Phosphatase-degradable nanoparticles providing sustained drug release.

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.

Polymer Nanoparticles with 2-HP-ß-Cyclodextrin for Enhanced Retention of Uptake into HCE-T Cells.

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-ß-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-ß-CD)/PLGA NPs and the drug-loaded TA-(2-HP-ß-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-ß-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-ß-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-ß-CD)/PLGA nanoparticles could elevate the bioavailability of the drug, and its Cmax was 51.91 times higher than that of the triamcinolone acetonide aqueous solution. Therefore, (2-HP-ß-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.

Advancements in transdermal drug delivery: A comprehensive review of physical penetration enhancement techniques.

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.

Anti-tumor effect of pH-sensitive drug-loaded nanoparticles optimized via an integrated computational/experimental approach.

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 (Fe3O4) 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.

Sulfonium-Cross-Linked Hyaluronic Acid-Based Self-Healing Hydrogel: Stimuli-Responsive Drug Carrier with Inherent Antibacterial Activity to Counteract Antibiotic-Resistant Bacteria.

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.

Engineering extracellular vesicles mimetics for targeted chemotherapy of drug-resistant ovary cancer.

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.

When treating cancer affecting the ovaries, which is an organ in the female reproductive system, two challenges that arise are the inefficient delivery of chemotherapeutic drugs and the development of drug resistance inside the tumor. In this study, very small nano-scale particles called nanovesicles, which contain a chemotherapeutic drug called doxorubicin, were developed in an attempt to overcome both of these concerns. These nanovesicles were secreted by a healthy cell from an ovary, isolated and loaded with doxorubicin. These nanovesicles were also loaded with siRNA, which, in this case, prevents the synthesis of a protein in ovarian tumor cells called P-glycoprotein. This protein is responsible for pumping chemotherapy drugs back out of tumor cells, so preventing its synthesis was intended to counter chemotherapeutic resistance. The targeting ability of the nanovesicle was also enhanced with folic acid, as folic acid receptors are present on the surface of these tumor cells in higher numbers. These nanovesicles were readily and specifically taken up by ovarian tumor cells in mice with induced ovarian cancer. This reversed drug resistance and enhanced the toxic effects of doxorubicin on the tumor cells, which, in turn, increased tumor cell death and prevented tumor cell migration. No obvious adverse effect was found in mice treated with the nanovesicle system compared with the free chemotherapy drug with critical systematic toxicity. This research provides new avenues for ovarian cancer treatment, with combined therapies of siRNAs and chemotherapeutic drugs, targeted to tumor cells specifically, within nanovesicles.

Development and In-Vitro Evaluation of Eugenol-Based Nanostructured Lipid Carriers for Effectual Topical Treatment Against C. albicans.

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.

Enhancing biofilm penetration and antibiofilm efficacy with protein nanocarriers against pathogenic biofilms.

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.

Novel nanomicelle butenafine formulation for ocular drug delivery against fungal keratitis: In Vitro and In Vivo study.

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.

Comparison of PLLA-PEG and PDLLA-PEG micelles for co-encapsulation of docetaxel and resveratrol.

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.

Quality by design endorsed atorvastatin-loaded nanostructured lipid carriers embedded in pH-responsive gel for melanoma.

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.

Engineered exosomes mediated targeted delivery of neuroprotective peptide NR2B9c for the treatment of traumatic brain injury.

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-ExoNR2B9c. RVG29 conjugated exosome had higher neuron targeting efficiency compared to naïve exosomes both in vivo and in vitro. RVG-ExoNR2B9c had great cytoprotective effect against oxygen glucose deprived Neuro2a cells. Intravenous administration of RVG-ExoNR2B9c 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-ExoNR2B9c have the potential to be translated both as therapeutic agent as well as cargo delivery system to the brain for the treatment of TBI.

QbD-Based Fabrication of Biomimetic Hydroxyapatite Embedded Gelatin Nanoparticles for Localized Drug Delivery against Deteriorated Arthritic Joint Architecture.

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.

A responsive cascade drug delivery scaffold adapted to the therapeutic time window for peripheral nerve injury repair.

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.

Intranasal administration of innovative triamcinolone acetonide encapsulated cubosomal in situ gel: formulation and characterization.

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.

Construction and efficacy evaluation of chitosan-based nanoparticles for colon-targeted release of linoleic acid in rat pups.

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.

Selective Endocytic Uptake of Targeted Liposomes Occurs within a Narrow Range of Liposome Diameters.

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.

Diethylaminoethyl-dextran and monocyte cell membrane coated 1,8-cineole delivery system for intracellular delivery and synergistic treatment of atherosclerosis.

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.

Enhanced mechanical properties and biocompatibility of bacterial cellulose composite films with inclusion of 2D MoS2 and helical carbon nanotubes for use as antimicrobial drug carriers.

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 (MoS2) 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/MoS2/HCNTs composite films are enhanced due to the synergistic effect of MoS2 and HCNTs embedded in the BC films. The MoS2/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/MoS2/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/MoS2/HCNTs films are thus potential BC-based candidates as biocompatible robust antibiotic carriers.

Recent advances in natural polysaccharides against hepatocellular carcinoma: A review.

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.