Unravelling the role of microneedles in drug delivery: Principle, perspectives, and practices.

In recent year, the research of transdermal drug delivery systems has got substantial attention towards the development of microneedles (MNs). This shift has occurred due to multifaceted advantages of MNs as they can be utilized to deliver the drug deeper to the skin with minimal invasion, offer successful delivery of drugs and biomolecules that are susceptible to degradation in gastrointestinal tract (GIT), act as biosensors, and help in monitoring the level of biomarkers in the body. These can be fabricated into different types based on their applications as well as material for fabrication. Some of their types include solid MNs, hollow MNs, coated MNs, hydrogel forming MNs, and dissolving MNs. These MNs deliver the therapeutics via microchannels deeper into the skin. The coated and hollow MNs have been found successful. However, they suffer from poor drug loading and blocking of pores. In contrast, dissolving MNs offer high drug loading. These MNs have also been utilized to deliver vaccines and biologicals. They have also been used in cosmetics. The current review covers the different types of MNs, materials used in their fabrication, properties of MNs, and various case studies related to their role in delivering therapeutics, monitoring level of biomarkers/hormones in body such as insulin. Various patents and clinical trials related to MNs are also covered. Covered are the major bottlenecks associated with their clinical translation and potential future perspectives.

Harnessing role of sesamol and its nanoformulations against neurodegenerative diseases.

Sesamol is a lignan of sesame seeds and a natural phenolic molecule that has emerged as a useful medical agent. Sesamol is a non-toxic phytoconstituent, which exerts certain valuable effects in the management of cancer, diabetes, cardiovascular diseases, neurodegenerative diseases (NDs), etc. Sesamol is known to depict its neuroprotective role by various mechanisms, such as metabolic regulators, action on oxidative stress, neuroinflammation, etc. However, its poor oral bioavailability, rapid excretion (as conjugates), and susceptibility to gastric irritation/toxicity (particularly in rats' forestomach) may restrict its effectiveness. To overcome the associated limitations, novel drug delivery system-based formulations of sesamol are emerging and being researched extensively. These can conjugate with sesamol and enhance the bioavailability and solubility of free sesamol, along with delivery at the target site. In this review, we have summarized various research works highlighting the role of sesamol on various NDs, including Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Parkinson's disease. Moreover, the formulation strategies and neuroprotective role of sesamol-based nano-formulations have also been discussed.

Role of CRISPR/Cas9 in the treatment of Duchenne muscular dystrophy and its delivery strategies.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder brought on by mutations in the DMD gene, which prevent muscle cells from expressing the dystrophin protein. CRISPR/Cas9 technology has evolved as potential option to treat DMD due to its ability to permanently skip exons, restoring the disrupted DMD reading frame and leading to dystrophin restoration. Even though, having potential to treat DMD, the delivery, safety and efficacy of this technology is still challenging. Several delivery methods, including viral vectors, nanoparticles, and electroporation, have been explored to deliver CRISPR/Cas9 to the targeted cells. Despite the potential of CRISPR/Cas9 technology in the treatment of DMD, several limitations need to be addressed. The off-target effects of CRISPR/Cas9 are a major concern that needs to be addressed to avoid unintended mutations. The delivery of CRISPR/Cas9 to the target cells and the immune response due to the viral vectors used for delivery are a few other limitations. The clinical trials of CRISPR/Cas9 for DMD provide valuable insights into the safety and efficacy of this technology in humans and the limitations that need to be known. Therefore, in this review we insightfully discussed the challenges and limitations of CRISPR/Cas9 in the treatment of DMD and delivery strategies used, and the ongoing efforts to overcome these challenges and restore dystrophin expression in DMD patients in the ongoing trials.

Quality by Design (QbD) Based Method for Estimation of Xanthohumol in Bulk and Solid Lipid Nanoparticles and Validation.

The analytical quality by design (AQbD) approach is utilized for developing and validating the simple, sensitive, cost-effective reverse-phase high performance liquid chromatographic method for the estimation of xanthohumol (XH) in bulk and nanoformulations. The Box-Behnken design (BBD) is applied for method optimization. The mobile phase ratio, pH and flow rate were selected as independent variables, whereas retention time, peak area, peak height, tailing factor, and theoretical plates were selected as dependent variables. The chromatogram of XH obtained under optimized conditions has given optimum conditions such as retention time (5.392 min), peak area (1,226,737 mAU), peak height (90,121 AU), tailing factor (0.991) and theoretical plates (4446.667), which are contoured in the predicted values shown by BBD. Validation of the method has been performed according to ICH Q2(R1) recommendations, using optimized conditions for linearity, limit of detection (LOD) and limit of quantification (LOQ), accuracy, precision, robustness and system suitability. All the values of validation parameters lie within the acceptable limits prescribed by ICH. Therefore, the developed and validated method of XH by the AQbD approach can be applied for the estimation of XH in bulk and various nanoformulations.

Development of Guar Gum-Pectin-Based Colon Targeted Solid Self-Nanoemulsifying Drug Delivery System of Xanthohumol.

Present study deciphers development of oral polysaccharide-based colon targeted solid self-nanoemulsifying drug delivery system (S-SNEDDS) of xanthohumol (XH). Several studies have shown that XH has anti-inflammatory and antioxidant properties, suggesting that it could be a good candidate for the treatment of colorectal diseases (CRD). Despite its potential, XH has a low aqueous solubility. As a result, its bioavailability is constrained by the dissolution rate. The liquid (L)-SNEDDS was constituted using Labrafac PG as oil, Tween 80 as surfactant and Transcutol P as co-surfactant. The L-SNEDDS was then adsorbed onto the surface of guar gum and pectin and developed into S-SNEDDS powder. Ternary phase diagram was used to optimize the process of developing L-SNEDDS. The formulation showed mean droplet size of 118.96 ± 5.94 nm and zeta potential of -19.08 ± 0.95 mV and drug loading of 94.20 ± 4.71%. Dissolution studies carried out in medium containing rat caecal contents (RCC) represented the targeted release of S-SNEDDS powder. It was observed that S-SNEDDS showed less than 10% release XH in initial 5 h and rapid release occurred between the 5th and 10th hour. Results of cytotoxicity studies revealed good cytotoxicity of XH loaded S-SNEDDS for Caco2 cells as compared to raw-XH.

Quality by Design Based Formulation of Xanthohumol Loaded Solid Lipid Nanoparticles with Improved Bioavailability and Anticancer Effect against PC-3 Cells.

Many natural products with greater therapeutic efficacy are limited to target several chronic diseases such as cancer, diabetes, and neurodegenerative diseases. Among the natural products from hops, i.e., Xanthohumol (XH), is a prenylated chalcone. The present research work focuses on the enhancement of the poor oral bioavailability and weak pharmacokinetic profile of XH. We exemplified the development of a Xanthohumol-loaded solid lipid nanoparticles (XH-SLNs) cargo system to overcome the limitations associated with its bioavailability. The XH-SLNs were prepared by a high-shear homogenization/ultrasonication method and graphical, numerical optimization was performed by using Box-Behnken Design. Optimized XH-SLNs showed PS (108.60 nm), PDI (0.22), ZP (-12.70 mV), %EE (80.20%) and an amorphous nature that was confirmed by DSC and PXRD. FE-SEM and HRTEM revealed the spherical morphology of XH-SLNs. The results of release studies were found to be 9.40% in 12 h for naive XH, whereas only 28.42% of XH was released from XH-SLNs. The slow release of drugs may be due to immobilization of XH in the lipid matrix. In vivo pharmacokinetic study was performed for the developed XH-SLNs to verify the enhancement in the bioavailability of XH than naive XH. The enhancement in the bioavailability of the XH was confirmed from an increase in Cmax (1.07-folds), AUC0-t (4.70-folds), t1/2 (6.47-folds) and MRT (6.13-folds) after loading into SLNs. The relative bioavailability of XH loaded in SLNs and naive XH was found to be 4791% and 20.80%, respectively. The cytotoxicity study of naive XH, XH-SLNs were performed using PC-3 cell lines by taking camptothecin as positive control. The results of cytotoxicity study revealed that XH-SLNs showed good cell inhibition in a sustained pattern. This work successfully demonstrated formulation of XH-SLNs with sustained release profile and improved oral bioavailability of XH with good anticancer properties against PC-3 cells.

Bioanalytical Method Development, Validation and Stability Assessment of Xanthohumol in Rat Plasma.

Xanthohumol (XH) a prenylated chalcone has diverse therapeutic effects against various diseases. In the present study, a bioanalytical method was developed for XH in rat plasma using reverse phase high performance liquid chromatography. The validation of the method was performed as per ICH M10 guidelines using curcumin as an internal standard. The Isocratic elution method was used with a run time of 10 min, wherein the mobile phase ratio 0.1% v/v OPA (A): Methanol (B) was 15:85 v/v at flow rate 0.8 mL/min and injection volume of 20 µL. The chromatograms of XH and curcumin was recorded at a wavelength of 370 nm. The retention time for XH and curcumin was 7.4 and 5.8 min, respectively. The spiked XH from plasma was extracted by the protein precipitation method. The developed method was linear with R2 value of 0.9996 over a concentration range of 50-250 ng/mL along with LLOQ. The results of all the validation parameters are found to be within the accepted limits with %RSD value less than 2 and the percentage recovery was found to be greater than 95%. Based on the %RSD and percentage recovery results it was confirmed that the method was precise and accurate among the study replicates. LOD and LOQ values in plasma samples were found to be 8.49 ng/mL and 25.73 ng/mL, respectively. The stability studies like freeze thaw, short term and long-term stability studies were also performed, %RSD and percentage recovery of the XH from plasma samples were within the acceptable limits. Therefore, the developed bioanalytical method can be used effectively for estimation of XH in plasma samples.

Nanoparticle and Nanostructure Synthesis and Controlled Growth Methods.

Nanomaterials are materials with one or more nanoscale dimensions (internal or external) (i.e., 1 to 100 nm). The nanomaterial shape, size, porosity, surface chemistry, and composition are controlled at the nanoscale, and this offers interesting properties compared with bulk materials. This review describes how nanomaterials are classified, their fabrication, functionalization techniques, and growth-controlled mechanisms. First, the history of nanomaterials is summarized and then the different classification methods, based on their dimensionality (0-3D), composition (carbon, inorganic, organic, and hybrids), origin (natural, incidental, engineered, bioinspired), crystal phase (single phase, multiphase), and dispersion state (dispersed or aggregated), are presented. Then, the synthesis methods are discussed and classified in function of the starting material (bottom-up and top-down), reaction phase (gas, plasma, liquid, and solid), and nature of the dispersing forces (mechanical, physical, chemical, physicochemical, and biological). Finally, the challenges in synthesizing nanomaterials for research and commercial use are highlighted.

Review on Nanoparticles and Nanostructured Materials: Bioimaging, Biosensing, Drug Delivery, Tissue Engineering, Antimicrobial, and Agro-Food Applications.

In the last few decades, the vast potential of nanomaterials for biomedical and healthcare applications has been extensively investigated. Several case studies demonstrated that nanomaterials can offer solutions to the current challenges of raw materials in the biomedical and healthcare fields. This review describes the different nanoparticles and nanostructured material synthesis approaches and presents some emerging biomedical, healthcare, and agro-food applications. This review focuses on various nanomaterial types (e.g., spherical, nanorods, nanotubes, nanosheets, nanofibers, core-shell, and mesoporous) that can be synthesized from different raw materials and their emerging applications in bioimaging, biosensing, drug delivery, tissue engineering, antimicrobial, and agro-foods. Depending on their morphology (e.g., size, aspect ratio, geometry, porosity), nanomaterials can be used as formulation modifiers, moisturizers, nanofillers, additives, membranes, and films. As toxicological assessment depends on sizes and morphologies, stringent regulation is needed from the testing of efficient nanomaterials dosages. The challenges and perspectives for an industrial breakthrough of nanomaterials are related to the optimization of production and processing conditions.

Xanthohumol for Human Malignancies: Chemistry, Pharmacokinetics and Molecular Targets.

Xanthohumol (XH) is an important prenylated flavonoid that is found within the inflorescence of Humulus lupulus L. (Hop plant). XH is an important ingredient in beer and is considered a significant bioactive agent due to its diverse medicinal applications, which include anti-inflammatory, antimicrobial, antioxidant, immunomodulatory, antiviral, antifungal, antigenotoxic, antiangiogenic, and antimalarial effects as well as strong anticancer activity towards various types of cancer cells. XH acts as a wide ranging chemopreventive and anticancer agent, and its isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity. The present review focuses on the bioactivity of XH on various types of cancers and its pharmacokinetics. In this paper, we first highlight, in brief, the history and use of hops and then the chemistry and structure-activity relationship of XH. Lastly, we focus on its prominent effects and mechanisms of action on various cancers and its possible use in cancer prevention and treatment. Considering the limited number of available reviews on this subject, our goal is to provide a complete and detailed understanding of the anticancer effects of XH against different cancers.