to enhance its penetration through the blood-brain barrier (BBB) when administered via the intranasal route, thus enabling efficient and rapid action., Method: Cubosomes were formulated by top-down approach using glyceryl monooleate (GMO), using pluronics127 (PF127) and polyvinyl alcohol (PVA) in varying proportions based on the Box-Behnken design. High resolution transmission electron microscopy (HR-TEM) analysis confirmed the morphology of the cubosomes. The in situ gel was formulated and optimized. Experiments involving ex vivo permeation and histopathology analyses were undertaken to evaluate drug permeation and tissue effects., Results: The cubosomes exhibited a particle size (PS) of 197.9 nm, zeta potential (ZP) of -31.11 mV, and entrapment efficacy (EE) of 84.31%, with low deviation. Batch F4 (19% PF127) showed favorable results. In vitro and ex vivo permeation studies revealed drug release of 78.59% and 76.65%, respectively, after 8 h. Drug release followed the Hixson Crowell model of release kinetics. The histopathological examination revealed no signs of toxicity or adverse effects on the nasal mucosa of the sheep. The formulation exhibited short-term stability, maintaining its integrity and properties when stored at room temperature., Conclusion: The utilization of an intranasal cubosomal in situ gel encapsulated with TCA was anticipated to lower intracranial pressure and improve patient adherence by offering effective relief for individuals suffering from Brain edema. This efficacy is attributed to its rapid onset of action and its safe and well-tolerated dosage form.

Aim: To develop nanocarriers for targeting the delivery of chemotherapeutics to overcome multidrug-resistant ovarian cancer. Materials & methods: Doxorubicin-loaded nanovesicles were obtained through serial extrusion, followed by loading of P-glycoprotein siRNA and folic acid. The targeting ability and anticancer efficacy of the nanovesicles were evaluated. Results: The doxorubicin-loaded nanovesicles showed a high production yield. The presence of P-glycoprotein siRNA and folic acid resulted in reversed drug resistance and tumor targeting. This nanoplatform tremendously inhibited the viability of multidrug-resistant ovarian cancer cells, which was able to target tumor tissue and suppress tumor growth without adverse effects. Conclusion: These bioengineered nanovesicles could serve as novel extracellular vesicles mimetics for chemotherapeutics delivery to overcome multidrug resistance.

Nanocarriers play an important role in enhancing the efficacy of antibiotics against biofilms by improving their penetration and prolonging retention in pathogenic biofilms. Herein, the multifunctional nanocarriers including nanospheres (NS) and nanotubes (NT) with a high biocompatibility and biodegradability were prepared through self-assembly of partially hydrolyzed α-lactalbumin. The effects of these two different shaped nanocarriers on the delivery of antibiotics for biofilm treatment were examined by conducting in vitro antibiofilm experiment and in vivo infected wound model. The strong affinity of NS and NT for the bacterial surface allows antibiotics to be concentrated in the bacteria. Notably, the high permeability of NT into biofilms facilitates deeper penetration and the easier diffusion of loaded antibiotics within the biofilm. Furthermore, the acidic biofilm environment triggers the release of antibiotics from the NT, resulting in the accumulation of high local antibiotic concentrations. Therefore, NT could efficiently clean and inhibit the biofilm formation while also destroying the mature biofilms. In a S. aureus infected wound animal model, treatment with antibiotic-loaded NT demonstrated accelerated healing of S. aureus infected wounds when compared to free antibiotic treatment. These findings indicate that NT nanocarrier strategy is promising for treating bacterial biofilm infections, offering the potential for lower antibiotics dosages and preventing the overuse of antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fungal keratitis (FK) is a serious infectious corneal disease that leads to blindness. Butenafine (BTF) is an allylamine drug with high antifungal activity, but its poor water solubility and low bioavailability limit its clinical application in ophthalmology. To increase its aqueous solubility and corneal permeability, butenafine was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) polymeric nanomicelles to improve the bioavailability of the drug for the treatment of FK. Butenafine was successfully fabricated into nanomicelles with a high EE of 96.34 ± 1.65 % and DL of 6.71 ± 0.099 %. The BTF-NM showed an average particle size of 13.12 ± 0.24 nm, a zeta potential of -0.56 ± 0.44 mV and a narrow PDI of 0.12 ± 0.02 with a nearly spherical shape. The characterization results of FTIR, XRD and DSC indicated that BTF was encapsulated in the TPGS nanomicelles. The BTF-NM formulation also showed high storage stability, and the in vitro drug release study showed typical biphasic-release characteristics. In addition, the BTF-NM formulation displayed good cellular tolerance and excellent ocular tolerance in rabbits. Significantly elevated in vitro antifungal activity was also observed in the BTF-NM formulation, and remarkable improvements regarding in vivo corneal permeation were observed compared with the BTF suspension formulation. Finally, the in vivo antifungal activity studies indicated that the BTF-NM formulation had a good therapeutic effect on FK and had similar efficacy to that of commercial natamycin suspension eye drops. These results suggest that the BTF-NM ophthalmic formulation could be a promising ocular drug delivery system for the treatment of FK., Competing Interests: Declaration of Competing Interest No conflict of interest exists in the submission of this manuscript, and manuscript has been approved by all authors for publication., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The interest in combining chemosensitizers with cytostatics in cancer therapy is growing, which causes also a need to develop their delivery systems. Example of the combination with beneficial therapeutic effects is docetaxel (Dtx) and resveratrol (Res). Although poly(lactide)-co-poly(ethylene glycol) (PLA-PEG) micelles have been considered as one of the most promising platforms for drug delivery, their properties may depend on the stereoisomeric form of hydrophobic block. Therefore, the aim of this study was evaluation of the effect of PLA block on co-encapsulation and release rate of Dtx and Res, which has not been studied so far. This article presents a comparison of single- (Dtx or Res) and dual-drug (Dtx and Res) loaded micelles obtained from poly(l,l-lactide)-co-poly(ethylene glycol) (PLLA-PEG) and poly(d,l-lactide)-co-poly(ethylene glycol) (PDLLA-PEG). The analyzes of the micelles have been conducted including morphology, drug(s) encapsulation efficiency, intermolecular interactions, in vitro drug release, and cytotoxicity. Differences in drug loading ability and release profile have been observed between Res and Dtx but also depending on the polymer and number of drugs in micelles (single vs. dual loaded). The PLLA-PEG micelles have a significantly higher Dtx encapsulation capacity than PDLLA-PEG micelles. The highest cytotoxicity was shown for Dtx and Res dual-loaded micelles, regardless of the polymer. The findings may be used for selection of PLA-based drug delivery systems containing Dtx and Res., (© 2023 Wiley Periodicals LLC.)

Owing to the importance of drug delivery, the synthesis of advanced nanomaterials for targeted drug delivery plays a considerable role in medical treatment. One of the most prominent nanomaterials is PIL, which is used as controlled anticancer drug delivery and significantly improves the half-life and antitumor effect. In this study, a stable and effective drug carrier containing silver nanoparticles was reported for the drug delivery with an antimicrobial effect, and the capability of the drug carrier . PILP was synthesized by radical polymerization, and silver nanoparticles were anchored into PIL voids by in-situ reduction, which developed the adsorption antimicrobial effect and capability of the drug carrier. The synthesized nanocomposite was characterized. The Ag-PILP nanocomposite showed antibacterial activityagainst both E. coli and S. aureus with a MIC of 256 μg/mL, and bactericidal activity against E. coli and S. aureus strains with a MBC of 256 and 512 μg/mL, respectively.

Aim: Our aim was to repurpose atorvastatin for melanoma by encapsulating in a nanostructured lipid carrier matrix to promote tumour cell internalisation and skin permeation. pH-responsive chitosan gel was employed to restrict At-NLCs in upper dermal layers., Methods: We utilised a quality by design approach for encapsulating At within the NLC matrix. Further, cellular uptake and cytotoxicity was evaluated along with pH-responsive release and ex vivo skin permeation., Results: Cytotoxicity assay showed 3.13-fold enhanced cytotoxicity on melanoma cells compared to plain drug with nuclear staining showing apoptotic markers. In vitro, release studies showed 5.9-fold rapid release in chitosan gel matrix at pH 5.5 compared to neutral pH., Conclusions: At-NLCs prevented precipitation, promoted skin permeation, and SK-MEL 28 cell internalisation. The localisation of NLCs on the upper dermal layer due to electrostatic interactions of skin with chitosan gel diminished the incidence of untoward systemic effects.

Bacterial cellulose (BC) is a biomaterial being investigated for a range of applications. Herein, BC films derived from nata de coco pieces are reinforced by two-dimensional molybdenum disulfide (MoS 2 ) and helical carbon nanotubes (HCNTs) to enhance their tensile mechanical properties, and the biocompatibility of the BC composite films is demonstrated. A simple preparation is presented using a kitchen blender to disperse and blend the BC fibers and additives in a common fabrication medium, followed by vacuum filtration. The mechanical properties of the BC/MoS 2 /HCNTs composite films are enhanced due to the synergistic effect of MoS 2 and HCNTs embedded in the BC films. The MoS 2 /HCNTs binary additive (1 phr) is capable of increasing the strength and Young's modulus by 148 % and 333 %, respectively, relative to the BC films. The cell cytotoxicity of the BC/MoS 2 /HCNTs films was assessed using an MTT assay. The composite films are biocompatible with a cell viability of L929 fibroblast cells >70 %, coupled with observations of direct cell attachment on the films. The composite films also exhibited good performance in absorbing and releasing gentamicin antibiotics to inhibit the growth of Escherichia coli and Staphylococcus aureus. The BC/MoS 2 /HCNTs films are thus potential BC-based candidates as biocompatible robust antibiotic carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is a malignant tumor of the digestive system that poses a serious threat to human life and health. Chemotherapeutic drugs commonly used in the clinic have limited efficacy and heavy adverse effects. Therefore, it is imperative to find effective and safe alternatives, and natural polysaccharides (NPs) fit the bill. This paper summarizes in detail the anti-HCC activity of NPs in vitro, animal and clinical trials. Furthermore, the addition of NPs can reduce the deleterious effects of chemotherapeutic drugs such as immunotoxicity, bone marrow suppression, oxidative stress, etc. The potential mechanisms are related to induction of apoptosis and cell cycle arrest, block of angiogenesis, invasion and metastasis, stimulation of immune activity and targeting of MircoRNA. And on this basis, we further elucidate that the anti-HCC activity may be related to the monosaccharide composition, molecular weight (Mw), conformational features and structural modifications of NPs. In addition, due to its good physicochemical properties, it is widely used as a drug carrier in the delivery of chemotherapeutic drugs and small molecule components. This review provides a favorable theoretical basis for the application of the anti-HCC activity of NPs., Competing Interests: Declaration of competing interest All authors have read and approved this version of the article, and due care has been taken to ensure the integrity of the work. Neither the entire paper nor any part of its content has been published or has been accepted elsewhere. It is not being submitted to any other journal., (Copyright © 2023. Published by Elsevier B.V.)

Long chain fatty acids in the colon play important roles in infant development. This study aimed to establish a colon-targeted long chain fatty acid release system in rat pups, with linoleic acid (LA) as the target model. LA-loaded chitosan nanoparticles (LA-CS NPs) synthesized via ionic crosslinkage showed spherical surface morphology and favorable encapsulation efficiency (84.96 %). In vivo distribution studies of LA-CS NPs demonstrated a significant increase in LA concentration in the colonic content after a 12-hour administration period. Additionally, oral administration of the delivery system (CS NPs: 18 μg/g/d, LA-CS NPs: 24 μg/g/d) exhibited no detrimental effects on the health of rat pups. In conclusion, this study presents a promising strategy for the targeted delivery of fatty acid to the colon in rat pups., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We have developed a biomimetic delivery system termed the Monocyte Cell Membrane-Coated 1,8-Cineole Biomimetic Delivery System (MM-CIN-BDS or BDS), which integrates diethylaminoethyl-dextran (DEAE) and monocyte cell membrane (MM). This innovative approach enhances the cellular uptake efficiency of 1,8-cineole (CIN) and facilitates targeted therapy for atherosclerosis. Our findings demonstrate the successful modification of the drug carrier with DEAE and MM, as validated by measurements of particle size, zeta potential, microscopic morphology, and western blotting analyses. Notably, cellular uptake experiments unveil a significant enhancement in cellular uptake efficiency due to DEAE modification. However, the introduction of monocyte cell membranes diminishes this effect in normal human umbilical vein endothelial cells (HUVECs), although this efficiency is notably restored in HUVECs activated with lipopolysaccharide (LPS). Through in vivo imaging investigations, we observe that the MM coating augments distribution in the spleen, brain, and atherosclerotic plaques, while concurrently diminishing distribution in the heart and kidneys. Animal studies corroborate these findings, illustrating that MM-CIN-BDS treatment curtails lipid parameters, dampens the expression of inflammatory factors and proteins, mitigates vascular tissue damage, and ultimately reduces the extent of atherosclerotic lesion areas. To encapsulate, DEAE emerges as an especially adept agent for modifying drug carriers with suboptimal cellular uptake efficiency in the realm of cardiovascular diseases. The potential therapeutic promise of MM-CIN-BDS for atherosclerosis treatment is evident from our research., Competing Interests: Declaration of competing interest The author reports no conflicts of interest in this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Cell surface receptors facilitate signaling and nutrient uptake. These processes are dynamic, requiring receptors to be actively recycled by endocytosis. Due to their differential expression in disease states, receptors are often the target of drug-carrier particles, which are adorned with ligands that bind specifically to receptors. These targeted particles are taken into the cell by multiple routes of internalization, where the best-characterized pathway is clathrin-mediated endocytosis. Most studies of particle uptake have utilized bulk assays rather than observing individual endocytic events. As a result, the detailed mechanisms of particle uptake remain obscure. To address this gap, we employed a live-cell imaging approach to study the uptake of individual liposomes as they interact with clathrin-coated structures. By tracking individual internalization events, we find that the size of liposomes rather than the density of the ligands on their surfaces primarily determines their probability of uptake. Interestingly, targeting has the greatest impact on endocytosis of liposomes of intermediate diameters, with the smallest and largest liposomes being internalized or excluded, respectively, regardless of whether they are targeted. These findings, which highlight a previously unexplored limitation of targeted delivery, can be used to design more effective drug carriers.

Background: Ursolic acid is a powerful drug that possesses many therapeutic properties, such as hepatoprotection, immunomodulation, anti-inflammatory, antidiabetic, antibacterial, antiviral, antiulcer, and anticancer activity. Centella asiatica (L.) Urban (Umbelliferae) contains a triterpene called asiatic acid, which has been used effectively in traditional Chinese and Indian medicine system for centuries. Anticancer, anti-inflammatory, and neuroprotective properties are only some of the many pharmacological actions previously attributed to asiatic acid ., Aim: The present work developed an optimized combinatorial drug-loaded nano-formulation by Quality by design approach., Materials and Methods: The optimize transliposome for accentuated dermal delivery of dual drug. The optimization of drug-loaded transliposome was done using the "Box-Behnken design." The optimized formulation was characterized for vesicles size, entrapment efficiency (%), and in vitro drug release. Additionally, transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), and dermatokinetic study were performed for further evaluation of drug-loaded optimized transliposome formulation., Results: The optimized combinatorial drug-loaded transliposome formulation showed a particle size of 86.36 ± 2.54 nm, polydispersity index (PDI) 0.230 ± 0.008, and an entrapment efficiency of 87.43 ± 2.66% which depicted good entrapment efficiency. In vitro drug release of ursolic acid and asiatic acid transliposomes was found to be 85.12 ± 2.54% and 80.23 ± 3.23%, respectively, as compared to optimized ursolic acid and asiatic acid transliposome gel drug release that was 67.18 ± 2.85% and 60.28 ± 4.12%, respectively. The skin permeation study of ursolic and asiatic acid conventional formulation was only 32.48 ± 2.42%, compared with optimized combinatorial drug-loaded transliposome gel (79.83 ± 4.52%) at 12 h. After applying combinatorial drug-loaded transliposome gel, rhodamine was able to more easily cross rat skin, as observed by confocal laser scanning microscopy, in comparison with when the rhodamine control solution was used., Discussion: The UA_AA-TL gel formulation absorbed more ursolic acid and asiatic acid than the UA_AA-CF gel formulation, as per dermatokinetic study. Even after being incorporated into transliposome vesicles, the antioxidant effects of ursolic and asiatic acid were still detectable. In most cases, transliposomes vesicular systems generate depots in the skin's deeper layers and gradually release the medicine over time, allowing for fewer applications., Conclusion: In overall our studies, it may be concluded that developed dual drug-loaded transliposomal formulation has great potential for effective topical drug delivery for skin cancer., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Non-melanoma skin cancer is one of the most common malignancies reported around the globe. Current treatment therapies fail to meet the desired therapeutic efficacy due to high degree of drug resistance. Thus, there is prominent demand in advancing the current conventional therapy to achieve desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The current investigation has been designed to evaluate the safety and efficacy of developed 5-Flurouracil and cannabidiol loaded combinatorial lipid-based nanocarrier (FU-CBD NLCs) gel for the effective treatment of skin cancer. Initially, confocal microscopy study results showed excellent uptake and deposition at epidermal and the dermal layer. Irritation studies performed by IR camera and HET cam shows FU-CBD NLCs was much more tolerated and less irritant compared to conventional treatment. Furthermore, gamma scintigraphy evaluation shows the skin retention behavior of the formulation. Later, in-ovo tumor remission studies were performed, and it was found that prepared FU-CBD NLCs was able to reduce tumor volume significantly compared to conventional formulation. Thus, obtained results disclosed that permeation and disposition of 5-FU and CBD into different layers of the skin FU-CBD NLCs gel could be more potential carrier than conventional gel. Furthermore, prepared formulation showed greater tumor remission, better survival rate, reduction in tumor number, area, and volume with improved biochemical profile. Thus, prepared gel could serve as a promising formulation approach for the skin cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Evodiamine (Evo) is a natural, biologically active plant alkaloid with wide range of pharmacological activities. In the present study Evo-loaded folate-conjugated Pluronic F108 nano-micelles (ENM) is synthesized to enhance the therapeutic efficacy of Evo against cervical cancer. ENM are synthesized, physicochemically characterized and in vitro anticancer activity is performed. The study demonstrates that ENM have nanoscale size (50.33 ± 3.09 nm), monodispersity of 0.122 ± 0.072, with high drug encapsulation efficiency (71.30 ± 3.76%) and controlled drug release at the tumor microenvironment. ENM showed dose-dependent and time-dependent cytotoxicity against HeLa human cervical cancer cells. The results of in vitro anticancer studies demonstrated that ENM have significant anticancer effects and greatly induce apoptosis as compared to pure Evo. The cellular uptake study suggests that increased anticancer activity of ENM is due to the improved intracellular delivery of Evo through overexpressed folate receptors. Overall, the designed ENM can be a potential targeted delivery system for hydrophobic anticancer bioactive compound like Evo., (© 2023 Wiley-VCH GmbH.)

Objective: In this work, a propranolol hydrochloride (PRH) transfersomes loaded cutaneous hydrogel patch was developed for topical drug delivery in the affected area of infantile haemangioma., Methods: Sodium cholate was used as the edge activator to prepare the transfersomes. Based on the central composite design, transfersomes hydrogel patch formulation was optimised with 48 h cumulative penetration and time lag as response values. Particle sizes and morphology of the prepared transfersomes were assessed. They were loaded in a cutaneous hydrogel patch, after which their skin permeation abilities were evaluated, and histopathological effects were investigated using guinea pigs. Moreover, in vivo pharmacokinetics studies were performed in rats., Results: The transfersomes system had a encapsulation efficiency of 81.84 ± 0.53%, particle size of 186.8 ± 3.38 nm, polydispersity index of 0.186 ± 0.002, and a zeta potential of -28.6 ± 2.39 mV. Transmission electron microscopy images revealed sphericity of the particles. The ex vivo drug's penetration of the optimised transfersomes hydrogel patch was 111.05 ± 11.97 μg/cm 2 through rat skin within 48 h. Assessment of skin tissue did not reveal any histopathological alterations in epidermal and dermal cells. Pharmacokinetic studies showed that skin C max (68.22 μg/cm 2 ) and AUC 0-24 (1007.33 μg/cm 2 × h) for PRH transfersomes hydrogel patch were significantly higher than those of commercially available oral dosage form and hydrogel patch without transfersomes. These findings imply that the transfersomes hydrogel patch can prolong drug accumulation in the affected skin area, and reduce systemic drug distribution via the blood stream., Conclusions: The hydrogel patch-loaded PRH transfersomes is a potentially useful drug formulation for infantile haemangioma.

The recent progress in nanoparticle applications, such as tumor-targeting, has enabled specific delivery of chemotherapeutics to malignant tissues with enhanced local efficacy while limiting side effects. However, existing delivery systems leave much room for improvement in terms of achieving enhanced colloidal stability in fluid medium, efficient targeting of intended sites, and effective release of therapeutic drugs into diseased cells. Here, an efficient stimuli-responsive nanocarrier for mammalian cells, termed RGD-NAMs, was developed, which enabled temperature- and pH-sensitive release of drug loads. The RGD-NAMs comprise two parts: a stimuli-responsive copolymer shell (NIBIm-AA-RGD) and drug-container core (MSNs). The RGD-NAMs have a stable drug-loading capacity with a marked difference in the release rate depending on the temperature and pH conditions. The RGD-NAMs also exhibit high colloidal stability in SBF (Stimulated body fluid) solutions and minimal toxicity in skeletal myoblasts (C2C12) and bovine arterial endothelial cells (BAEC). The doxorubicin-loaded RGD-NAMs induced a cytotoxic effect in a dose-dependent manner, which was furthered by an increase in temperature from 37 to 40 °C. Moreover, significant control of the release rate and the amount were achieved through pH change. This novel, smart drug-delivery system with high responsiveness to temperature and pH changes has wide application prospects in biomedical fields, including the theragnosis of tumors and vascular diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Although subcellular targeting can enhance the therapeutic performance of most drugs, such targeting requires appropriate carrier-based delivery that can bypass endosomal/lysosomal trafficking. Recent works show that nanocarriers can be designed for direct cell membrane translocation and nonendocytic uptake, bypassing the usual endocytosis processes. Here we show that this approach can be adapted for the rapid cell nucleus delivery of molecular drugs. In particular, a guanidinium-terminated nanocarrier is used to create a weak interaction-based carrier-drug nanoassembly for direct membrane translocation into the cytosol. The rapid and extensive entry of a drug-loaded nanocarrier into the cell without any vesicular coating and affinity of the drug to the nucleus allows their nucleus labeling. Compared to endocytotic uptake that requires more than hours for cell uptake followed by predominant lysosomal entrapment, this nonendocytic uptake labels the nucleus within a few minutes without any lysosomal trafficking. This approach may be utilized for nanocarrier-based subcellular targeting of drugs for more effective therapy.

Ocular drug delivery is enigmatic on account of various physiological precorneal barriers that ultimately hinder efficient drug penetration and corneal absorption. Ultradeformable vesicles embody non-ionic surfactants, edge activators and vesicular builders that provide enormous elasticity and deformability. The elastic vesicles can cross the ocular barriers owing to their peculiar squeezability and distorting ability and, thus, establish an infallible shot for ocular delivery. This review provides an overview of the recent advancements and updates of elastic vesicles as effective ocular drug delivery vehicles., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Bovine serum albumin (BSA) nanoparticles (BSA-MTX-CUR-NPs) encapsulating methotrexate (MTX) and curcumin (CUR) was developed with an aim to co-deliver the drugs at the inflamed joint so as to maximize the therapeutic efficacy and alleviate toxic side effects associated with MTX., Methods: Nanoparticle albumin-bound technology was used to formulate nanoparticles, followed by characterization for its particle size, polydispersity index, encapsulation efficiency, zeta potential, surface morphology, in-vitro drug release and drug release kinetics. Further, we investigated the pharmacokinetics and pharmacodynamics of the developed nanoparticles in the adjuvant-induced arthritis model., Results: BSA-MTX-CUR-NPs exhibited particle size of 163.05 ± 1.708 nm, polydispersity index of 0.195 ± 0.0024 and % encapsulation efficiency of 68.23 ± 0.640% for MTX and 75.71 ± 0.216% for CUR with controlled release pattern for both the drugs. The scanning electron microscopy revealed nanoparticles exhibited a spherical shape. DSC study confirmed the absence of incompatibility between the drugs and the excipients. Half-life and area under the curve were significantly higher for MTX in the nanoparticulate form in comparison to free MTX. Pharmacodynamic studies revealed that BSA-MTX-CUR-NPs possessed better disease-modifying effects in comparison to free MTX., Conclusion: Hence, it can be concluded that albumin nanoparticles constitute a viable method for delivering MTX and CUR to inflamed joints simultaneously, because of the strong affinity of albumin and enhanced permeability and retention effect at the inflamed joint. This combinational therapy of MTX & CUR in nanoparticulate form has the potential for the holistic management of rheumatoid arthritis.

The use of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) as carriers for chemotherapeutic drugs is regarded as an actively targeted nano-therapy for the specific delivery of anti-cancer drugs to target cells. However, the exact mechanism by which PLGA NPs boost anticancer cytotoxicity at the molecular level remains largely unclear. This study employed different molecular approaches to define the response of carcinoma FaDu cells to different types of treatment, specifically: paclitaxel (PTX) alone, drug free PLGA NPs, and PTX-loaded PTX-PLGA NPs. Functional cell assays revealed that PTX-PLGA NPs treated cells had a higher level of apoptosis than PTX alone, whereas the complementary, UHPLC-MS/MS (TIMS-TOF) based multi-omics analyses revealed that PTX-PLGA NPs treatment resulted in increased abundance of proteins associated with tubulin, as well as metabolites such as 5-thymidylic acid, PC(18:1(9Z)/18:1(9Z0), vitamin D, and sphinganine among others. The multi-omics analyses revealed new insights about the molecular mechanisms underlying the action of novel anticancer NP therapies. In particular, PTX-loaded NPs appeared to exacerbate specific changes induced by both PLGA-NPs and PTX as a free drug. Hence, the PTX-PLGA NPs' molecular mode of action, seen in greater detail, depends on this synergy that ultimately accelerates the apoptotic process, resulting in cancer cell death., (© 2023 Wiley-VCH GmbH.)

Ibuprofen is a member of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-inflammatory, analgesic, and antipyretic activities used to relieve a variety of pains. The objective of this study was to formulate, characterize and evaluate the in vitro and in vivo properties of ibuprofen formulated as solid lipid microspheres (SLMs) for enhanced delivery. The mixtures of Irvingia wombolu fat (IRW) and moringa oil (MO) each with Phospholipon® 90G (PL90G) at the ratio of 2:1 w/w were prepared by fusion, characterized and used to prepare SLMs. The SLMS were thereafter evaluated using the following parameters: particle size and morphology, stability, and encapsulation efficiency EE (%). In vitro release was carried out in phosphate buffer (pH 7.4). The ibuprofen based SLMs were also evaluated for anti-inflammatory and anti-ulcer effects using animal models. The pH showed significant increase after two months of formulation with a maximum value of 6.4 while the EE obtained were 95.6, 89.4 and 61.6% for SLMs formulated with lipid matrix of Phospholipon® 90G (1% and 2%), and MO (1%) respectively. The in vitro release showed maximum release of 87.8 and 98.97% of the two different lipid-based formulations while anti-inflammatory effect was up to 89.90% after 5 h of inducing inflammation. The SLMs did not show any lesion thus conferring gastroprotection on the formulations. The SLMs exhibited good anti-inflammatory property with gastroprotective action., (© 2023. The Author(s).)

Dual-drug delivery systems for anticancer therapy have recently attracted substantial attention due to their potency to overcome limitations of conventional anti-cancer drugs, tackle drug resistance problems, as well as improve the therapeutic efficacy. In this study, we introduced a novel nanogel based on folic acid-gelatin-pluronic P123 (FA-GP-P123) conjugate to simultaneously deliver quercetin (QU) and paclitaxel (PTX) to the targeted tumor. The results indicated that the drug loading capacity of FA-GP-P123 nanogels was significantly higher than that of P123 micelles. The kinetic release profiles of QU and PTX from the nanocarriers were governed by Fickian diffusion and swelling behavior, respectively. Notably, FA-GP-P123/QU/PTX dual-drug delivery system induced higher toxicity to MCF-7 and Hela cancer cells than either QU or PTX individual delivery system, and the non-targeted dug delivery system (GP-P123/QU/PTX), indicating the synergistic combination of dual drugs and FA positive targeting effect. Furthermore, FA-GP-P123 could effectively deliver QU and PTX to tumors in vivo after administration into MCF-7 tumor-bearing mice, which resulted in 94.20 ± 5.90 % of tumor volume reduced at day 14. Moreover, the side effects of the dual-drug delivery system were significantly reduced. Overall, we suggest FA-GP-P123 as potential nanocarrier for dual-drug delivery for targeted chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Radiotherapy as one of the most important cancer treatment modalities has been widely used in the therapy of various cancers. The clinically used radiation ( e.g. X-ray) for radiotherapy has the advantages of precise spatiotemporal controllability and deep tissue penetration. However, traditional radiotherapy is frequently limited by the high side effects and tumor hypoxia. The combination of radiotherapy and other cancer treatment modalities may overcome the disadvantages of radiotherapy and improve the final therapeutic efficacy. In recent years, X-ray-activable prodrugs and polymeric nanocarriers have been extensively explored to introduce other treatment modalities in the precise position during radiotherapy, which can reduce the side toxicity of the drugs and improve the combination therapeutic efficacy. In this review, we focus on recent advances in X-ray-activable prodrugs and polymeric nanocarriers to boost X-ray-based multimodal synergistic therapy with reduced toxicity. The design strategies of prodrugs and polymeric nanocarriers are highlighted. Finally, challenges and outlooks of X-ray-activable prodrugs and polymeric nanocarriers are discussed.

Purpose: Due to the inimitable anatomical structure of the eyeball and various physiological barriers, conventional ocular local administration is often complicated by apparent shortcomings, such as limited bioavailability and short drug retention. Thus, developing methods for sustainable, safe and efficient drug delivery to ocular target sites has long been an urgent need. This study briefly summarizes the barriers to ocular drug administration and various ocular drug delivery routes and highlights recent progress in ocular implantable sustained-release drug delivery systems (DDSs) to provide literature evidence for developing novel ocular implants for sustained drug delivery., Methods: We conducted a comprehensive search of studies on ocular implantable sustained-release DDSs in PubMed and Web of Science using the following keywords: ocular, implantable and drug delivery system. More than 400 papers were extracted. Publications focused on sustained and controlled drug release were primarily considered. Experimental articles involving DDSs that cannot be implanted into the eye through surgeries and cannot be inserted into ocular tissues in solid form were excluded. Approximately 143 publications were reviewed to summarize the most current information on the subject., Results: In recent years, numerous ocular sustained-release DDSs using lipids, nanoparticles and hydrogels as carriers have emerged. With unique properties and systematic design, ocular implantable sustained-release DDSs are able to continuously maintain drug release, effectively sustain the therapeutic concentration in target tissues, and substantially enhance the therapeutic efficacy. Nevertheless, few ocular implantable sustained-release DDSs have been available in clinical use., Conclusions: Ocular implantable sustained-release DDSs have become a new focus in the field of ocular drug development through unique designs and improvements in the materials of drug carriers, administration methods and dosage forms. With more ocular implantable sustained-release DDSs being commercialized, ocular therapeutics may be revolutionized., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Pancreatic adenocarcinoma (PDAC) remains largely refractory to chemotherapeutic treatment regimens and, consequently, has the worst survival rate of all cancers. The low efficacy of current treatments results largely from toxicity-dependent dose limitations and premature cessation of therapy. Recently, targeted delivery approaches that may reduce off-target toxicities have been developed. In this paper, we present a preclinical evaluation of a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSNs) functionalized with a protease linker that is specifically cleaved by PDAC cells. Our previous work demonstrated that ADAM9 is a PDAC-enriched protease and that paclitaxel-loaded ADAM9-responsive MSNs effectively kill PDAC cells in vitro. Here, we show that paclitaxel-loaded ADAM9-MSNs result in off-target cytotoxicity in clinically relevant models, which spurred the development of optimized ADAM9-responsive MSNs (OPT-MSNs). We found that these OPT-MSNs still efficiently kill PDAC cells but, as opposed to free paclitaxel, do not induce death in neuronal or bone marrow cells. In line with these in vitro data, paclitaxel-loaded OPT-MSNs showed reduced organ damage and leukopenia in a preclinical PDAC xenograft model. However, no antitumor response was observed upon OPT-MSN administration in vivo. The poor in vivo antitumor activity of OPT-MSNs despite efficient antitumor effects in vitro highlights that although MSN-based tumor-targeting strategies may hold therapeutic potential, clinical translation does not seem as straightforward as anticipated.

A cell-based drug delivery system has emerged as a promising drug delivery platform. Due to their innate inflammatory tropism, natural and engineered macrophages have exhibited targeted accumulation in inflammatory tissues, which has allowed targeted delivery of medicine for the treatment of a variety of inflammatory diseases. Nevertheless, live macrophages may take up the medicine and metabolize it during preparation, storage, and in vivo delivery, sometimes causing unsatisfactory therapeutic efficacy. In addition, live macrophage-based drug delivery systems are usually freshly prepared and injected, due to the poor stability that does not allow storage. "Off-the-shelf" products would be indeed conducive to the timely therapy of acute diseases. Herein, a cryo-shocked macrophage-based drug delivery system was developed via supramolecular conjugation of cyclodextrin (CD)-modified "zombie" macrophages and adamantane (ADA)-functionalized nanomedicine. "Zombie" macrophages exhibited a much better storage stability over time than their counterpart live macrophage drug carriers and maintained cell morphology, membrane integrity, and biological functions. In an acute pneumonia mouse model, "zombie" macrophages carried quercetin-loaded nanomedicine, hand-in-hand, to the inflammatory lung tissues and effectively alleviated the inflammation in mice.

A calcium-chitosan-triazole nanocomplex (Ca@CS-Tz) was synthesized via the robust copper catalyzed azide-alkyne cycloaddition using calcium carbide (CaC2) as an in-situ source of acetylene. The nanocomplex was characterized by various techniques and it was proved to be an efficient drug carrier with satisfactory antimicrobial and antioxidant properties. Quercetin loaded nanocomplex (encapsulation efficiency- 68.2 ± 1.0 %) was studied for targeted drug release and the drug release after 120 h was found to be 80.7 ± 0.8 % and 8.69 ± 0.5 % at pH 5.0 and 7.4 respectively. On biological evaluation, the nanocomplex showed enhanced antimicrobial activity against gram-negative bacteria Escherichia coli (E. coli), gram-positive bacteria Bacillus subtilis (B. subtilis) and a fungi Aspergillus niger (A. niger). Moreover, the synthesized Ca@CS-Tz nanocomplex also exhibited significant antioxidant property. Herein, the novel results corresponding to the antimicrobial effect on A. niger and drug delivery studies performed using our previously synthesized chitosan triazole (CS-triazole) derivative have also been reported. Finally, the results of the present study were compared to the results obtained to our previously reported derivative. The incorporation of calcium ions into CS-triazole can lead to the utilization of this complex in various other biomedical applications e.g. bone tissue engineering., Competing Interests: Declaration of competing interest We assert no potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aliphatic polyesters are intrinsically enzymatic-biodegradable, and there is ever-increasing demand for safe and smart next-generation biomaterials including drug delivery nano-vectors in cancer research. Using bioresource-based biodegradable polyesters is one of the elegant strategies to meet this requirement; here, we report an l-amino acid-based amide-functionalized polyester platform and explore their lysosomal enzymatic biodegradation aspects to administrate anticancer drugs in cancer cells. l-Aspartic acid was chosen and different amide-side chain-functionalized di-ester monomers were tailor-made having aromatic, aliphatic, and bio-source pendant units. Under solvent-free melt polycondensation methodology; these monomers underwent polymerization to yield high molecular weight polyesters with tunable thermal properties. PEGylated l-aspartic monomer was designed to make thermo-responsive amphiphilic polyesters. This amphiphilic polyester was self-assembled into a 140 ± 10 nm-sized spherical nanoparticle in aqueous medium, which exhibited lower critical solution temperature at 40-42 °C. The polyester nano-assemblies showed excellent encapsulation capabilities for anticancer drug doxorubicin (DOX), anti-inflammatory drug curcumin, biomarkers such as rose bengal (RB), and 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt. The amphiphilic polyester NP was found to be very stable under extracellular conditions and underwent degradation upon exposure to horse liver esterase enzyme in phosphate-buffered saline at 37 °C to release 90% of the loaded cargoes. Cytotoxicity studies in breast cancer MCF 7 and wild-type mouse embryonic fibroblasts cell lines revealed that the amphiphilic polyester was non-toxic to cell lines up to 100 μg/mL, while their drug-loaded polyester nanoparticles were able to inhibit the cancerous cell growth. Temperature-dependent cellular uptake studies further confirmed the energy-dependent endocytosis of polymer NPs across the cellular membranes. Confocal laser scanning microscopy assisted time-dependent cellular uptake analysis directly evident for the endocytosis of DOX loaded polymer NP and their internalization for biodegradation. In a nutshell, the present investigation opens up an avenue for the l-amino acid-based biodegradable polyesters from l-aspartic acids, and the proof of concept is demonstrated for drug delivery in the cancer cell line.

In this study, elastic nanovesicles, constructed of phospholipids optimized by Quality by Design (QbD), release 6-gingerol (6-G), a natural chemical that may alleviate osteoporosis and musculoskeletal-related pain. A 6-gingerol-loaded transfersome (6-GTF) formulation was developed using a thin film and sonication approach. 6-GTFs were optimized using BBD. Vesicle size, PDI, zeta potential, TEM, in vitro drug release, and antioxidant activity were evaluated for the 6-GTF formulation. The optimized 6-GTF formulation had a 160.42 nm vesicle size, a 0.259 PDI, and a -32.12 mV zeta potential. TEM showed sphericity. The 6-GTF formulation's in vitro drug release was 69.21%, compared to 47.71% for the pure drug suspension. The Higuchi model best described 6-G release from transfersomes, while the Korsmeyer-Peppas model supported non-Fickian diffusion. 6-GTF had more antioxidant activity than the pure 6-G suspension. The optimized transfersome formulation was converted into a gel to improve skin retention and efficacy. The optimized gel had a spreadability of 13.46 ± 4.42 g·cm/s and an extrudability of 15.19 ± 2.01 g/cm 2 . The suspension gel had a 1.5 μg/cm 2 /h ex vivo skin penetration flux, while the 6-GTF gel had 2.71 μg/cm 2 /h. Rhodamine B-loaded TF gel reached deeper skin layers (25 μm) compared to the control solution in the CLSM study. The gel formulation's pH, drug concentration, and texture were assessed. This study developed QbD-optimized 6-gingerol-loaded transfersomes. 6-GTF gel improved skin absorption, drug release, and antioxidant activity. These results show that the 6-GTF gel formulation has the ability to treat pain-related illnesses effectively. Hence, this study offers a possible topical treatment for conditions connected to pain.

Nanorobotic manipulation to access subcellular organelles remains unmet due to the challenge in achieving intracellular controlled propulsion. Intracellular organelles, such as mitochondria, are an emerging therapeutic target with selective targeting and curative efficacy. We report an autonomous nanorobot capable of active mitochondria-targeted drug delivery, prepared by facilely encapsulating mitochondriotropic doxorubicin-triphenylphosphonium (DOX-TPP) inside zeolitic imidazolate framework-67 (ZIF-67) nanoparticles. The catalytic ZIF-67 body can decompose bioavailable hydrogen peroxide overexpressed inside tumor cells to generate effective intracellular mitochondriotropic movement in the presence of TPP cation. This nanorobot-enhanced targeted drug delivery induces mitochondria-mediated apoptosis and mitochondrial dysregulation to improve the in vitro anticancer effect and suppression of cancer cell metastasis, further verified by in vivo evaluations in the subcutaneous tumor model and orthotopic breast tumor model. This nanorobot unlocks a fresh field of nanorobot operation with intracellular organelle access, thereby introducing the next generation of robotic medical devices with organelle-level resolution for precision therapy.