Treatment avenues for age-related macular degeneration: Breakthroughs and bottlenecks.

Age-related macular degeneration (AMD) is a significant factor contributing to serious vision loss in adults above 50. The presence of posterior segment barriers serves as chief roadblocks in the delivery of drugs to treat AMD. The conventional treatment strategies use is limited due to its off-targeted distribution in the eye, shorter drug residence, poor penetration and bioavailability, fatal side effects, etc. The above-mentioned downside necessitates drug delivery using some cutting-edge technology including diverse nanoparticulate systems and microneedles (MNs) which provide the best therapeutic delivery alternative to treat AMD efficiently. Furthermore, cutting-edge treatment modalities including gene therapy and stem cell therapy can control AMD effectively by reducing the boundaries of conventional therapies with a single dose. This review discusses AMD overview, conventional therapies for AMD and their restrictions, repurposed therapeutics and their anti-AMD activity through different mechanisms, and diverse barriers in drug delivery for AMD. Various nanoparticulate-based approaches including polymeric NPs, lipidic NPs, exosomes, active targeted NPs, stimuli-sensitive NPs, cell membrane-coated NPs, inorganic NPs, and MNs are explained. Gene therapy, stem cell therapy, and therapies in clinical trials to treat AMD are also discussed. Further, bottlenecks of cutting-edge (nanoparticulate) technology-based drug delivery are briefed. In a nutshell, cutting-edge technology-based therapies can be an effective way to treat AMD.

Unravelling the success of transferosomes against skin cancer: Journey so far and road ahead.

Skin cancer remains one of the most prominent types of cancer. Melanoma and non-melanoma skin cancer are commonly found together, with melanoma being the more deadly type. Skin cancer can be effectively treated with chemotherapy, which mostly uses small molecular medicines, phytoceuticals, and biomacromolecules. Topical delivery of these therapeutics is a non-invasive way that might be useful in effectively managing skin cancer. Different skin barriers, however, presented a major obstacle to topical cargo administration. Transferosomes have demonstrated significant potential in topical delivery by improving cargo penetration through the circumvention of diverse skin barriers. Additionally, the transferosome-based gel can prolong the residence of drug on the skin, lowering the frequency of doses and their associated side effects. However, the choice of appropriate transferosome compositions, such as phospholipids and edge activators, and fabrication technique are crucial for achieving improved entrapment efficiency, penetration, and regulated particle size. The present review discusses skin cancer overview, current treatment strategies for skin cancer and their drawbacks. Topical drug delivery against skin cancer is also covered, along with the difficulties associated with it and the importance of transferosomes in avoiding these difficulties. Additionally, a summary of transferosome compositions and fabrication methods is provided. Furthermore, topical delivery of small molecular drugs, phytoceuticals, and biomacromolecules using transferosomes and transferosomes-based gel in treating skin cancer is discussed. Thus, transferosomes can be a significant option in the topical delivery of drugs to manage skin cancer efficiently.

Harnessing DNA origami's therapeutic potential for revolutionizing cardiovascular disease treatment: A comprehensive review.

DNA origami is a cutting-edge nanotechnology approach that creates precise and detailed 2D and 3D nanostructures. The crucial feature of DNA origami is how it is created, which enables precise control over its size and shape. Biocompatibility, targetability, programmability, and stability are further advantages that make it a potentially beneficial technique for a variety of applications. The preclinical studies of sophisticated programmable nanomedicines and nanodevices that can precisely respond to particular disease-associated triggers and microenvironments have been made possible by recent developments in DNA origami. These stimuli, which are endogenous to the targeted disorders, include protein upregulation, pH, redox status, and small chemicals. Oncology has traditionally been the focus of the majority of past and current research on this subject. Therefore, in this comprehensive review, we delve into the intricate world of DNA origami, exploring its defining features and capabilities. This review covers the fundamental characteristics of DNA origami, targeting DNA origami to cells, cellular uptake, and subcellular localization. Throughout the review, we emphasised on elucidating the imperative for such a therapeutic platform, especially in addressing the complexities of cardiovascular disease (CVD). Moreover, we explore the vast potential inherent in DNA origami technology, envisioning its promising role in the realm of CVD treatment and beyond.

Antibody-Drug Conjugates: A promising breakthrough in cancer therapy.

Antibody-drug conjugates (ADCs) provide effective cancer treatment through the selective delivery of cytotoxic payloads to the cancer cells. They offer unparalleled precision and specificity in directing drugs to cancer cells while minimizing off-target effects. Despite several advantages, there is a requirement for innovations in the molecular design of ADC owing to drug resistance, cancer heterogeneity along the adverse effects of treatment. The review critically analyses ADC function mechanisms, unraveling the intricate interplay between antibodies, linkers, and payloads in facilitating targeted drug delivery to cancer cells. The article also highlights notable advancements in antibody engineering, which aid in creating highly selective and potent ADCs. Additionally, the review details significant progress in clinical ADC development with an in-depth examination of pivotal trials and approved formulations. Antibody Drug Conjugates (ADCs) are a ground-breaking approach to targeted drug delivery, especially in cancer treatment. They offer unparalleled precision and specificity in directing drugs to cancer cells while minimizing off-target effects. This review provides a comprehensive examination of the current state of ADC development, covering their design, mechanisms of action, and clinical applications. The article emphasizes the need for greater precision in drug delivery and explains why ADCs are necessary.

Formulation development of nanostructured lipid carrier-based nanogels encapsulating tacrolimus for sustained therapy of psoriasis.

The goal of this study was to formulate tacrolimus nanogel based on nanostructured lipid carrier (NLC) in order to improve the efficacy, aesthetic, and patient compliance for the treatment of psoriasis. The microemulsion method was used to create phase diagrams and NLCs were prepared using points obtained from the microemulsion region and characterized. The gelling agent carbopol was used to develop an NLC-based nanogel. The pH, drug assay, viscosity, spreadability, and in vitro release of the nanogel, were evaluated. Ex vivo cytotoxicity of the formulation was assessed in murine fibroblast cells. Oxazolone and imiquimod models of psoriasis were used to assess the effectiveness of the nanogel. The NLCs exhibited a submicron particle size of 320 ±â€¯10 nm, a low polydispersity index (<0.3), and a zeta potential of -19.4 mV. Morphological analysis revealed spherical nanoparticles with an encapsulation efficiency of 60 ±â€¯3 %. The nanogel maintained a pH of 6.0 ±â€¯0.5 and possessed a remarkable drug content of 99.73 ±â€¯1.4 %. It exhibited pseudoplastic flow behaviour, ensuring easy spreadability, and demonstrated sustained drug release exceeding 90 % over a 24-hr period. Ex vivo cytotoxicity assessments revealed that the nanogel was safe because no cell death was induced. Nanogel resolved psoriatic blisters, was non-irritating and improved skin elasticity. The favorable properties, safety profile, and remarkable efficacy show the potential of the nanogel as a patient-friendly and effective therapeutic option for psoriasis treatment.

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.

Protein subunit vaccines: Promising frontiers against COVID-19.

The emergence of COVID-19 has posed an unprecedented global health crisis, challenging the healthcare systems worldwide. Amidst the rapid development of several vaccine formulations, protein subunit vaccines have emerged as a promising approach. This article provides an in-depth evaluation of the role of protein subunit vaccines in the management of COVID-19. Leveraging viral protein fragments, particularly the spike protein from SARS-CoV-2, these vaccines elicit a targeted immune response without the risk of inducing disease. Notably, the robust safety profile of protein subunit vaccines makes them a compelling candidate in the management of COVID-19. Various innovative approaches, including reverse vaccinology, virus like particles, and recombinant modifications are incorporated to develop protein subunit vaccines. In addition, the utilization of advanced manufacturing techniques facilitates large-scale production, ensuring widespread distribution. Despite these advancements, challenges persist, such as the requirement for cold-chain storage and the necessity for booster doses. This article evaluates the formulation and applications of protein subunit vaccines, providing a comprehensive overview of their clinical development and approvals in the context of COVID-19. By addressing the current status and challenges, this review aims to contribute to the ongoing discourse on optimizing protein subunit vaccines for effective pandemic control.

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.

Microneedle and Polymeric Films: Delivery of Proteins, Peptides and Nucleic Acids.

In the last 20 years, protein, peptide and nucleic acid-based therapies have become the fastest growing sector in the pharmaceutical industry and play a vital role in disease therapy. However, the intrinsic sensitivity and large molecular sizes of biotherapeutics limit the available routes of administration. Currently, the main administration routes of biomacromolecules, such as parenteral, oral, pulmonary, nasal, rectal and buccal routes, each have their limitations. Several non-invasive strategies have been proposed to overcome these challenges. Researchers were particularly interested in microneedles (MNs) and polymeric films because of their less invasiveness, convenience and greater potential to preserve the bioactivity of biotherapeutics. By facilitating with MNs and polymeric films, biomacromolecules could provide significant benefits to patients suffering from various diseases such as cancer, diabetes, infectious and ocular diseases. However, before these devices can be used on patients, how to upscale MN manufacture in a cost-effective and timely manner, as well as the long-term safety of MN and polymeric film applications necessitates further investigation.

Exploring the influence of the microbiome on the pharmacology of anti-asthmatic drugs.

The microbiome is increasingly implicated in playing a role in physiology and pharmacology; in this review, we investigate the literature on the possibility of bacterial influence on the pharmacology of anti-asthmatic drugs, and the potential impact this has on asthmatic patients. Current knowledge in this area of research reveals an interaction between the gut and lung microbiome and the development of asthma. The influence of microbiome on the pharmacokinetics and pharmacodynamics of anti-asthmatic drugs is limited; however, understanding this interaction will assist in creating a more efficient treatment approach. This literature review highlighted that bioaccumulation and biotransformation in the presence of certain gut bacterial strains could affect drug metabolism in anti-asthmatic drugs. Furthermore, the bacterial richness in the lungs and the gut can influence drug efficacy and could also play a role in drug response. The implications of the above findings suggest that the microbiome is a contributing factor to an individuals' pharmacological response to anti-asthmatic drugs. Hence, future directions for research should follow investigating how these processes affect asthmatic patients and consider the role of the microbiome on drug efficacy and modify treatment guidelines accordingly.

Polysaccharide-based hydrogels for medical devices, implants and tissue engineering: A review.

Hydrogels are highly biocompatible biomaterials composed of crosslinked three-dimensional networks of hydrophilic polymers. Owing to their natural origin, polysaccharide-based hydrogels (PBHs) possess low toxicity, high biocompatibility and demonstrate in vivo biodegradability, making them great candidates for use in various biomedical devices, implants, and tissue engineering. In addition, many polysaccharides also show additional biological activities such as antimicrobial, anticoagulant, antioxidant, immunomodulatory, hemostatic, and anti-inflammatory, which can provide additional therapeutic benefits. The porous nature of PBHs allows for the immobilization of antibodies, aptamers, enzymes and other molecules on their surface, or within their matrix, potentiating their use in biosensor devices. Specific polysaccharides can be used to produce transparent hydrogels, which have been used widely to fabricate ocular implants. The ability of PBHs to encapsulate drugs and other actives has been utilized for making neural implants and coatings for cardiovascular devices (stents, pacemakers and venous catheters) and urinary catheters. Their high water-absorption capacity has been exploited to make superabsorbent diapers and sanitary napkins. The barrier property and mechanical strength of PBHs has been used to develop gels and films as anti-adhesive formulations for the prevention of post-operative adhesion. Finally, by virtue of their ability to mimic various body tissues, they have been explored as scaffolds and bio-inks for tissue engineering of a wide variety of organs. These applications have been described in detail, in this review.

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.

Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties. This picture was generated with BioRender.

Liposome-loaded polymeric microneedles for enhanced skin deposition of rifampicin.

Methicillin-resistant Staphylococcus aureus (MRSA) is a prevailing bacterial pathogen linked to superficial skin and soft tissue infections (SSTIs). Rifampicin (RIF), a potent antibiotic against systemic and localised staphylococcal infections, faces limitations due to its low solubility. This constraint hampers its therapeutic potential for MRSA-induced SSTIs. To address this, an advanced liposomal system was designed for efficient dermal RIF delivery. Rifampicin-loaded liposomes (LipoRIF) were embedded within polymeric dissolving microneedles (DMNs) to enable targeted intradermal drug delivery. A robust Design of Experiment (DoE) methodology guided the systematic preparation and optimisation of LipoRIF formulations. The optimal LipoRIF formulation integrated within polymeric DMNs. These LipoRIF-DMNs exhibited favourable mechanical properties and effective skin insertion characteristics. Notably, in vitro assays on skin deposition unveiled a transformative result - the DMN platform significantly enhanced LipoRIF deposition within the skin, surpassing LipoRIF dispersion alone. Moreover, LipoRIF-DMNs displayed minimal cytotoxicity toward cells. Encouragingly, rigorous in vitro antimicrobial evaluations demonstrated LipoRIF-DMNs' capacity to inhibit MRSA growth compared to the control group. LipoRIF-DMNs propose a potentially enhanced, minimally invasive approach to effectively manage SSTIs and superficial skin ailments stemming from MRSA infections.

Polymeric in situ forming depots for long-acting drug delivery systems.

Polymeric in situ forming depots have emerged as highly promising drug delivery systems for long-acting applications. Their effectiveness is attributed to essential characteristics such as biocompatibility, biodegradability, and the ability to form a stable gel or solid upon injection. Moreover, they provide added versatility by complementing existing polymeric drug delivery systems like micro- and nanoparticles. The formulation's low viscosity facilitates manufacturing unit operations and enhances delivery efficiency, as it can be easily administered via hypodermic needles. The release mechanism of drugs from these systems can be predetermined using various functional polymers. To enable unique depot design, numerous strategies involving physiological and chemical stimuli have been explored. Important assessment criteria for in situ forming depots include biocompatibility, gel strength and syringeability, texture, biodegradation, release profile, and sterility. This review focuses on the fabrication approaches, key evaluation parameters, and pharmaceutical applications of in situ forming depots, considering perspectives from academia and industry. Additionally, insights about the future prospects of this technology are discussed.

Nattokinase prevents ß-amyloid peptide (Aß1-42) induced neuropsychiatric complications, neuroinflammation and BDNF signalling disruption in mice.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular ß-amyloid (Aß) plaques and neuronal damage. Although AD is typically considered a cognitive neurodegenerative disorder, almost all people diagnosed with AD develop neuropsychiatric complications at some stage in their life span. The present study investigated the effect of chronic Nattokinase (NK) administration on ß-Amyloid peptide (Aß1-42) induced neuropsychiatric conditions (depression-like behaviour, anxiety, and memory impairment) in mice. Aß1-42 peptide injected mice demonstrated depression, anxiety, and impairment of cognitive abilities evaluated as increased immobility time in forced swim test (FST), decreased open arm time/entries in elevated plus maze (EPM) and reference and working memory error in radial arm maze (RAM) respectively with elevation in Interleukin-6 (IL-6), Tumour necrosis factor-α (TNF-α), reduction in Interleukin-10 (IL-10) and Brain-derived neurotrophic factor (BDNF) immunocontent within the hippocampus. Chronic administration of NK (50-100 mg/kg, i.p.) from day 8-27, prevented depression-like behaviour, anxiety, and memory impairment and normalized the neurochemical alteration within the hippocampus of mice injected with Aß1-42 peptide. The effect of NK on psychiatric complications, learning, and memory was comparable to peripheral donepezil treatment. This study suggests that NK improves learning, memory impairment, and neuropsychiatric complications possibly through the downregulation of neuroinflammatory pathways and restoring BDNF signalling in AD.

Radiolabelled folate micellar carriers as proposed diagnostic aid for CNS tumors by nasal route.

Glioma refers to the most atypical variant of the malignant central nervous system tumors posturing massive challenge to the research fraternity owing to the flimsy improvement in the patient survival rate over the past years. The aim of the proposed work was developing a diagnostic aid for brain tumors, which could be administered via the non-invasive intranasal route. Since overexpression of folate receptors in the central nervous system tumors is 500 times more than the normal healthy cells, we aimed at fabricating a radiolabeled folate encapsulated micellar delivery system to be given via the nasal route. Folate conjugated bifunctional chelating agent was synthesized, radiolabeled with 99mTc, and encapsulated in a micellar carrier. The fabricated micelles were further evaluated for in vivo nasal toxicity in rats and the same were found safe for intranasal administration. The fabricated micelles owing to their nano size, mucoadhesive nature, and enhanced permeation were observed to have a higher uptake into the brain (around 16% in 4 h) than as compared to the radiolabeled conjugated folate solution when studied for in vivo biodistribution in mice. Single-photon emission computerized tomography imaging performed in higher animals upon intranasal administration of the micellar formulation revealed enhanced uptake of the micelles into the animal brain. It is believed that the aforementioned formulation can be of a great diagnostic value in the detection of not only brain tumors but also other folate expressing cancers such as cervical, breast, and lungs as the system is fast, non-toxic, accurate, non-invasive, and simple.

Safe Subunit Green Vaccines Confer Robust Immunity and Protection against Mucosal Brucella Infection in Mice.

Brucellosis is a zoonotic disease that causes significant negative impacts on the animal industry and affects over half a million people worldwide every year. The limited safety and efficacy of current animal brucellosis vaccines, combined with the lack of a licensed human brucellosis vaccine, have led researchers to search for new vaccine strategies to combat the disease. To this end, the present research aimed to evaluate the safety and efficacy of a green vaccine candidate that combines Brucella abortus S19 smooth lipopolysaccharide (sLPS) with Quillaja saponin (QS) or QS-Xyloglucan mix (QS-X) against mucosal brucellosis in BALB/C mice. The results of the study indicate that administering two doses of either sLPS-QS or sLPS-QS-X was safe for the animals, triggered a robust immune response, and enhanced protection following intranasal challenge with S19. Specifically, the vaccine combinations led to the secretion of IgA and IgG1 in the BALF of the immunized mice. We also found a mixed IgG1/IgG2a systemic response indicating evidence of both Th1 and Th2 activation, with a predominance of the IgG1 over the IgG2a. These candidates resulted in significant reductions in the bioburden of lung, liver, and spleen tissue compared to the PBS control group. The sLPS-QS vaccination had conferred the greatest protection, with a 130-fold reduction in Brucella burdens in lung and a 55.74-fold reduction in the spleen compared to PBS controls. Vaccination with sLPS-QS-X resulted in the highest reduction in splenic Brucella loads, with a 364.6-fold decrease in bacterial titer compared to non-vaccinated animals. The study suggests that the tested vaccine candidates are safe and effective in increasing the animals' ability to respond to brucellosis via mucosal challenge. It also supports the use of the S19 challenge strain as a safe and cost-effective method for testing Brucella vaccine candidates under BSL-2 containment conditions.

Polymeric micelles as potent islet amyloid inhibitors: Current advances and future perspectives.

Diabetes mellitus (DM) has become one of the most prevalent diseases across the globe, mainly because of the inability of existing treatment strategies to target its root cause (i.e., pancreatic ß cell damage). Polymeric micelles (PMs) have gained attention as a treatment option for DM by targeting misfolded islet amyloid polypeptide protein (IAPP), which is common in more than 90% of DM patients. Such misfolding could result from either oxidative stress or mutation in the gene encoding IAPP. In this review, we discuss progress in the designing of PMs to halt islet amyloidosis along with their mechanism and dynamics of interactions with IAPP. We also discuss the clinical challenges associated with the translation of PMs as anti-islet amyloidogenic agents.

Aptamers and nanobodies as alternatives to antibodies for ligand-targeted drug delivery in cancer.

Targeted drug delivery (TDD) is the selective delivery of a therapeutic agent specifically to the site of action to avoid adverse effects and systemic toxicity and to reduce the dose required. Ligand TDD or active TDD involves using a ligand-drug conjugate comprising a targeting ligand linked to an active drug moiety that can either be free or encapsulated within a nanocarrier (NC). Aptamers are single-stranded oligonucleotides that bind to specific biomacromolecules because of their 3D conformation. Nanobodies are the variable domains of unique heavy chain-only antibodies (HcAbs) produced by animals of the Camelidae family. Both these types of ligand are smaller than antibodies and have been used to efficiently target drugs to particular tissues or cells. In this review, we describe the applications of aptamers and nanobodies as ligands for TDD, their advantages and disadvantages compared with antibodies, and the various modalities for targeting cancers using these ligands. Teaser: Aptamers and nanobodies are macromolecular ligands that can actively chaperone drug molecules to particular cancerous cells or tissues in the body to target their pharmacological effects and improve their therapeutic index and safety.