Chitosan-coated bovine serum albumin nanoparticles for topical tetrandrine delivery in glaucoma: in vitro and in vivo assessment.

Glaucoma is one of the leading causes of blindness. Therapies available suffer from several drawbacks including low bioavailability, repeated administration and poor patient compliance with adverse effects thereafter. In this study, bovine serum albumin nanoparticles (BSA-NPs) coated with chitosan(CS) were developed for the topical delivery of tetrandrine (TET) for glaucoma management. Optimized nanoparticles were prepared by desolvation. pH, BSA, CS and cross-linking agent concentrations effects on BSA-NPs colloidal properties were investigated. CS-BSA-NPs with particle size 237.9 nm and zeta potential 24 mV was selected for further evaluation. EE% exceeded 95% with sustained release profile. In vitro mucoadhesion was evaluated based on changes in viscosity and zeta potential upon incubation with mucin. Ex vivo transcorneal permeation was significantly enhanced for CS coated formulation. In vitro cell culture studies on corneal stromal fibroblasts revealed NPs biocompatibility with enhanced cellular uptake and improved antioxidant and anti-proliferative properties for the CS-coated formulation. Moreover, BSA-NPs were nonirritant as shown by HET-CAM test. Also, bioavailability in rabbit aqueous humor showed 2-fold increase for CS-TET-BSA-NPs compared to TET with a sustained reduction in intraocular pressure in a rabbit glaucoma model. Overall, results suggest CS-BSA-NPs as a promising platform for topical ocular TET delivery in the management of glaucoma.

3D printed bioinspired scaffolds integrating doxycycline nanoparticles: Customizable implants for in vivo osteoregeneration.

3D printing has revolutionized pharmaceutical research, with applications encompassing tissue regeneration and drug delivery. Adopting 3D printing for pharmaceutical drug delivery personalization via nanoparticle-reinforced hydrogel scaffolds promises great regenerative potential. Herein, we engineered novel core/shell, bio-inspired, drug-loaded polymeric hydrogel scaffolds for pharmaceutically personalized drug delivery and superior osteoregeneration. Scaffolds were developed using biopolymeric blends of gelatin, polyvinyl alcohol and hyaluronic acid and integrated with composite doxycycline/hydroxyapatite/polycaprolactone nanoparticles (DX/HAp/PCL) innovatively via 3D printing. The developed scaffolds were optimized for swelling pattern and in-vitro drug release through tailoring the biphasic microstructure and wet/dry state to attain various pharmaceutical personalization platforms. Freeze-dried scaffolds with nanoparticles reinforcing the core phase (DX/HAp/PCL-LCS-FD) demonstrated favorably controlled swelling, preserved structural integrity and controlled drug release over 28 days. DX/HAp/PCL-LCS-FD featured double-ranged pore size (90.4 ± 3.9 and 196.6 ± 38.8 µm for shell and core phases, respectively), interconnected porosity and superior mechanical stiffness (74.5 ± 6.8 kPa) for osteogenic functionality. Cell spreading analysis, computed tomography and histomorphometry in a rabbit tibial model confirmed osteoconduction, bioresorption, immune tolerance and bone regenerative potential of the original scaffolds, affording complete defect healing with bone tissue. Our findings suggest that the developed platforms promise prominent local drug delivery and bone regeneration.

Thymoquinone and Curcumin Defeat Aging-Associated Oxidative Alterations Induced by D-Galactose in Rats' Brain and Heart.

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.

Engineering 3D-printed core-shell hydrogel scaffolds reinforced with hybrid hydroxyapatite/polycaprolactone nanoparticles for in vivo bone regeneration.

The versatility of 3D printing has rendered it an indispensable tool for the fabrication of composite hydrogel scaffolds, offering bone biomimetic features through inorganic and biopolymeric components as promising platforms for osteoregeneration. In this work, extrusion-based 3D printing was employed for the realization of osteoconductive composite biopolymer-based hydrogel scaffolds reinforced with hybrid bioactive hydroxyapatite/polycaprolactone nanoparticles (HAp/PCL NPs) for osteoregeneration. The printing technique was optimized for ink printability and viscosity and crosslinking parameters, where a biopolymeric blend of gelatin, polyvinyl alcohol and hyaluronic acid was developed as innovative plain polymeric ink (PPI). Scaffolds were fabricated by 3D printing adopting a biphasic core/shell geometry, where the core phase of the scaffolds was reinforced with HAp/PCL NPs; the scaffolds were then freeze-dried. Novel composite freeze-dried, loaded-core scaffolds, HAp/PCL NPs-LCS-FD exhibited controlled swelling and maintained structural integrity for 28 days. The developed HAp/PCL NPs-LCS-FD also demonstrated double-ranged pore size, interconnected porosity and efficient mechanical stiffness and strength, favorable for osteoconductive actions. Cell infiltration studies, computed tomography and histomorphometry demonstrated that HAp/PCL NPs-LCS-FD afforded osteoconduction, biodegradation, biocompatibility and bone healing in rabbit tibial model, acting as a template for new bone formation. Our findings suggest that HAp/PCL NPs-LCS-FD could offer prominent bone regeneration and could be involved in various bone defects.

Inhalable Dual-Targeted Hybrid Lipid Nanocore-Protein Shell Composites for Combined Delivery of Genistein and All-Trans Retinoic Acid to Lung Cancer Cells.

Localized pulmonary delivery of anticancer agents to lungs has proven to be pioneering approach for lung cancer therapy. Hybrid lipid nanocore-protein shell nanoparticles (HLPNPs) coloaded with all-trans retinoic acid (ATRA) and genistein (GNS) were prepared via sequential solvent evaporation followed by nanoprecipitation of zein shell onto the lipid core. The outer protein shell of HLPNPs provided additional drug reservoir for encapsulation of ATRA/stearyl amine ion pair and enabled dual tumor-targeting with biotin and ATRA. Enhanced uptake and cytotoxic activity of HLPNPs against A549 lung cancer cells was confirmed. To improve their deep lung deposition, dual-targeted drug-loaded HLPNP nanocomposites were fabricated. The nanocomposites prepared using mannitol/HPßCD/leucine demonstrated favorable aerosolization (MMAD = 2.47 µm and FPF = 70.81%). In vivo, the inhalable nanocomposites were superior to aerosolized or i.v. nanoparticle suspension against lung carcinoma bearing mice. Overall, inhalable dual-targeted HLPNPs nanocomposites provided localized codelivery of GNS and ATRA for lung cancer therapy.

Inhalable Lactoferrin/Chondroitin-Functionalized Monoolein Nanocomposites for Localized Lung Cancer Targeting.

Localized drug delivery to lung cancer can overcome the limitations of systemic nanocarriers including low drug amounts reaching lung tissues and severe off-target toxicity. The current work presented novel inhalable nanocomposites as noninvasive platforms for lung cancer therapy. Nanoparticulate liquid crystals (LCNPs) based on monoolein were developed for synergistic co-encapsulation of the cytotoxic chemotherapeutic drug, pemetrexed, and the phytoherbal drug, resveratrol (PEM-RES-LCNPs). For active tumor targeting, lactoferrin (LF) and chondroitin sulfate (CS), natural polymers with intrinsic tumor-targeting capabilities, were exploited to functionalize the surface of LCNPs using a layer-by-layer (LbL) self-assembly approach. To maximize their deep lung deposition, LF/CS-coated PEM-RES-LCNPs were then microencapsulated within various carriers to obtain inhalable nanocomposites via spray-drying techniques. The inhalable dry powder nanocomposites prepared using a mannitol-inulin-leucine (1:1:1 wt) mixture displayed superior in vitro aerosolization performance (2.72 µm of MMAD and 61.6% FPF), which ensured deep lung deposition. In lung cancer-bearing mice using urethane as a chemical carcinogen, the inhalable LF/CS-coated PEM-RES-LCNP nanocomposites showed superior antitumor activity as revealed by a considerable decrease of the average lung weight, reduced number and diameter of cancerous lung foci, decreased expression of VEGF-1, and increased expression of active caspase-3 as well as reduced Ki-67 expression compared to the spray-dried free PEM/RES powder mixture and positive control. Moreover, the in vivo fluorescence imaging confirmed successful lung deposition of the inhalable nanocomposites. Conclusively, the inhalable liquid crystalline nanocomposites elaborated in the current work could open new avenues for noninvasive lung cancer treatment.

Inhalable lactoferrin-chondroitin nanocomposites for combined delivery of doxorubicin and ellagic acid to lung carcinoma.

AIM: The use of inhalable nanomedicines can overcome the Enhanced permeation and retention effect (EPR)-associated drawbacks in lung cancer therapy via systemic nanomedicines. METHODS: We developed a lactoferrin-chondroitin sulfate nanocomplex for the co-delivery of doxorubicin and ellagic acid nanocrystals to lung cancer cells. Then, the nanocomplex was converted into inhalable nanocomposites via spray drying. RESULTS: The resulting 192.3 nm nanocomplex exhibited a sequential faster release of ellagic acid, followed by doxorubicin. Furthermore, the nanocomplex demonstrated superior cytotoxicity and internalization into A549 lung cancer cells mediated via Tf and CD44 receptors. The inhalable nanocomposites exhibited deep lung deposition (89.58% fine particle fraction [FPF]) with powerful antitumor efficacy in lung cancer bearing mice. CONCLUSION: Overall, inhalable lactoferrin-chondroitin sulfate nanocomposites would be a promising carrier for targeted drug delivery to lung cancer.

Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy.

Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200 nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over-expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112 µm) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy.

Inhalable multi-compartmental phospholipid enveloped lipid core nanocomposites for localized mTOR inhibitor/herbal combined therapy of lung carcinoma.

Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28 µm and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.