Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia.

Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.

Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Magnetic Lipid-Based hybrid nanosystems: A combined stimuli- responsive nanocarriers for enriched chemotherapeutic potential of L-carnosine in induced breast Ehrlich ascites tumor model.

Magnetic Lipid-Based Hybrid Nanosystems (M-LCNPs) is a novel nanoplatform that can respond to magnetic stimulus and are designed for delivering L-carnosine (CN), a challenging dipeptide employed in the treatment of breast cancer. CN exhibits considerable water solubility and undergoes in-vivo degradation, hence restricting its application. Consequently, it is anticipated that the developed M-LCNPs will enhance the effectiveness of CN. To ensure the physical stability of MNPs, they were initially coated with a mixture of oleic acid and oleylamine before being included in pegylated liquid crystalline nanoparticles (PLCNPs). The proposed M-LCNPs exhibited promising in-vitro characteristics, notably a small particle size (143.5 nm ± 1.25) and a high zeta potential (-39.5 mV ± 1.54), together with superparamagnetic behavior. The in-vitro release profile exhibited a prolonged release pattern. The IC50 values of M-LCNPs were 1.57 and 1.59 times lower than these of the CN solution after 24 and 48 hours, respectively. Female BALB/C female mice with an induced breast cancer (Ehrlich Ascites tumor [EAT] model) were used to study the influence of an external magnetic field on the chemotherapeutic activity and toxicity of CN loaded in the developed M-LCNPs. Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LCNPs and CN solution, as evidenced by a reduction of % tumor growth (11.7%), VEGF levels (22.95 pg/g tissue), and cyclin D1 levels (27.61 ng/g tissue), and an increase in caspase-3 level (28.9 ng/g tissue). Ultimately, the developed stimuli-responsive CN loaded M-LCNPs presented a promising nanoplatform for breast cancer therapy.

Non-invasive caffeinated-nanovesicles as adipocytes-targeted therapy for cellulite and localized fats.

Caffeine (CAF) is a non-selective adenosine A1 receptor antagonist which predominates in fat cells. When CAF binds to adenosine receptors, it increases cyclic adenosine monophosphate; inhibiting adipogenesis and inducing fat lipolysis. Resveratrol (RSV) is an antioxidant polyphenol possessing different anti-obesity mechanisms. Topical application of both hydrophilic CAF and lipophilic RSV is limited. This study aimed to develop novel caffeinated-resveratrol bilosomes (CRB) and caffeine-bilosomes (CB) that could non-invasively target and deposit in fat cells. RSV bilosomes (RB) were prepared as a non-targeted system for comparison. CRB showed nanosize (364.1 nm ±6.5 nm) and high entrapment for both active compounds. Rats treated topically with CRB revealed a significant decrease (P = 0.039) in body weight. Histological analysis of the excised skin demonstrated a reduction in the subcutaneous fatty layer thickness and a decrease in the size of connective tissue-imbedded fat cells. Kidney histological examination of RB-treated rats showed subcapsular tubular epithelial cells with cytoplasmic vacuolation. This reflects a systemic effect of RSV from the non-targeted RB compared to CRB, which had a targeting effect on the adipose tissue. In conclusion, CAF in CRB significantly enhanced RSV deposition in adipose tissue and assisted its local-acting effect for managing obesity and cellulite.

Targeted DPPC/DMPG surface-modified voriconazole lipid nanoparticles control invasive pulmonary aspergillosis in immunocompromised population: in-vitro and in-vivo assessment.

Invasive pulmonary aspergillosis (IPA) is the most devastating Aspergillus-related lung disease. Voriconazole (VRZ) is the first-line treatment against IPA. Despite availability in oral and parenteral dosage forms, risks of systemic toxicity dictate alternative pulmonary administration. Inspired by natural lung surfactants, dipalmitoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DPPC/DMPG) surface-modified lipid nanoparticles (LNPs) were scrutinized for pulmonary administration. DPPC/DMPG-VRZ-LNPs prepared using ultrasonication/thin film hydration were investigated for colloidal properties over 3-month shelf storage. They were stable with a slight change in entrapment efficiency. They provided a sustained VRZ release over 24 h, with a rapid initial release. In vitro aerosolization indicated higher percentages of VRZ deposited on stages corresponding to secondary bronchi and alveolar ducts. Moreover, intrapulmonary administration maintained high lung VRZ concentration (27 ± 1.14 µg/g) after 6 h. A preclinical study using a cyclophosphamide-induced neutropenic rat model demonstrated a 3-fold reduction in BALF-Galactomannan down to 0.515 ± 0.22 µg/L confirming DPPC/DMPG-VRZ-LNPs potential in hyphal growth inhibition. Histopathological examination of infected/nontreated lung sections exhibited dense fungal load inside alveoli and blood vessels indicating massive tissue and angio-invasiveness. Nevertheless, DPPC/DMPG-VRZ-LNPs-treated animals displayed minimal hyphae with no signs of invasiveness. The developed bioinspired nanoparticles serve as prospective bioactive nanocarrier candidates for pulmonary administration of VRZ in the management of IPA.

Controlled release, chitosan-tethered luteolin phytocubosomes; Formulation optimization to in-vivo antiglaucoma and anti-inflammatory ocular evaluation.

A chitosan-coated luteolin-loaded phytocubosomal system was prepared to improve the pharmacodynamic performance of luteolin in the treatment of glaucoma and ocular inflammation after topical ocular administration. Luteolin, a potent anti-oxidant herbal drug with poor aqueous solubility, was complexed with phospholipid. The prepared phytocubosomes were coated with chitosan, producing homogenously distributed nanosized particles (258 ± 9.05 nm) with a positive charge (+49 ± 6.09 mV), improved EE% (96 %), and increased concentration of encapsulated drug to 288 µg/ml. Polarized light microscopy revealed a cubic phase. Chitosan-coated phytocubosomes showed a sustained drug release profile (38 % over 24 h) and improved anti-oxidant activity (IC50 of 32 µg/ml). Ex vivo transcorneal permeation was higher by 3.60 folds compared to luteolin suspension. Irritancy tests confirmed their safety in ocular tissues after single and multiple administrations. The pharmacodynamic studies on glaucomatous rabbit eyes demonstrated 6.46-, 3.88-, and 1.89-fold reductions in IOP of chitosan-coated phytocubosomes compared to luteolin suspension, cubosomes, and phytocubosomes, respectively. Pharmacodynamic anti-inflammatory studies revealed faster recovery capabilities of chitosan-coated phytocubosomes over other formulations. Thus, chitosan-coated phytocubosomes could be a promising ocular hybrid system for delivering herbal lipophilic drugs such as luteolin.

Novel PEGylated cholephytosomes for targeting fisetin to breast cancer: in vitro appraisal and in vivo antitumoral studies.

Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer drug against various cancers including breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work, fisetin is complexed for the first time with soy phosphatidylcholine in the presence of cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve fisetin antitumor activity against breast cancer, stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with hyaluronic acid (HPHY) to allow their orientation to cancer cells through their surface exposed phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (Ë·100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free drug and conventional drug-phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free drug cytotoxicity. TGF-ß1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.

Carrageenan tethered ion sensitive smart nanogel containing oleophytocubosomes for improved ocular luteolin delivery.

Ophthalmic delivery of luteolin (LU) was studied after formulating a carrageenan-based novel ion-sensitive in situ gel (ISG) incorporating oleophytocubosomes for prolonged ocular residence time and improved ocular bioavailability of the poorly absorbed herbal drug luteolin. The prepared oleophytocubosomes and ISG were compared with LU suspension. Optimized oleophytocubosomes possessed small, homogenously distributed negatively charged particles with high entrapment efficiency. Polarized light microscope revealed a cubic phase. Optimized ISG matrix composed of 0.4% kappa carrageenan (KC), and 2% hydroxypropylmethylcellulose (HPMC) demonstrated rapid gelation, high resistance to dilution, increased viscosity after gelation, and strong mucoadhesive properties. oleophytocubosomes exerted improved drug release, while a more sustained release was observed for ISG oleophytocubosomes. The antioxidant activity of both formulations was significantly higher than that of LU suspension. Oleophytocubosome and ISG oleophytocubosome revealed significantly higher apparent permeability coefficients of 3.62 and 2.90 folds, respectively, compared to LU suspension. Irritation tests showed the safety of both formulations for single- and multiple-ocular administration. In-vivo studies demonstrated that the ISG system showed prolonged antiglaucoma effects and a faster anti-inflammatory effect, followed by oleophytocubosomes.

Novel tetrahydrocurcumin integrated mucoadhesive nanocomposite κ-carrageenan/xanthan gum sponges: a strategy for effective local treatment of oral cancerous and precancerous lesions.

Oral cancer is one of the leading causes of death worldwide. Oral precancerous lesions (OPL) are the precursors of oral cancer, with varying degrees of progression. Tetrahydrocurcumin (THC) is a major metabolite of curcumin with superior anticancer properties against various types of cancer. However, THC's clinical outcome is limited by its poor aqueous solubility. Herein, we developed novel mucoadhesive biopolymer-based composite sponges for buccal delivery of THC, exploiting nanotechnology and mucoadhesion for efficient prevention and treatment of oral cancer. Firstly, THC-nanocrystals (THC-NC) were formulated and characterized for subsequent loading into mucoadhesive composite sponges. The anticancer activity of THC-NC was assessed on a human tongue squamous carcinoma cell line (SCC-4). Finally, the chemopreventive activity of THC-NC loaded sponges (THC-NC-S) was examined in DMBA-induced hamster OPL. The selected THC-NC exhibited a particle size of 532.68 ± 13.20 nm and a zeta potential of -46.08 ± 1.12 mV. Moreover, THC-NC enhanced the anticancer effect against SCC-4 with an IC50 value of 80 µg/mL. THC-NC-S exhibited good mucoadhesion properties (0.24 ± 0.02 N) with sustained drug release, where 90% of THC was released over 4 days. Furthermore, THC-NC-S had a magnificent potential for maintaining high chemopreventive activity, as demonstrated by significant regression in the dysplasia degree and a decline in cyclin D1 (control: 40.4 ± 12.5, THC-NC-S: 12.07 ± 5.2), culminating in significant amelioration after 25 days of treatment. Conclusively, novel THC-NC-S represent a promising platform for local therapy of OPL, preventing their malignant transformation into cancer.

Self-assembled fisetin-phospholipid complex: Fisetin-integrated phytosomes for effective delivery to breast cancer.

Nowadays, fisetin (FIS) is extensively studied as potent anticancer surrogate with a multitarget actions against various types of cancers including breast cancer. However, its poor aqueous solubility handicapped its clinical utility. The current work endeavored, for the first time, to develop FIS phytosomes (FIS-PHY) for improving its physicochemical properties and subsequently its anticancer activity. Optimization of FIS- phytosomes involved different preparation techniques (Thin film hydration and ethanol injection) and different FIS: phospholipid molar ratios (1:1, 1:2, and 1:3). Complex formation was confirmed by complexation efficiency, infrared spectroscopy (IR), solubility studies and transmission electron microscope. The optimized FIS-PHY of 1:1 M ratio (PHY1) exhibited a nanometric particle size of 233.01 ± 9.46 nm with homogenous distribution (PDI = 0.27), negative zeta potential of - 29.41 mV, 100% complexation efficiency and controlled drug release over 24 h. In-vitro cytotoxicity study showed 2.5-fold decrease in IC50 of PHY1 compared with free FIS. Also, pharmacodynamic studies confirmed the promoted cytotoxicity of PHY1 against breast cancer through modulating TGF-ß1/MMP-9 molecular pathways of tumorigenesis. Overall, overcoming FIS drawbacks were successfully achieved through development of innovative biocompatible phytosomal system.

Development of Verapamil Hydrochloride-loaded Biopolymer-based Composite Electrospun Nanofibrous Mats: In vivo Evaluation of Enhanced Burn Wound Healing without Scar Formation.

Introduction: Researchers aim for new heights in wound healing to produce wound dressings with unique features. Natural, synthetic, biodegradable, and biocompatible polymers especially in the nanoscale are being employed to support and provide efficient wound management. Economical and environmentally friendly sustainable wound management alternatives are becoming an urgent issue to meet future needs. Nanofibrous mats possess unique properties for ideal wound healing. They mimic the physical structure of the natural extracellular matrix (ECM), promote hemostasis, and gas permeation. Their interconnected nanoporosity prevents wound dehydration and microbial infiltration. Purpose: To prepare and evaluate a novel verapamil HCl-loaded environmentally friendly composite, with biopolymer-based electrospun nanofibers suitable for application as wound dressings providing adequate wound healing with no scar formation. Methods: Composite nanofibers were prepared by electrospinning of a blend of the natural biocompatible polymers, sodium alginate (SA) or zein (Z) together with polyvinyl alcohol (PVA). Composite nanofibers were characterized in terms of morphology, diameter, drug entrapment efficiency, and release. In vivo study of the therapeutic efficacy of verapamil HCl-loaded nanofibers on a Sprague Dawley rat model with dermal burn wound was investigated in terms of percent wound closure, and presence of scars. Results: Combining PVA with SA or Z improved the electrospinnability and properties of the developed nanofibers. Verapamil HCl-loaded composite nanofibers showed good pharmaceutical attributes favorable for wound healing including, fiber diameter ∼150 nm, high entrapment efficiency (∼80-100%) and biphasic controlled drug release for 24 h. In vivo study demonstrated promising potentials for wound healing without scaring. Conclusion: The developed nanofibrous mats combined the beneficial properties of the biopolymers and verapamil HCl to provide an increased functionality by exploiting the unique advantages of nanofibers in wound healing at a small dose proved to be insufficient in case of the conventional dosage form.

Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7,8/NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu, and Tregs/Th17 balance.

Diosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug's bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.

Fucoidan/hyaluronic acid cross-linked zein nanoparticles loaded with fisetin as a novel targeted nanotherapy for oral cancer.

Fisetin (FS) is an anticancer drug having potential role in oral tumors management. However, its clinical application is limited due to its hydrophobicity and instability. Bioactive polymers-based nanosystems have a great potential in cancer therapy. Herein, different biopolymers were selected for their anticancer activity and targeting ability for nanoparticles preparation namely; fucoidan (FU), zein (Zn) and hyaluronic acid (HA). The selected FS-loaded cross-linked Zn nanoparticles (ZFH) which contains HA& FU for Zn nanoparticles stabilization showed the most suitable particle size (196 ± 6.53 nm), mean surface net charge (-38.8 ± 1.47 mV) and entrapment efficiency (98 ± 1.2 %). This is the first study to utilize both HA &FU not only for stabilization but also for dual targeting effect due to their targeting ability to multiple tumor targets. In-vitro anticancer activity of ZHF revealed remarkable uptake by SCC-4 cells with significant cytotoxic action. Further, ZHF was appraised using 4-nitroquinoline 1-oxide (4-NQO)-induced oral cancer in-vivo; ZHF significantly reduced OSCC-specific serum biomarkers levels, histologic tumor grade and increased caspase-3 level. Moreover, potential of destroying two key tumor regulatory cells; TECs and CSCs, was evaluated using their specific markers. The elaborated ZFH nanoparticles could be considered as promising targeted nanotherapy for oral cancer treatment with enhanced efficacy and survival rate.

Development and evaluation of local regenerative biomimetic bone-extracellular matrix scaffold loaded with nano-formulated quercetin for orthopedic fractures.

The prevalence of bone injuries is greatly increasing each year and the proper healing of fractures without any complications is very challenging. Self-setting calcium phosphate cements (CPCs) have attracted great attention as bioactive synthetic bone substitutes. Quercetin (QT) is a multipurposed drug with reported bone-conserving properties. The loading of QT and QT-phospholipid complex within nanostructured lipid carriers (NLC) was proposed to overcome the poor physical properties of the drug and to introduce the use of bioactive excipients as phospholipids and olive oil. The aim of this work was to formulate a regenerative scaffold loaded with nano-formulated QT for local treatment of orthopedic fractures. For the first time, scaffolds composed of brushite CPC were prepared and loaded with quercetin lipid nano-systems. In vitro tests proved that the addition of lipid nano-systems did not deteriorate the properties of CPC where QT-NLC/CPC showed an adequate setting time, appropriate compressive strength, and porosity. The scanning electron microscope confirmed maintenance of nanoparticles integrity within the cement. Using a rat femur bone defect animal model, the histological results showed that the QT-NLC/CPC had a superior bone healing potential compared to crude unformulated QT/CPC. In conclusion, QT-NLC /CPC are promising lipid nano-composite materials that could enhance bone regeneration.

Surface modified genistein phytosome for breast cancer treatment: In-vitro appraisal, pharmacokinetics, and in-vivo antitumor efficacy.

Based on phytosomes advantages over liposomes, hyaluronic acid (HA) with/out pegylated phospholipid was used to develop surface-modified genistein (Gen) phytosome as Gen pegylated hyaluophytosomes (G-PHA) and Gen hyaluophytosomes (G-HA) as novel delivery systems for breast cancer treatment. In this study, in-vitro characterization of G-HA and G-PHA shows PS 144.2 ±1.266 nm and 220.3 ±2.51 nm, ZP -30.9 ±0.75 and -32.06 ±0.305 respectively. Morphological elucidation shows HA covers the surface of G-HA and the presence of a transparent layer of PEG surrounding G-PHA. In-vitro release shows a significant slow Gen release from G-HA, and G-PHA compared to Gen solution and Gen phytosomes. In-vivo bioavailability data shows improvement in bioavailability for G-HA and G-PHA compared to Gen suspension (AUC0-t: 3.563 ± 0.067, 2.092 ± 0.058, 0.374 ± 0.085 µg/ml*h respectively). Therapeutic evaluation of the prepared targeted formulations was carried out by subcutaneous injection in an EAC-induced breast cancer model in mice. G-HA and G-PHA show a promising chemotherapeutic effect in terms of lowering the tumor size and tumor biomarkers (CEA: -34.6, -44.7 & CA15.3: -77.8, -81.6, respectively). This reduction in their values compared to Gen phytosomes, Gen suspension, and the control group is attributed to high Gen accumulation at the target organ owing to targeting properties of HA that are used in phytosomal surface modification in G-HA. Additionally, the presence of MPEG2000-DSPE in G-PHA tends to improve interstitium lymphatic drainage following SC administration, resulting in maximizing the therapeutic benefits of breast cancer despite the difference in pharmacokinetics behavior compared to G-HA. These formulations can be further studied for metastatic breast cancer.

Pectin coated nanostructured lipid carriers for targeted piperine delivery to hepatocellular carcinoma.

Piperine (PIP) is a herbal drug with well-known anticancer activity against different types of cancer including hepatocellular carcinoma. However, low aqueous solubility and extensive first-pass metabolism limit its clinical use. In this study, positively charged PIP-loaded nanostructured lipid carriers (PIP-NLCs) were prepared via melt-emulsification and ultra-sonication method followed by pectin coating to get novel pectin-coated NLCs (PIP-P-NLCs) targeting hepatocellular carcinoma. Complete in vitro characterization was performed. In addition, cytotoxicity and cellular uptake of nanosystems in HepG2 cells were evaluated. Finally, in vivo anticancer activity was tested in the diethylnitrosamine-induced hepatocellular carcinoma mice model. Successful pectin coating was confirmed by an increased particle size of PIP-NLCs from 150.28 ± 2.51 nm to 205.24 ± 5.13 nm and revered Zeta potential from 33.34 ± 3.52 mV to -27.63 ± 2.05 mV. Nanosystems had high entrapment efficiency, good stability, spherical shape, and sustained drug release over 24 h. Targeted P-NLCs enhanced the cytotoxicity and cellular uptake compared to untargeted NLCs. Furthermore, PIP-P-NLCs improved in vivo anticancer effect of PIP as proved by histological examination of liver tissues, suppression of liver enzymes and oxidative stress environment in the liver, and alteration of cell cycle regulators. To conclude, PIP-P-NLCs can act as a promising approach for targeted delivery of PIP to hepatocellular carcinoma.

Phenytoin-loaded bioactive nanoparticles for the treatment of diabetic pressure ulcers: formulation and in vitro/in vivo evaluation.

Drug repurposing offers the chance to explore the full potential of existing drugs while reducing drug development time and costs. For instance, the anticonvulsant drug phenytoin (PHT) has been investigated for its wound healing properties. However, its poor solubility and variability of doses used topically limit its use. Hence, the aim of this study was to improve the properties and wound healing efficacy of PHT for the treatment of diabetic bedsores. PHT was encapsulated, using a modified ionic gelation method, in either positively or negatively charged chitosan-alginate nanoparticles (NPs), which possess previously demonstrated wound healing potential. These NPs were characterized by transmission electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. PHT-loaded NPs were evaluated in vivo for their pressure ulcers' healing potential using diabetic rats. The prepared NPs, especially the positively charged particles, exhibited superior wound healing efficacy compared to PHT suspension, with respect to healing rates, granulation tissue formation, tissue maturation, and collagen content. The positively charged NPs resulted in a 56.54% wound closure at day 7, compared to 37% for PHT suspension. Moreover, skin treated with these NPs showed a mature dermis structure with skin appendages, which were absent in all other groups, in addition to the highest collagen content of 63.65%. In conclusion, the use of a bioactive carrier enhanced the healing properties of PHT and allowed the use of relatively low doses of the drug. Our findings suggest that the prepared NPs offer an effective antibiotic-free delivery system for diabetic wound healing applications.

Chondroitin sulfate-functionalized lipid nanoreservoirs: a novel cartilage-targeting approach for intra-articular delivery of cassic acid for osteoarthritis treatment.

Novel intra-articular nanoreservoirs were implemented employing different cartilage targeting approaches to improve cartilage bioavailability of a chondroprotective drug, cassic acid (CA), for effective amelioration of cartilage deterioration off-targeting CA gastrointestinal disorders. Herein, we compared active cartilage-targeting approach via chondroitin sulfate (CHS) functionalization versus passive targeting using positively charged nanoparticles to target negatively charged cartilage matrix. Firstly, CA integrated nanoreservoirs (CA-NRs) were fabricated based on ionic conjugation between CA and cationic hydrophobic surface modifier octadecylamine (ODA) and were further functionalized with CHS to develop CHS-CA-NRs. Confocal laser microscope was used to visualize the accumulation of nanoparticles into the cartilage tissue. Both targeting approaches promoted CA local cartilage availability and prolonged its residence time. Compared to passive targeted CA-NRs, active targeted CHS-CA-NRs showed higher fluorescence signals in proximity to and inside chondrocytes which lasted for up to 21 days. In MIA-osteoarthritic rats, CHS-CA-NRs showed superior antiosteoarthritic activity, exhibiting highest cartilage repair compared to CA-NRs. Additionally, CHS-CA-NRs significantly inhibited OA inflammatory cytokine, degradation enzyme and oxidative stress and improved cartilage matrix biosynthesis. Conclusively, CHS-CA-NRs improved OA repair showing a superior efficacy for articular cartilage targeting with CHS which could be a potential advance for OA therapy.

Cationic nanocarrier of rhein based on hydrophobic ion pairing approach as intra-articular targeted regenerative therapy for osteoarthritis.

Cartilage deterioration is the hallmark of osteoarthritis (OA). Rapid clearance of intra-articularly injected drugs and inherent cartilage barrier properties represent enormous challenges facing the effective local OA therapy. Rhein (RH), a dihydroxy-anthraquinone acid molecule, possess a potential chondroprotective effect. However, RH suffers from poor oral bioavailability besides its gastrointestinal side effects. Herein, for the first time, we exploited cationic carriers to target anionic cartilage matrix to create a RH-reservoir within the cartilage matrix, improving RH therapeutic efficacy with reduced side effects. Firstly, we improved RH lipophilic characteristics employing hydrophobic ion pairing (HIP) to be efficiently loaded within lipid nanoparticles with slow-release properties. RH-HIP integrated solid lipid nanoparticles (RH-SLNs) rapidly penetrated through cartilage tissue and lasted for 3 weeks into healthy and arthritic rat joints. Furthermore, RH-SLNs significantly inhibited inflammatory response, oxidative stress and cartilage deterioration in MIA-arthritic rats. In conclusion, intra-articular cationic RH-SLNs represented a meaningful step towards OA therapy.