Fabrication of Ciprofloxacin-Loaded Sodium Alginate Nanobeads Coated with Thiol-Anchored Chitosan Using B-390 Encapsulator Following Optimization by DoE.

Most infectious diseases of the gastrointestinal tract can easily be treated by exploiting the already available antibiotics with the change in administration approach and delivery system. Ciprofloxacin (CIP) is used as a drug of choice for many bacterial infections; however, long-term therapy and off-site drug accumulation lead to an increased risk of tendinitis and peripheral neuropathy. To overcome this issue, nanotechnology is being exploited to encapsulate antibiotics within polymeric structures, which not only facilitates dose maintenance at the infection site but also limits off-site side effects. Here, sodium alginate (SA) and thiol-anchored chitosan (TC) were used to encapsulate CIP via a calcium chloride (CaCl2) cross-linker. For this purpose, the B-390 encapsulator was employed in the preparation of nanobeads using a simple technique. The hydrogel-like sample was then freeze-dried, using trehalose or mannitol as a lyoprotectant, to obtain a fine dry powder. Design of Experiment (DoE) was utilized to optimize the nanobead production, in which the influence of different independent variables was studied for their outcome on the polydispersity index (PDI), particle size, zeta potential, and percentage encapsulation efficiency (% EE). In vitro dissolution studies were performed in simulated saliva fluid, simulated gastric fluid, and simulated intestinal fluid. Antibacterial and anti-inflammatory studies were also performed along with cytotoxicity profiling. By and large, the study presented positive outcomes, proving the advantage of using nanotechnology in fabricating new delivery approaches using already available antibiotics.

Holistic Study Design Following Quality by Design Approach for Fabrication of Hybrid Polymeric Nanoparticulate Based Dry Powders as Carriers for Ciprofloxacin.

Resistance to antibiotics such as Ciprofloxacin (CIP) is becoming a critical issue and needs to be addressed globally. CIP is widely used because of manifold uses; however, the long-term therapy poses serious health risks including FDA black box warnings such as tendinitis and peripheral neuropathy. Therefore, nanotechnology-based products can be an effective measure to improve therapeutic outcomes by maintaining the dose at the target site while reducing the dose-dependent toxicity. Biodegradable and biocompatible polymers, Chitosan (CS) and Hyaluronic acid (HA) were used in this work due to their diverse biological characteristics. A simple yet economical ionic gelation method was employed to synthesize nanoparticles with a plexus-like network; nanoplexes, followed by spray-drying to obtain the dry powders to improve stability. Quality by Design (QbD) approach was utilized during the study for robustness and standardization followed by Design of Experiment (DoE) for optimization in a holistic way. The mean particle size of the optimized powder sample was found to be 301.1 nm with a percentage encapsulation efficiency (% EE) of 78.8%. In-vitro dissolution studies corroborated the controlled release of CIP over 48 h. Also, mathematical kinetic modeling was applied to obtain thorough insight into the mechanism of drug release. Moreover, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were presented to be lower in the case of prepared dry powder as compared to CIP, stating that nanotechnology can improve antimicrobial activity.

Spray-Dried Chitosan Hydrogel Particles as a Potential Delivery System for Benzydamine Hydrochloride.

Chitosan, being a biocompatible and mucoadhesive polysaccharide, is one of the most preferred hydrogel-forming materials for drug delivery. The objectives of the present study are to obtain spray-dried microparticles based on low-molecular-weight chitosan and study their potential application as cargo systems for the orally active drug benzydamine hydrochloride. Three types of particles are obtained: raw chitosan particles (at three different concentrations), cross-linked with sodium tripolyphosphate (NaTPP) particles (at three different chitosan:NaTPP ratios), and particles coated with mannitol (at three different chitosan:mannitol ratios), all of them in the size range between 1 and 10 µm. Based on the loading efficiency and the yields of the formulated hydrogel particles, one model of each type is chosen for further investigation of the effect of the cross-linker or the excipient on the properties of the gel structures. The morphology of both empty and benzydamine hydrochloride-loaded chitosan particles was examined by scanning electron microscopy, and it was quite regular and spherical. Interactions and composition in the samples are investigated by Fourier-transformed infrared spectroscopy. The thermal stability and phase state of the drug and drug-containing polymer matrixes were tested by differential scanning calorimetry and X-ray powdered diffraction, revealing that the drug underwent a phase transition. A drug release kinetics study of the chosen gel-based structures in simulated saliva buffer (pH = 6.8) and mathematical modeling of the process were performed, indicating the Weibull model as the most appropriate one.

Process development of inhalation powders containing simvastatin loaded liposomes using spray drying technology.

The development of an inhalation powder (IP) for cancer therapy is desired to improve the therapeutic response and patient compliance. The latest studies highlighted that statins, a class of drugs used in hypercholesterolemia, can have anticancer and antiinflammatory properties. Therefore, the aim of the study was to develop an IP containing liposomes loaded with simvastatin using spray drying technology, as well as to investigate the influence of formulation factors on the quality attributes of the IP by means of experimental design. Results highlighted that the composition of liposomes, namely type of phospholipid and cholesterol concentration, highly influences the quality attributes of IP, and the use of optimal concentrations of excipients, i.e. D-mannitol and L-leucine, is essential to preserve the characteristics of liposomes throughout the spray drying process. The in vitro characterization of the optimal IP formulation revealed that the total percentage of released drug is higher from the IP formulation compared to the powder of active substance (53.38 vs. 42.76%) over a period of six hours, and 39.67% of dry particles have a size less than 5 µm, making them suitable for inhalation. As a conclusion, spray drying technology can be effectively used in the development and preparation of IP containing liposomes.

Biomedical applications of aptamer-modified chitosan nanomaterials: An updated review.

Among polysaccharides of environmental and economic interest, chitosan (CS) is receiving much attention, particularly in the food and biotechnology industries to encapsulate active food ingredients and immobilize enzymes. CS nanoparticles (CS NPs) combine the intrinsic beneficial properties of both natural polymers and nanoscale particles such as quantum size effect, biocompatibility, biodegradability, and ease of modification, possessing enhanced capacity for bioimaging, drug delivery, and biosensing applications. Aptamers are single-stranded oligonucleotides that can fold into predetermined structures and bind to the corresponding biomolecules. They are mainly used as targeting ligands in biosensors, disease diagnostic kits, and treatment strategies. They can deliver contrast agents and drugs into cancer cells and tissues, control microorganism growth, and also precisely target pathogens. Aptamer-conjugated CS NPs can significantly improve the efficacy of conventional therapies, minimize their side effects on normal tissues, and overcome the enhanced permeability retention (EPR) effect. Further, aptamer-conjugated carbohydrate-based nanobiopolymers have shown excellent antibacterial and antiviral properties and can be used to develop novel biosensors for the efficient detection of antibiotics, toxins, and other biomolecules. This updated review aims to provide a comprehensive overview of the bioapplications of aptamer-conjugated CS NPs used as innovative diagnostic and therapeutic platforms, their limitations, and potential future directions.

Dry Powder Comprised of Isoniazid-Loaded Nanoparticles of Hyaluronic Acid in Conjugation with Mannose-Anchored Chitosan for Macrophage-Targeted Pulmonary Administration in Tuberculosis.

Marketed dosage forms fail to deliver anti-tubercular drugs directly to the lungs in pulmonary Tuberculosis (TB). Therefore, nanomediated isoniazid (INH)-loaded dry powder for inhalation (Nano-DPI) was developed for macrophage-targeted delivery in TB. Mannosylated chitosan (MC) and hyaluronic acid (HA) with an affinity for the surface mannose and CD44 receptors of macrophages were used in conjugation to prepare hybrid nanosuspension by ionic gelation method using cross-linker, sodium tri-polyphosphate (TPP) followed by freeze-drying to obtain a dry powder composed of nanoparticles (INH-MC/HA NPs). Nanoformulations were evaluated for aerodynamic characteristics, cytotoxicity, hemocompatibility, macrophage phenotype analysis, and immune regulation. Cellular uptake imaging was also conducted to evaluate the uptake of NPs. The nanopowders did not pose any significant toxicity to the cells, along with good compatibility with red blood cells (RBCs). The pro-inflammatory costimulatory markers were upregulated, demonstrating the activation of T-cell response. Moreover, the NPs did not show any tolerogenic effect on the macrophages. Furthermore, confocal imaging exhibited the translocation of NPs in the cells. Altogether, the findings present that nano-DPI was found to be a promising vehicle for targeting macrophages.

Opportunities and challenges of using high-sensitivity nanobiosensors to detect long noncoding RNAs: A preliminary review.

The two types ofncRNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are responsible for several biological processes within cells, such as the immune responses, cell growth and invasion, and regulation of the cell cycle. Rapidly expanding class of ncRNAs, lncRNAsinteract with other molecules to form chromatin-remodeling complexes. These potential hallmarks of diseases contribute to transcriptional and post-transcriptional regulation of several genes, possibly via cross-talk with other RNAs. Aberrant expression of lncRNAshas drawn increasing attention to the pathophysiology of different diseases, includingcancer and cardiovasculardiseases. Unfortunately, circulating lncRNAs are presented in the bloodstream at very low levels, making sensitive detection difficult. Currently, there are few methods for detecting these ncRNAs from which quantitative real-time-polymerase chain reaction (qRT-PCR) is the most routinely used technique. These techniqueslack sensitivity for intracellular detection of lncRNAs. Moreover, they are tedious and require a large sample size. Currently, nanotechnology has taken over the diagnostic field because of the tunable properties and modification opportunities. Furthermore, these conventional techniques can be merged with nanotechnology to improve detection sensitivity.This review highlights some of the most recent findings on nanotechnology-based methods and possible obstacles intheir application for moreaccurate sensing of lncRNAs.

Active Targeted Nanoparticles for Delivery of Poly(ADP-ribose) Polymerase (PARP) Inhibitors: A Preliminary Review.

Nanotechnology has revolutionized novel drug delivery strategies through establishing nanoscale drug carriers, such as niosomes, liposomes, nanomicelles, dendrimers, polymeric micelles, and nanoparticles (NPs). Owing to their desirable cancer-targeting efficacy and controlled release, these nanotherapeutic modalities are broadly used in clinics to improve the efficacy of small-molecule inhibitors. Poly(ADP-ribose) polymerase (PARP) family members engage in various intracellular processes, including DNA repair, gene transcription, signal transduction, cell cycle regulation, cell division, and antioxidant response. PARP inhibitors are synthetic small-molecules that have emerged as one of the most successful innovative strategies for targeted therapy in cancer cells harboring mutations in DNA repair genes. Despite these advances, drug resistance and unwanted side effects are two significant drawbacks to using PARP inhibitors in the clinic. Recently, the development of practical nanotechnology-based drug delivery systems has tremendously improved the efficacy of PARP inhibitors. NPs can specifically accumulate in the leaky vasculature of the tumor and cancer cells and release the chemotherapeutic moiety in the tumor microenvironment. On the contrary, NPs are usually unable to permeate across the body's normal organs and tissues; hence the toxicity is zero to none. NPs can modify the release of encapsulated drugs based on the composition of the coating substance. Delivering PARP inhibitors without modulation often leads to the toxic effect; therefore, a delivery vehicle is essential to encapsulate them. Various nanocarriers have been exploited to deliver PARP inhibitors in different cancers. Through this review, we hope to cast light on the most innovative advances in applying PARP inhibitors for therapeutic purposes.

A holistic QBD approach to design galactose conjugated PLGA polymer and nanoparticles to catch macrophages during intestinal inflammation.

Recruited macrophages in inflammation attract various ligand-receptor drug delivery approaches. Galactose bound nanocarriers are promising to catch macrophages because of surface-expressed macrophage galactose type-lectin-C (MGL-2) receptor. The present study reported fabrication of galactose conjugated PLGA (GAL-PLGA) polymer and nanoparticles under quality by design (QBD) approach to investigate macrophages targeting potential at inflamed intestine. GAL-PLGA nanoparticles were fabricated through O/W emulsion-evaporation method under QBD approach and Box-Behnken design. Obtained GAL-PLGA nanoparticles have optimum particle size (~118 nm), drug entrapment (87%) and zeta potential (-9.5). TGA, XPRD and FTIR confirmed stability and negate drug-polymer interactions. Further, nanoparticles have considerable hemocompatibility, biocompatibility and cellular uptake; macrophage uptake was inhibited by D-galactose confirming involvement of MGL-2. Moreover, drug retention studies in the DSS-colitis model provide background for potential of nanoparticles to target and reside inflamed intestine. It is concluded that GAL-PLGA nanoparticles are suitable platform to target macrophages at the inflamed intestine through oral route.

Application of Nanotechnology for Sensitive Detection of Low-Abundance Single-Nucleotide Variations in Genomic DNA: A Review.

Single-nucleotide polymorphisms (SNPs) are the simplest and most common type of DNA variations in the human genome. This class of attractive genetic markers, along with point mutations, have been associated with the risk of developing a wide range of diseases, including cancer, cardiovascular diseases, autoimmune diseases, and neurodegenerative diseases. Several existing methods to detect SNPs and mutations in body fluids have faced limitations. Therefore, there is a need to focus on developing noninvasive future polymerase chain reaction (PCR)-free tools to detect low-abundant SNPs in such specimens. The detection of small concentrations of SNPs in the presence of a large background of wild-type genes is the biggest hurdle. Hence, the screening and detection of SNPs need efficient and straightforward strategies. Suitable amplification methods are being explored to avoid high-throughput settings and laborious efforts. Therefore, currently, DNA sensing methods are being explored for the ultrasensitive detection of SNPs based on the concept of nanotechnology. Owing to their small size and improved surface area, nanomaterials hold the extensive capacity to be used as biosensors in the genotyping and highly sensitive recognition of single-base mismatch in the presence of incomparable wild-type DNA fragments. Different nanomaterials have been combined with imaging and sensing techniques and amplification methods to facilitate the less time-consuming and easy detection of SNPs in different diseases. This review aims to highlight some of the most recent findings on the aspects of nanotechnology-based SNP sensing methods used for the specific and ultrasensitive detection of low-concentration SNPs and rare mutations.

Recent Advances in Nanotechnology-Based Diagnosis and Treatments of Human Osteosarcoma.

Osteosarcoma (OSA) is a type of bone cancer that begins in the cells that form bones.OSA is a rare mesenchymal bone neoplasm derived from mesenchymal stem cells. Genome disorganization, chromosomal modifications, deregulation of tumor suppressor genes, and DNA repair defects are the factors most responsible for OSA development. Despite significant advances in the diagnosing and treatment of OSA, patients' overall survival has not improved within the last twenty years. Lately, advances in modern nanotechnology have spurred development in OSA management and offered several advantages to overcome the drawbacks of conventional therapies. This technology has allowed the practical design of nanoscale devices combined with numerous functional molecules, including tumor-specific ligands, antibodies, anti-cancer drugs, and imaging probes. Thanks to their small sizes, desirable drug encapsulation efficiency, and good bioavailability, functionalized nanomaterials have found wide-spread applications for combating OSA progression. This review invokes the possible utility of engineered nanomaterials in OSA diagnosis and treatment, motivating the researchers to seek new strategies for tackling the challenges associated with it.

Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections.

The blood-brain barrier (BBB) is the protective sheath around the brain that protects the sensitive microenvironments of the brain. However, certain pathogens, viruses, and bacteria disrupt the endothelial barrier and cause infection and hence inflammation in meninges. Macromolecular therapeutics are unable to cross the tight junctions, thereby limiting their bioavailability in the brain. Recently, nanotechnology has brought a revolution in the field of drug delivery in brain infections. The nanostructures have high targeting accuracy and specificity to the receptors in the case of active targeting, which have made them the ideal cargoes to permeate across the BBB. In addition, nanomaterials with biomimetic functions have been introduced to efficiently cross the BBB to be engulfed by the pathogens. This review focuses on the nanotechnology-based drug delivery approaches for exploration in brain infections, including meningitis. Viruses, bacteria, fungi, or, rarely, protozoa or parasites may be the cause of brain infections. Moreover, inflammation of the meninges, called meningitis, is presently diagnosed using laboratory and imaging tests. Despite attempts to improve diagnostic instruments for brain infections and meningitis, due to its complicated and multidimensional nature and lack of successful diagnosis, meningitis appears almost untreatable. Potential for overcoming the difficulties and limitations related to conventional diagnostics has been shown by nanoparticles (NPs). Nanomedicine now offers new methods and perspectives to improve our knowledge of meningitis and can potentially give meningitis patients new hope. Here, we review traditional diagnosis tools and key nanoparticles (Au-NPs, graphene, carbon nanotubes (CNTs), QDs, etc.) for early diagnosis of brain infections and meningitis.

Aerodynamic properties and in silico deposition of isoniazid loaded chitosan/thiolated chitosan and hyaluronic acid hybrid nanoplex DPIs as a potential TB treatment.

Existing therapies yield low drug encapsulation or accumulation in the lungs, hence the site-specific drug delivery remains the challenge for tuberculosis. Lately, dry powder inhalers (DPIs) are showing promising drug deposition in the deeper lung tissues. Biocompatible polymers with the ability to naturally recognize and bind to the surface receptors of alveolar macrophages, the reservoir of the causative organism, were selected. DPIs comprised of chitosan (CS)/thiolated chitosan (TC) in conjugation with Hyaluronic acid (HA) were synthesized loaded with isoniazid (INH) by using the Design of Experiment (DoE) approach. Nanosuspensions were prepared by ionic gelation method using cross-linker, sodium-tripolyphosphate (TPP) and were optimized by using Box-Behnken 3-level screening design and later freeze-dried to obtain nanopowders. Physico-chemical compatibility of nanoplex systems was investigated using in-vitro characterization techniques. In-vitro release and permeation studies were correlated in terms of the pattern of drug content dissolved over time. In addition, the cytotoxicity studies on A549 cells demonstrated the safety profile of the nanoplexes. Moreover, in-silico studies and aerodynamic profiles verify the suitability of DPIs for further in-vivo tuberculosis therapeutics. DoE analyses affirmed the lack of linearity in the model for the certain response of studied parameters in a holistic way, which was not possible else ways.

Drug delivery to macrophages: a review of nano-therapeutics targeted approach for inflammatory disorders and cancer.

INTRODUCTION: Macrophages are involved in the normal defense of the body; however, the varying phenotypes of macrophages and imbalance in their ratio lead to the impairment of immune response initiating the production of inflammation. As the role of macrophages in immunological disorders and their surface receptors modulation has already been manifested; hence, macrophages can be exploited to make them a viable candidate for targeted delivery, which was not possible with previously designed conventional therapies for the immune disorders. AREAS COVERED: Nanotechnology is a promising, clear cut, efficient, and adequate approach for targeting macrophages. Literature addresses the receptors available for targeting and the novel small dimensional therapeutic delivery vehicles to target them along with a brief overview of the role of macrophages in these diseases. Furthermore, the patents based on this idea are also listed. EXPERT OPINION: Targeted drug delivery to macrophages should take into consideration the plasticity of macrophages and their modulation over time in the diseases. A cost-effective scale-up method of development will further facilitate the clinical trials. Besides, the implementation of safety guidelines to target macrophages and the studies of long-term effects of targeted approaches in humans would highly encourage the clinical outcomes.

Glycyrrhizic acid-loaded pH-sensitive poly-(lactic-co-glycolic acid) nanoparticles for the amelioration of inflammatory bowel disease.

Aim: To fabricate and evaluate the therapeutic efficacy of glycyrrhizic acid (GA)-loaded pH-sensitive nanoformulations that specifically target and combat mucosal inflammation of the colon. Methods: GA-loaded Eudragit® S100/poly-(lactic-co-glycolic acid) nanoparticles were developed through modified double-emulsion evaporation coupled with solvent evaporation coating techniques and analyzed for physicochemical characteristics, surface chemistry, release kinetics, site-retention and therapeutic effectiveness. Results: Nanoparticles have a particle size of approximately 200 nm, high encapsulation efficiency, desired surface chemistry with pH-dependent and sustained drug release behavior following the Gompertz kinetic model. In vivo retention and therapeutic effectiveness in the inflamed colon tissues were confirmed by macroscopic and microscopic indices, cytokine analysis and antioxidant assays. Conclusion: GA-loaded Eudragit S100/poly-(lactic-co-glycolic acid) nanoparticles could efficiently deliver GA to the colon and ameliorate the mucosal inflammation for a prolonged duration.