The interplay of solvent-drug-protein interactions during albumin nanoparticles formulations for temozolomide delivery to brain cancer cells.

OBJECTIVES: Temozolomide (TMZ), the first line for glioma therapy, suffers from stability at physiological pH. TMZ was selected as a challenging model drug for loading into human serum albumin nanoparticles (HSA NPs). Our aim is to optimise the conditions for TMZ loading into HSA NPs while ensuring TMZ stability. METHODS: Blank and TMZ-HSA NPs were fabricated using the de-solvation technique and the effect of different formulation parameters was evaluated. KEY FINDINGS: For blank NPs, crosslinking time had no significant effect on NPs' size while acetone produced significantly smaller particles than ethanol. Upon drug loading, though TMZ was stable in acetone and ethanol as single agents yet, ethanol-based NPs showed misleadingly high EE% due to drug instability in ethanol formulations as evident by the UV spectrum.The optimum conditions for drug-loaded particles were: 10 mg/ml HSA, 4 mg TMZ using acetone, yielded NPs with 145 nm in diameter, ξ of -16.98 mV and 0.16% DL. The selected formula reduced the cell viabilities of GL261 glioblastoma cells and BL6 glioblastoma stem cells to 61.9% and 38.3%, respectively. CONCLUSIONS: Our results corroborated that careful manipulation of TMZ formulation processing parameters is crucial for encapsulating such chemically unstable dug while simultaneously ensuring its chemical stability.

Hyaluronic acid-entecavir conjugates-core/lipid-shell nanohybrids for efficient macrophage uptake and hepatotropic prospects.

Drug covalently bound to polymers had formed, lately, platforms with great promise in drug delivery. These drug polymer conjugates (DPC) boosted drug loading and controlled medicine release with targeting ability. Herein, the ability of entecavir (E) conjugated to hyaluronic acid (HA) forming the core of vitamin E coated lipid nanohybrids (EE-HA LPH), to target Kupffer cells and hepatocyte had been proved. The drug was associated to HA with efficiency of 93.48 ± 3.14 % and nanohybrids loading of 22.02 ± 2.3 %. DiI labelled lipidic nanohybrids improved the macrophage uptake in J774 cells with a 21 day hepatocytes retention post intramuscular injection. Finally, in vivo biocompatibility and safety with respect to body weight, organs indices and histopathological alterations were demonstrated. Coating with vitamin E and conjugation of E to HA (a CD44 ligand), could give grounds for prospective application for vectored nano-platform in hepatitis B.

A natural protein based platform for the delivery of Temozolomide acid to glioma cells.

Glioblastoma is one of the most difficult to treat cancers with poor prognosis and survival of around one year from diagnosis. Effective treatments are desperately needed. This work aims to prepare temozolomide acid (TMZA) loaded albumin nanoparticles, for the first time, to target glioblastoma (GL261) and brain cancer stem cells (BL6). TMZA was loaded into human serum albumin nanoparticles (HSA NPs) using the desolvation method. A response surface 3-level factorial design was used to study the effect of different formulation parameters on the drug loading and particle size of NPs. The optimum conditions were found to be: 4 mg TMZA with 0.05% sodium cholate. This yielded NPs with particle size and drug loading of 111.7 nm and 5.5% respectively. The selected formula was found to have good shelf life and serum stability but with a relatively fast drug release pattern. The optimized NPs showed excellent cellular uptake with âˆ¼ 50 and 100% of cells were positive for NP uptake after 24 h incubation with both GL261 and BL6 glioblastoma cell lines, respectively. The selected formula showed high cytotoxicity with Ì´ 20% cell viability at 1 mM TMZA after 72 h incubation time. Finally, the fluorescently labelled NPs showed co-localization with the bioluminescent syngeneic BL6 intra-cranial tumour mouse model after intravenous administration.

Moxifloxacin-loaded in situ synthesized Bioceramic/Poly(L-lactide-co-ε-caprolactone) composite scaffolds for treatment of osteomyelitis and orthopedic regeneration.

High local intraosseous levels of antimicrobial agents are required for adequate long-term treatment of chronic osteomyelitis (OM). In this study, biodegradable composite scaffolds of poly-lactide-co-ε-caprolactone/calcium phosphate (CaP) were in-situ synthesized using two different polymer grades and synthesis pathways and compared to composites prepared by pre-formed (commercially available) CaP for delivery of the antibiotic moxifloxacin hydrochloride (MOX). Phase identification and characterization by Fourier transform infra-red (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) confirmed the successful formation of different CaP phases within the biodegradable polymer matrix. The selected in-situ formed CaP scaffold showed a sustained release for MOX for six weeks and adequate porosity. Cell viability study on MG-63 osteoblast-like cells revealed that the selected composite scaffold maintained the cellular proliferation and differentiation. Moreover, it was able to diminish the bacterial load, inflammation and sequestrum formation in the bones of OM-induced animals. The results of the present work deduce that the selected in-situ formed CaP composite scaffold is a propitious candidate for OM treatment, and further clinical experiments are recommended.

Investigating the Internalization and COVID-19 Antiviral Computational Analysis of Optimized Nanoscale Zinc Oxide.

Global trials are grappling toward identifying prosperous remediation against the ever-emerging and re-emerging pathogenic respiratory viruses. Battling coronavirus, as a model respiratory virus, via repurposing existing therapeutic agents could be a welcome move. Motivated by its well-demonstrated curative use in herpes simplex and influenza viruses, utilization of the nanoscale zinc oxide (ZnO) would be an auspicious approach. In this direction, ZnO nanoparticles (NPs) were fabricated herein and relevant aspects related to the formulation such as optimization, structure, purity, and morphology were elucidated. In silico molecular docking was conducted to speculate the possible interaction between ZnO NPs and COVID-19 targets including the ACE2 receptor, COVID-19 RNA-dependent RNA polymerase, and main protease. The cellular internalization of ZnO NPs using human lung fibroblast cells was also assessed. Optimized hexagonal and spherical ZnO nanostructures of a crystallite size of 11.50 ± 0.71 nm and positive charge were attained. The pure and characteristic hexagonal wurtzite P63mc crystal structure was also observed. Interestingly, felicitous binding of ZnO NPs with the three tested COVID-19 targets, via hydrogen bond formation, was detected. Furthermore, an enhanced dose-dependent cellular uptake was demonstrated. The obtained results infer a rationale, awaiting validation from further biological and therapeutic studies.

Bioinspired lipid-polysaccharide modified hybrid nanoparticles as a brain-targeted highly loaded carrier for a hydrophilic drug.

Lipid-polysaccharide modified biohybrid nanoparticles (NPs) are eminent drug carriers for brain targeting, owing to their ability to prolong the circulation time and penetrate the blood brain barrier (BBB). Biohybrid NPs particular interest arises from their potential to mimic biological components. Herein, we prepared bioinspired lipid polymeric NPs, either naked or surface modified by a synthesized biocompatible dextran-cholic acid (DxC). The nanoprecipitation method was tailored to allow the assembly of the multicomponent NPs in a single step. Modulating the solvent/antisolvent system provided lipid polymer hybrid NPs in the size of 111.6 ± 11.4 nm size. The NPs encapsulated up to 92 ± 1.2% of a hydrophilic anti-Alzheimer drug, rivastigmine (Riv). The brain uptake, biodistribution and pharmacokinetics studies, proved the efficient fast penetration of the bioinspired surface modified NPs to the brain of healthy albino rats. The modified nanocarrier caused a 5.4 fold increase in brain targeting efficiency compared to the drug solution. Furthermore, the presence of DxC increased Riv's brain residence time up to 40 h. The achieved results suggest that the fabricated biohybrid delivery system was able to circumvent the BBB and is expected to minimize Riv systemic side effects.

Polypeptide and glycosaminoglycan polysaccharide as stabilizing polymers in nanocrystals for a safe ocular hypotensive effect.

Improved ocular delivery of a poorly soluble anti-glaucoma drug, acetazolamide (ACZ), in a stable nanosuspension (NS) was the main target of the study. The anionic polypeptide, poly-γ-glutamic acid (PG) and the glycosaminoglycan, hyaluronic acid, were used to stabilize ACZ-NS prepared using the antisolvent precipitation (AS-PT) coupled with sonication technique. To endue in site biocompatibility with high tolerability, soya lecithin (SL) phospholipid has been also combined with polyvinyl alcohol (PVA). NS with uniform PS in the range 100-300 nm, high ζ > ±20 mV, and enhanced saturation solubility were produced. Targeting solvent removal with control on future particle growth, post-production processing of NS was done using spray drying. The carriers' composition and amount relative to ACZ-NS were optimized to allow for the production of a redispersible dry crystalline powder. Particles crystallinity was confirmed using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) in liquid and spray dried NS. The modified Draize test proved the safety and tolerability following application to rabbit eyes accompanying an efficient ocular hypotensive activity using a steroid glaucoma model.

Novel thymoquinone lipidic core nanocapsules with anisamide-polymethacrylate shell for colon cancer cells overexpressing sigma receptors.

The biggest challenge in colorectal cancer therapy is to avoid intestinal drug absorption before reaching the colon, while focusing on tumor specific delivery with high local concentration and minimal toxicity. In our work, thymoquinone (TQ)-loaded polymeric nanocapsules were prepared using the nanoprecipitation technique using Eudragit S100 as polymeric shell. Conjugation of anisamide as a targeting ligand for sigma receptors overexpressed by colon cancer cells to Eudragit S100 was carried out via carbodiimide coupling reaction, and was confirmed by thin layer chromatography and 1H-NMR. TQ nanocapsules were characterized for particle size, surface morphology, zeta potential, entrapment efficiency % (EE%), in vitro drug release and physical stability. A cytotoxicity study on three colon cancer cell lines (HT-29, HCT-116, Caco-2) was performed. Results revealed that the polymeric nanocapsules were successfully prepared, and the in vitro characterization showed a suitable size, zeta potential, EE% and physical stability. TQ exhibited a delayed release pattern from the nanocapsules in vitro. Anisamide-targeted TQ nanocapsules showed higher cytotoxicity against HT-29 cells overexpressing sigma receptors compared to their non-targeted counterparts and free TQ after incubation for 48 h, hence delineating anisamide as a promising ligand for active colon cancer targeting.

Chitosan-calcium phosphate composite scaffolds for control of post-operative osteomyelitis: Fabrication, characterization, and in vitro-in vivo evaluation.

Osteomyelitis is a progressive inflammatory disease requiring prolonged systemic treatment with high antibiotic doses, and is very challenging to be treated. The use of locally applied antibiotics loaded on a biodegradable carrier at surgery sites is hypothesized to prevent post-operative osteomyelitis, while providing site-specific drug release. In this work, chitosan-based calcium phosphate composites were prepared and loaded with moxifloxacin hydrochloride. The in-situ formation of calcium phosphates within the composite was experimentally confirmed by Fourier transform infra-red spectroscopy, X-ray powder diffraction, and scanning electron microscopy. Results showed that the composites provided complete drug release over three days, and the selected composite formulation induced differentiation and proliferation of osteoblasts, while reducing bacterial count, inflammation and intra-medullary fibrosis in bone tissue specimens of osteomyelitis-induced animal model. Hence, we can conclude that the in situ prepared antibiotic-loaded calcium phosphate chitosan composite is promising in preventing post-operative osteomyelitis, and is worthy of clinical experimentation.

Near IR responsive targeted integrated lipid polymer nanoconstruct for enhanced magnolol cytotoxicity in breast cancer.

Advances in cancer nanotechnology aim at improving specificity and effectiveness for tumor treatment. Amalgamation of different treatment modalities is expected to provide better cancer combating. Herein, We developed a long circulating nanocarrier comprising trastuzumab (TZB) surface modified polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) co-encapsulating magnolol (Mag) and gold nanoparticles (GNPs). A modified single step nanoprecipitation method was adopted ensuring particle coating with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) while co-encapsulating GNPs. TZB was then anchored on NPs surface using a carbodiimide chemistry. The cytotoxicity of the developed system was evaluated with and without photothermal irradiation. NPs cellular uptake was then followed using confocal microscopical imaging. A hybrid matrix composed of PLGA/TPGS and surface decorated with TZB with a conjugation efficiency of ˃65%, was confirmed via FTIR, 1HNMR. GNPs could only be included in the NPs, when placed in the organic phase as evidenced by the shifted GNPs surface plasmonic resonance and confirmed via imaging coupled with energy dispersive X-ray analysis. Optimized NPs (136.1 ± 1.3 nm, -8.2 ± 1 mV and Mag encapsulation efficiency of 81.4 ± 1.8%) were able to boost Mag cytotoxicity on breast cancer cells while providing a selective multifunctional therapy with an added photothermal effect.

An integrated vitamin E-coated polymer hybrid nanoplatform: A lucrative option for an enhanced in vitro macrophage retention for an anti-hepatitis B therapeutic prospect.

A platform capable of specifically delivering an antiviral drug to the liver infected with hepatitis B is a major concern in hepatology. Vaccination has had a major effect on decreasing the emerging numbers of new cases of infection. However, the total elimination of the hepatitis B virus from the body requires prolonged therapy. In this work, we aimed to target the liver macrophages with lipid polymer hybrid nanoparticles (LPH), combining the merit of polymeric nanoparticles and lipid vesicles. The hydrophilic antiviral drug, entecavir (E), loaded LPH nanoparticles were optimized and physicochemically characterized. A modulated lipidic corona, as well as, an additional coat with vitamin E were used to extend the drug release enhance the macrophage uptake. The selected vitamin E coated LPH nanoparticles enriched with lecithin-glyceryl monostearate lipid shell exhibited high entrapment for E (80.47%), a size ≤ 200 nm for liver passive targeting, extended release over one week, proven serum stability, retained stability after refrigeration storage for 6 months. Upon macrophage uptake in vitro assessment, the presented formulation displayed promising traits, enhancing the cellular retention in J774 macrophages cells. In vivo and antiviral activity futuristic studies would help in the potential application of the ELPH in hepatitis B control.

A Tailored Thermosensitive PLGA-PEG-PLGA/Emulsomes Composite for Enhanced Oxcarbazepine Brain Delivery via the Nasal Route.

The use of nanocarrier delivery systems for direct nose to brain drug delivery shows promise for achieving increased brain drug levels as compared to simple solution systems. An example of such nanocarriers is emulsomes formed from lipid cores surrounded and stabilised by a corona of phospholipids (PC) and a coating of Tween 80, which combines the properties of both liposomes and emulsions. Oxcarbazepine (OX), an antiepileptic drug, was entrapped in emulsomes and then localized in a poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymer thermogel. The incorporation of OX emulsomes in thermogels retarded drug release and increased its residence time (MRT) in rats. The OX-emulsome and the OX-emulsome-thermogel formulations showed in vitro sustained drug release of 81.1 and 53.5%, respectively, over a period of 24 h. The pharmacokinetic studies in rats showed transport of OX to the systemic circulation after nasal administration with a higher uptake in the brain tissue in case of OX-emulsomes and highest MRT for OX-emulsomal-thermogels as compared to the IN OX-emulsomes, OX-solution and Trileptal® suspension. Histopathological examination of nasal tissues showed a mild vascular congestion and moderate inflammatory changes around congested vessels compared to saline control, but lower toxic effect than that reported in case of the drug solution.

Radiosynthesis, molecular modeling studies and biological evaluation of 99mTc-Ifosfamide complex as a novel probe for solid tumor imaging.

PURPOSE: Ifosfamide as a chemotherapeutic drug is used for the treatment of different cancer types. The purpose of this study is the preparation of 99mTc-ifosfamide complex to be evaluated as a potential candidate for tumor imaging. MATERIALS AND METHODS: The radiolabeling of ifosfamide with technetium-99m was carried out by mixing 4mg ifosfamide and 5 µg of SnCl2.2H2O with 400 MBq Na99mTcO4 at pH 9 for 30 min at room temperature. Computer simulation studies were performed using Accelrys Discovery Studio 2.5 operating system to illustrate the interaction of ifosfamide and 99mTc-ifosfamide complexes with DNA. The in-vivo biodistribution of 99mTc-ifosfamide was studied in tumor-bearing Albino mice. RESULTS: A new 99mTc-ifosfamide complex was synthesized with a good radiochemical yield of 90.3 ± 2.1% under the optimized conditions and exhibited in-vitro stability up to 2 h. Biodistribution studies showed good uptake in tumor site and high uptake in tumor site with T/NT ∼3 after 60 min post-injection. Besides, the molecular docking study confirmed that the complexation of ifosfamide with technetium-99m does not abolish its binding to the target receptor. CONCLUSION: These promising results afford a new radiopharmaceutical that could be used as a potential tumor imaging.

Polysaccharides-based nanocomplexes for the prolonged delivery of enoxaparin: In-vitro and in-vivo evaluation.

Thromboprophylaxis and anticoagulant therapy face serious medical challenges in terms of how crucial it is to maintain therapeutic activity of the anticoagulant agent over the required period of time. Failure to do so will lead to an increased risk of clot propagation if a subtherapeutic drug level is reached. On the other hand, higher-than intended anticoagulation levels might lead to an enhanced risk of hemorrhagic complications. Nanocomplexes (NCs) for the controlled delivery of the antithrombotic Enoxaparin (Enox) with dextran sulfate (DS) and chitosan (CS) were formulated, in an attempt to circumvent therapeutic and compliance challenges associated with the prolonged administration of the current dosage form. Using polyelectrolyte complexation method, various fabrication and formulation parameters were tested. Assessment of ex-vivo stability of selected formulae in rat serum was done prior to determination of their pharmacokinetic profile. High EE% was achieved in all systems prepared. In absence of DS, target size was obtained when 0.54mg/mL CS at an initial pH of 5 and Enox to CS mass ratio of 1:2.5 were employed at room temperature. These parameters were shifted to new optima upon introduction of DS. The anticoagulant activity of NCs (in absence/presence of DS) was significantly sustained compared to the market product (135 and >144h versus 5h, respectively).

Cancer nanotheranostics: A review of the role of conjugated ligands for overexpressed receptors.

Cancer treatment using chemotherapy has many drawbacks because of its non-specificity, in which the chemotherapeutic agent attacks both normal and cancerous cells, leading to severe damage to the normal cells, especially rapidly proliferating ones. Cancer targeting enables the drug to kill only tumor cells without adversely affecting healthy tissues, which leads to the improvement of the patient's well-being. Nanoparticles offer several advantages in drug delivery such as enhancing the solubility of hydrophobic drugs, sustaining their release and prolonging their circulation time. The ability of nanoparticles to specifically target tumor cells makes them a useful delivery system for anticancer agents. The type of the delivery system and formulation additives used can also improve the delivery of the anticancer agent. This review highlights some of the most highly sought receptors to be targeted in selective cancer treatment. It also reports some of the recent advances in cancer targeting using drug-loaded ligand-conjugated nanocarriers.

Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats.

Pulmonary bed can retain microparticles (MP) larger than their capillaries' diameter, hence we offer a promising way for lung passive targeting following intravenous (IV) administration. In this study, enoxaparin (Enox)-albumin microspheres (Enox-Alb MS) were, optimally, developed as lung targeted sustained release MP for IV use. Lung tolerability and targeting efficiency of Enox-Alb MS were tested, and the pharmacokinetic profile following IV administration to albino rats was constructed. In vivo studies confirmed high lung targeting efficiency of Enox-Alb MS with lack of potential tissue toxicity. The anticoagulant activity of the selected Alb MS was significantly sustained for up to 38 h compared to 5 h for the market product. Alb MS are promising delivery carriers for controlled and targeted delivery of Enox to the lungs for prophylaxis and treatment of pulmonary embolism.

Identifying lipidic emulsomes for improved oxcarbazepine brain targeting: In vitro and rat in vivo studies.

Lipid-based nanovectors offer effective carriers for brain delivery by improving drug potency and reducing off-target effects. Emulsomes are nano-triglyceride (TG) carriers formed of lipid cores supported by at least one phospholipid (PC) sheath. Due to their surface active properties, PC forms bilayers at the aqueous interface, thereby enabling encapsulated drug to benefit from better bioavailability and stability. Emulsomes of oxcarbazepine (OX) were prepared, aimed to offer nanocarriers for nasal delivery for brain targeting. Different TG cores (Compritol(®), tripalmitin, tristearin and triolein) and soya phosphatidylcholine in different amounts and ratios were used for emulsomal preparation. Particles were modulated to generate nanocarriers with suitable size, charge, encapsulation efficiency and prolonged release. Cytotoxicity and pharmacokinetic studies were also implemented. Nano-spherical OX-emulsomes with maximal encapsulation of 96.75% were generated. Stability studies showed changes within 30.6% and 11.2% in the size and EE% after 3 months. MTT assay proved a decrease in drug toxicity by its encapsulation in emulsomes. Incorporation of OX into emulsomes resulted in stable nanoformulations. Tailoring emulsomes properties by modulating the surface charge and particle size produced a stable system for the lipophilic drug with a prolonged release profile and mean residence time and proved direct nose-to-brain transport in rats.

Dextran-based Nanocarriers for Delivery of Bioactives.

BACKGROUND: Dextran (DX) is a natural polysaccharide produced in the laboratory by fermentation of sucrose under the effect of the enzyme DX sucrase (1,6-α-D-glucan-α- glucosyltransferase). After harvesting and purification DX is subjected to cracking and separation to obtain the desired molecular weight. METHODS: The hydroxyl groups present in DX offer many sites for derivatization allowing the production of functionalized glycoconjugates biocompatible compound. DX and its derivatives are getting increased attention for use in core decoration or as carriers in novel drug delivery systems. This includes, among others, ion-pairing, self-aggregate, protein and drug conjugates. DX carriers and camouflaged particles will be dealt with in this review to give emphasis on the great versatility of this natural biocompatible polysaccharide. CONCLUSION: With the continuous development in the area of drug delivery, we believe that the unique properties of this versatile nanocarrier platform will elect it as one of the cornerstones of safe nanodelivery systems.

Tunable Biodegradable Nanocomposite Hydrogel for Improved Cisplatin Efficacy on HCT-116 Colorectal Cancer Cells and Decreased Toxicity in Rats.

This work describes the development of a modified nanocomposite thermosensitive hydrogel for controlled cisplatin release and improved cytotoxicity with decreased side effects. The system was characterized in terms of physical properties, morphological architecture and in vitro cisplatin release. Cytotoxicity was tested against human colorectal carcinoma HCT-116. In vivo studies were conducted to evaluate the acute toxicity in terms of rats' survival rate and body weight loss. Nephro and hepatotoxicities were evaluated followed by histopathological alterations of various tissue organs. Nanocomposite thermosensitive hydrogel containing nanosized carrier conferred density and stiffness allowing a zero order drug release for 14 days. Enhanced cytotoxicity with 2-fold decrease in cisplatin IC50 was accomplished. A linear in vivo-in vitro correlation was proved for the system degradation. Higher animal survival rate and lower tissue toxicities proved the decreased toxicity of cisplatin nanocomposite compared to its solution.

Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery.

Low molecular weight heparins (LMWHs), the anticoagulant drug of choice in many indications, had been suggested as novel drug treatment for a range of diseases. Their superior pharmacokinetic properties compared to unfractionated heparin (UFH), motivated scientists to explore new delivery systems for improved therapeutic outcomes. Micro- and nano-carriers, with the versatile nature and characteristics of materials used for their fabrication, are able to surmount the challenges opposed by their native structures. The present review discusses the recent perspectives on the development of micro- and nano-particulate vectors for the delivery of LMWHs through various routes. Special focus on the application of the suggested systems, their characterization and the achieved improved bioavailability will be given throughout the review.