Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies.

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.

Essential oils for clinical aromatherapy: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aromatherapy, a holistic healing practice utilizing the aromatic essences of plant-derived essential oils, has gained significant attention for its therapeutic potential in promoting overall well-being. Use of phytoconstituent based essential oil has played a significant role in the evolving therapeutic avenue of aromatherapy as a complementary system of medicine. AIM OF THE STUDY: This comprehensive review article aims to explore the usage of essential oils for aromatherapy, shedding light on their diverse applications, scientific evidence, and safety considerations. Furthermore, the growing interest in using essential oils as complementary therapies in conjunction with conventional medicine is explored, underscoring the significance of collaborative healthcare approaches. MATERIALS AND METHODS: Literature search was performed from databases like PubMed, ScienceDirect, Scopus, and Bentham using keywords like Aromatherapy, Aromatic Plants, Essential oils, Phytotherapy, and complementary medicine. The keywords were used to identify literature with therapeutic and mechanistic details of herbal agents with desired action. RESULTS: The integration of traditional knowledge with modern scientific research has led to a renewed interest in essential oils as valuable tools in contemporary healthcare. Various extraction methods used to obtain essential oils are presented, emphasizing their impact on the oil's chemical composition and therapeutic properties. Additionally, the article scrutinizes the factors influencing the quality and purity of essential oils, elucidating the significance of standardization and certification for safe usage. A comprehensive assessment of the therapeutic effects of essential oils is provided, encompassing their potential as antimicrobial, analgesic, anxiolytic, and anti-inflammatory agents, among others. Clinical trials and preclinical studies are discussed to consolidate the existing evidence on their efficacy in treating diverse health conditions, both physical and psychological. Safety considerations are of paramount importance when employing essential oils, and this review addresses potential adverse effects, contraindications, and best practices to ensure responsible usage. CONCLUSIONS: This comprehensive review provides valuable insights into the exploration of essential oils for aromatherapy, emphasizing their potential as natural and potent remedies for a wide range of ailments. By amalgamating traditional wisdom and modern research, this article aims to encourage further investigation into the therapeutic benefits of essential oils while advocating for their responsible and evidence-based incorporation into healthcare practices.

Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance.

Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived from plants that have similar structures and biological effects as human estrogens. These compounds do not directly affect biological functions but can act as agonists or antagonists depending on the level of endogenous estrogen in the body. Phytoestrogens may have an epigenetic mechanism of action independent of estrogen receptors. These compounds are found in more than 300 plant species and are synthesized through the phenylpropanoid pathway, with specific enzymes leading to various chemical structures. Phytoestrogens, primarily phenolic compounds, include isoflavonoids, flavonoids, stilbenes, and lignans. Extensive research in animals and humans has demonstrated the protective effects of phytoestrogens on estrogen-dependent diseases. Clinical trials have also shown their potential benefits in conditions such as osteoporosis, Parkinson's disease, and certain types of cancer. This review provides a concise overview of phytoestrogen classification, chemical diversity, and biosynthesis and discusses the potential therapeutic effects of phytoestrogens, as well as their preclinical and clinical development.

Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Design, development, and technical considerations for dry powder inhaler devices.

The dry powder inhaler (DPI) stands out as a highly patient-friendly and effective pulmonary formulation, surpassing traditional and other pulmonary dosage forms in certain disease conditions. The development of DPI products, however, presents more complexities than that of other dosage forms, particularly in device design and the integration of the drug formulation. This review focuses on the capabilities of DPI devices in pulmonary drug delivery, with a special emphasis on device design and formulation development. It also discusses into the principles of deep lung particle deposition and device engineering, and provides a current overview of the market for DPI devices. Furthermore, the review highlights the use of computational fluid dynamics (CFD) in DPI product design and discusses the regulatory environment surrounding these devices.

Porous microneedle arrays as promising tools for the quantification of drugs in the skin: a proof of concept study.

This study aimed to demonstrate the potential of using porous microneedles (PMNs) as a promising tool for the noninvasive quantification of topically applied pharmaceutical products. We fabricated a porous microneedle (PMN) from a blend of cellulose acetate and dimethyl sulfoxide by casting and phase separation; it was characterized using scanning electron microscopy, Raman spectroscopy, differential scanning calorimetry, and a Texture Analyzer. An ex vivo study was conducted as a proof-of-concept study to assess whether this PMN could be used to quantify drug absorption through the skin after the topical administration of two nonequivalent products of sodium ibuprofen (gel and dissolving microneedles). Three cellulose acetate formulations (PMN1: 37.5%, PMN-2: 44.4%, and PMN-3: 50%) were used to prepare PMN patches; subsequently, these were evaluated for their morphological and insertion properties. Only PMN-2 microneedle patches were chosen to continue with the ex vivo study. The ex vivo study results demonstrated that PMNs could absorb and release sodium ibuprofen (SDIB) and differentiate between two different SDIB topical products. This can be attributed to the porous and interconnected architecture of these microneedles. This developmental study highlights the potential success of such a tool for the quantification of dermal drug concentration and supports moving to in vivo tests.

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients' needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.

Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

A Bilayer Microarray Patch (MAP) for HIV Pre-Exposure Prophylaxis: The Role of MAP Designs and Formulation Composition in Enhancing Long-Acting Drug Delivery.

Microarray patches (MAPs) have shown great potential for efficient and patient-friendly drug delivery through the skin; however, improving their delivery efficiency for long-acting drug release remains a significant challenge. This research provides an overview of novel strategies aimed at enhancing the efficiency of MAP delivery of micronized cabotegravir sodium (CAB Na) for HIV pre-exposure prophylaxis (PrEP). The refinement of microneedle design parameters, including needle length, shape, density, and arrangement, and the formulation properties, such as solubility, viscosity, polymer molecular weight, and stability, are crucial for improving penetration and release profiles. Additionally, a bilayer MAP optimization step was conducted by diluting the CAB Na polymeric mixture to localize the drug into the tips of the needles to enable rapid drug deposition into the skin following MAP application. Six MAP designs were analyzed and investigated with regard to delivery efficiency into the skin in ex vivo and in vivo studies. The improved MAP design and formulations were found to be robust and had more than 30% in vivo delivery efficiency, with plasma levels several-fold above the therapeutic concentration over a month. Repeated weekly dosing demonstrated the robustness of MAPs in delivering a consistent and sustained dose of CAB. In summary, CAB Na MAPs were able to deliver therapeutically relevant levels of drug.

Pharmacokinetics of vitamin dosage forms: A complete overview.

Vitamins are crucial for sustaining life because they play an essential role in numerous physiological processes. Vitamin deficiencies can lead to a wide range of severe health issues. In this context, there is a need to administer vitamin supplements through appropriate routes, such as the oral route, to ensure effective treatment. Therefore, understanding the pharmacokinetics of vitamins provides critical insights into absorption, distribution, and metabolism, all of which are essential for achieving the desired pharmacological response. In this review paper, we present information on vitamin deficiencies and emphasize the significance of understanding vitamin pharmacokinetics for improved clinical research. The pharmacokinetics of several vitamins face various challenges, and thus, this work briefly outlines the current issues and their potential solutions. We also discuss the feasibility of enhanced nanocarrier-based pharmaceutical formulations for delivering vitamins. Recent studies have shown a preference for nanoformulations, which can address major limitations such as stability, solubility, absorption, and toxicity. Ultimately, the pharmacokinetics of pharmaceutical dosage forms containing vitamins can impede the treatment of diseases and disorders related to vitamin deficiency.

Dual stimuli-responsive delivery system for self-regulated colon-targeted delivery of poorly water-soluble drugs.

Inflammatory bowel disease (IBD) are chronic inflammatory conditions which cause significant patient morbidity. Local drug delivery to the colon can improve treatment efficacy and reduce side effects associated with IBD treatment. Smart drug delivery systems are designed to regulate the release of therapeutic agents at the desired site of action. pH-responsive drug carriers have been previously utilised for improved oral drug delivery beyond stomach harsh conditions. Additionally, the colon possesses a diverse microbiome secreting bioactive molecules e.g., enzymes, that can be exploited for targeted drug delivery. We herein synthesised and characterised a 2-hydroxyethyl methacrylate and methacrylic acid copolymer, crosslinked with an azobenzyl crosslinker, that displayed pH- and enzyme-responsive properties. The swelling and drug release from hydrogel were analysed in pH 1.2, 6.5 and 7.4 buffers, and in the presence of rat caecal matter using metronidazole and mesalamine as model BCS Class I and IV drugs, respectively. Swelling studies displayed pH-responsive swelling behaviour, where swelling was maximum at pH 7.4 and minimum at pH 1.2 (69 % versus 32 %). Consequently, drug release was limited in gastric and small intestinal conditions but increased significantly when exposed to colonic conditions containing caecal matter. This system displays promising capacity for achieving colon-targeted drug delivery with enhanced dissolution of poorly water-soluble drugs for local treatment of IBD and other colon-targeted therapies.

Glioblastoma preclinical models: Strengths and weaknesses.

Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.

Physiologically Based Pharmacokinetic Modelling of Cabotegravir Microarray Patches in Rats and Humans.

Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC90) (0.664 µg/mL) and >8 × PA-IC90 (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC90. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP.

Tumor-derived systems as novel biomedical tools-turning the enemy into an ally.

Cancer is a complex illness that presents significant challenges in its understanding and treatment. The classic definition, "a group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body," fails to convey the intricate interaction between the many entities involved in cancer. Recent advancements in the field of cancer research have shed light on the role played by individual cancer cells and the tumor microenvironment as a whole in tumor development and progression. This breakthrough enables the utilization of the tumor and its components as biological tools, opening new possibilities. This article delves deeply into the concept of "tumor-derived systems", an umbrella term for tools sourced from the tumor that aid in combatting it. It includes cancer cell membrane-coated nanoparticles (for tumor theranostics), extracellular vesicles (for tumor diagnosis/therapy), tumor cell lysates (for cancer vaccine development), and engineered cancer cells/organoids (for cancer research). This review seeks to offer a complete overview of the tumor-derived materials that are utilized in cancer research, as well as their current stages of development and implementation. It is aimed primarily at researchers working at the interface of cancer biology and biomedical engineering, and it provides vital insights into this fast-growing topic.

Lyotropic liquid crystalline phases: Drug delivery and biomedical applications.

Liquid crystal (LC)-based nanoformulations may efficiently deliver drugs and therapeutics to targeted biological sites. Lyotropic liquid crystalline phases (LLCPs) have received much interest in recent years due to their unique structural characteristics of both isotropic liquids and crystalline solids. These LLCPs can be utilized as promising drug delivery systems to deliver drugs, proteins, peptides and vaccines because of their improved drug loading, stabilization, and controlled drug release. The effects of molecule shape, microsegregation, and chirality are very important in the formation of liquid crystalline phases (LCPs). Homogenization of self-assembled amphiphilic lipids, water and stabilizers produces LLCPs with different types of mesophases, bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes). Moreover, many studies have also shown higher bioadhesivity and biocompatibility of LCs due to their structural resemblance to biological membranes, thus making them more efficient for targeted drug delivery. In this review, an outline of the engineering aspects of LLCPs and polymer-based LLCPs is summarized. Moreover, it covers parenteral, oral, transdermal delivery and medical imaging of LC in targeting various tissues and is discussed with a scope to design more efficient next-generation novel nanosystems. In addition, a detailed overview of advanced liquid crystal-based drug delivery for vaccines and biomedical applications is reviewed.

Advancements in gelatin-based hydrogel systems for biomedical applications: A state-of-the-art review.

A gelatin-based hydrogel system is a stimulus-responsive, biocompatible, and biodegradable polymeric system with solid-like rheology that entangles moisture in its porous network that gradually protrudes to assemble a hierarchical crosslinked arrangement. The hydrolysis of collagen directs gelatin construction, which retains arginyl glycyl aspartic acid and matrix metalloproteinase-sensitive degeneration sites, further confining access to chemicals entangled within the gel (e.g., cell encapsulation), modulating the release of encapsulated payloads and providing mechanical signals to the adjoining cells. The utilization of various types of functional tunable biopolymers as scaffold materials in hydrogels has become highly attractive due to their higher porosity and mechanical ability; thus, higher loading of proteins, peptides, therapeutic molecules, etc., can be further modulated. Furthermore, a stimulus-mediated gelatin-based hydrogel with an impaired concentration of gellan demonstrated great shear thinning and self-recovering characteristics in biomedical and tissue engineering applications. Therefore, this contemporary review presents a concise version of the gelatin-based hydrogel as a conceivable biomaterial for various biomedical applications. In addition, the article has recapped the multiple sources of gelatin and their structural characteristics concerning stimulating hydrogel development and delivery approaches of therapeutic molecules (e.g., proteins, peptides, genes, drugs, etc.), existing challenges, and overcoming designs, particularly from drug delivery perspectives.

Delivery of gene editing therapeutics.

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues. While viral vector-based systems and viral particles demonstrate high efficiency and stable transgene expression, each are limited in their packaging capacities and secondary untoward immune responses. In contrast, the nonviral vector lipid nanoparticles were successfully used for as vaccine and therapeutic deliverables. Herein, we highlight each available gene delivery systems for treating and preventing a broad range of infectious, inflammatory, genetic, and degenerative diseases. STATEMENT OF SIGNIFICANCE: CRISPR-Cas9 gene editing for disease treatment and prevention is an emerging field that can change the outcome of many chronic debilitating disorders.

Microneedles for advanced ocular drug delivery.

In the field of ocular drug delivery, topical delivery remains the most common treatment option for managing anterior segment diseases, whileintraocular injectionsare the current gold standard treatment option for treating posterior segment diseases. Nonetheless, topical eye drops are associated with low bioavailability (<5%), and theintravitreal administration procedure is highly invasive, yielding poor patient acceptability. In both cases, frequent administration is currently required. As a result, there is a clear unmet need for sustained drug delivery to the eye, particularly in a manner that can be localised. Microneedles, which are patches containing an array of micron-scale needles (<1 mm), have the potential to meet this need. These platforms can enable localised drug delivery to the eye while enhancing penetration of drug molecules through key ocular barriers, thereby improving overall therapeutic outcomes. Moreover, the minimally invasive manner in which microneedles are applied could provide significant advantages over traditional intravitreal injections regarding patient acceptability. Considering the benefitsofthis novel ocular delivery system, this review provides an in-depth overviewofthe microneedle systems for ocular drug delivery, including the types of microneedles used and therapeutics delivered. Notably, we outline and discuss the current challenges associated with the clinical translation of these platforms and offer opinions on factors which should be considered to improve such transition from lab to clinic.

The cubosome-based nanoplatforms in cancer therapy: Seeking new paradigms for cancer theranostics.

Lyotropic liquid crystals are self-assembled, non-lamellar, and mesophase nanostructured materials that have garnered significant attention as drug carriers. Cubosomes, a subtype of lyotropic liquid crystalline nanoparticles, possess three-dimensional structures that display bicontinuous cubic liquid-crystalline patterns. These patterns are formed through the self-organization of unsaturated monoglycerides (amphphilic lipids such as glyceryl monooleate or phytantriol), followed by stabilization using steric polymers (poloxamers). Owing to their bicontinuous structure and steric polymer-based stabilization, cubosomes have been demonstrated to possess greater entrapment efficiency for hydrophobic drugs compared to liposomes, while also exhibiting high stability. In the past decade, there has been significant interest in cubosomes due to their ability to deliver therapeutic and contrast agents for cancer treatment and imaging with minimal side effects, establishing them as a safe and effective approach. Concerning these advantages, the present review elaborates on the general aspects, composition, and preparation techniques of cubosomes, followed by explanations of their mechanisms of drug loading and release patterns. Furthermore, the review provides meticulous discussions on the use of cubosomes in the treatment and imaging of various types of cancer, culminating in the enumeration of patents related to cubosome-based drug delivery systems.