Advanced Delivery Strategies of Nintedanib for Lung Disorders and Beyond: A Comprehensive Review.

Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib, inhibits multiple signalling receptors, including endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) and ultimately inhibits fibroblast proliferation and differentiation. Therefore, nintedanib has been studied widely for other ailments like cancers and hepatic fibrosis, apart from lung disorders. Commercially, nintedanib is available as soft gelatin capsules for treatment against idiopathic pulmonary fibrosis. Since it has very low oral bioavailability (4.7%), high doses of a drug, such as 100-150 mg, are administered, which can cause problems of gastrointestinal irritation and hepatotoxicity. The article begins with exploring the mechanism of action of nintedanib, elucidating its complex interactions within cellular pathways that govern fibrotic processes. It also emphasizes the pharmacokinetics of nintedanib, clinical trial insights, and the limitations of conventional formulations. The article mainly focuses on the emerging landscape of nanoparticle-based carriers such as hybrid liposome-exosome, nano liquid crystals, discoidal polymeric, and magnetic systems, offering promising avenues to optimize drug targeting, address its efficacy issues and minimise adverse effects. However, none of these delivery systems are commercialised, and further research is required to ensure safety and effectiveness in clinical settings. Yet, as research progresses, these advanced delivery systems promise to revolutionise the treatment landscape for various fibrotic disorders and cancers, potentially improving patient outcomes and quality of life.

Revolutionizing the Treatment of Idiopathic Pulmonary Fibrosis: From Conventional Therapies to Advanced Drug Delivery Systems.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease that has been well-reported in the medical literature. Its incidence has risen, particularly in light of the recent COVID-19 pandemic. Conventionally, IPF is treated with antifibrotic drugs-pirfenidone and nintedanib-along with other drugs for symptomatic treatments, including corticosteroids, immunosuppressants, and bronchodilators based on individual requirements. Several drugs and biologicals such as fluorofenidone, thymoquinone, amikacin, paclitaxel nifuroxazide, STAT3, and siRNA have recently been evaluated for IPF treatment that reduces collagen formation and cell proliferation in the lung. There has been a great deal of research into various treatment options for pulmonary fibrosis using advanced delivery systems such as liposomal-based nanocarriers, chitosan nanoparticles, PLGA nanoparticles, solid lipid nanocarriers, and other nanoformulations such as metal nanoparticles, nanocrystals, cubosomes, magnetic nanospheres, and polymeric micelles. Several clinical trials are also ongoing for advanced IPF treatments. This article elaborates on the pathophysiology of IPF, its risk factors, and different advanced drug delivery systems for treating IPF. Although extensive preclinical data is available for these delivery systems, the clinical performance and scale-up studies would decide their commercial translation.

Advanced Drug Delivery Micro- and Nanosystems for Cardiovascular Diseases.

Advanced drug delivery micro- and nanosystems have been widely explored due to their appealing specificity/selectivity, biodegradability, biocompatibility, and low toxicity. They can be applied for the targeted delivery of pharmaceuticals, with the benefits of good biocompatibility/stability, non-immunogenicity, large surface area, high drug loading capacity, and low leakage of drugs. Cardiovascular diseases, as one of the primary mortalities cause worldwide with significant impacts on the quality of patients' life, comprise a variety of heart and circulatory system pathologies, such as peripheral vascular diseases, myocardial infarction, heart failure, and coronary artery diseases. Designing novel micro- and nanosystems with suitable targeting properties and smart release behaviors can help circumvent crucial challenges of the tolerability, low stability, high toxicity, and possible side- and off-target effects of conventional drug delivery routes. To overcome different challenging issues, namely physiological barriers, low efficiency of drugs, and possible adverse side effects, various biomaterials-mediated drug delivery systems have been formulated with reduced toxicity, improved pharmacokinetics, high bioavailability, sustained release behavior, and enhanced therapeutic efficacy for targeted therapy of cardiovascular diseases. Despite the existing drug delivery systems encompassing a variety of biomaterials for treating cardiovascular diseases, the number of formulations currently approved for clinical use is limited due to the regulatory and experimental obstacles. Herein, the most recent advancements in drug delivery micro- and nanosystems designed from different biomaterials for the treatment of cardiovascular diseases are deliberated, with a focus on the important challenges and future perspectives.

Near-infrared light-responsive hydrogels for on-demand dual delivery of proangiogenic growth factors.

Achieving precise spatiotemporal control over the release of proangiogenic factors is crucial for vasculogenesis, the process of de novo blood vessel formation. Although various strategies have been explored, there is still a need to develop cell-laden biomaterials with finely controlled release of proangiogenic factors at specific locations and time points. We report on the developed of a near-infrared (NIR) light-responsive collagen hydrogel comprised of gold nanorods (GNRs)-conjugated liposomes containing proangiogenic growth factors (GFs). We demonstrated that this system enables on-demand dual delivery of GFs at specific sites and over selected time intervals. Liposomes were strategically formulated to encapsulate either platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF), each conjugated to gold nanorods (GNRs) with distinct geometries and surface plasmon resonances at 710 nm (GNR710) and 1064 nm (GNR1064), respectively. Using near infrared (NIR) irradiation and two-photon (2P) luminescence imaging, we successfully demonstrated the independent release of PDGF from GNR710 conjugated liposomes and VEGF from GNR1064-conjugated liposomes. Our imaging data revealed rapid release kinetics, with localized PDGF released in approximately 4 min and VEGF in just 1 and a half minutes following NIR laser irradiation. Importantly, we demonstrated that the release of each GF could be independently triggered using NIR irradiation with the other GF formulation remaining retained within the liposomes. This light-responsive collagen hydrogels holds promise for various applications in regenerative medicine where the establishment of a guided vascular network is essential for the survival and integration of engineered tissues. STATEMENT OF SIGNIFICANCE: In this study, we have developed a light-responsive system with gold nanorods (GNRs)-conjugated liposomes in a collagen hydrogel, enabling precise dual delivery of proangiogenic growth factors (GFs) at specific locations and timepoints. Liposomes, containing platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF), release independently under near- infrared irradiation. This approach allows external activation of desired GF release, ensuring high cell viability. Each GF can be triggered independently, retaining the other within the liposomes. Beyond its application in establishing functional vascular networks, this dual delivery system holds promise as a universal platform for delivering various combinations of two or more GFs.

Advances in intranasal vaccine delivery: A promising non-invasive route of immunization.

The importance of vaccination has been proven particularly significant the last three years, as it is revealed to be the most efficient weapon for the prevention of several infections including SARS-COV-2. Parenteral vaccination is the most applicable method of immunization, for the prevention of systematic and respiratory infections, or central nervous system disorders, involving T and B cells to a whole-body immune response. However, the mucosal vaccines, such as nasal vaccines, can additionally activate the immune cells localized on the mucosal tissue of the upper and lower respiratory tract. This dual stimulation of the immune system, along with their needle-free administration favors the development of novel nasal vaccines to produce long-lasting immunity. In recent years, the nanoparticulate systems have been extensively involved in the formulation of nasal vaccines as polymeric, polysaccharide and lipid ones, as well as in the form of proteosomes, lipopeptides and virosomes. Advanced delivery nanosystems have been designed and evaluated as carriers or adjuvants for nasal vaccination. To this end, several nanoparticulate vaccines are undergone clinical trials as promising candidates for nasal immunization, while nasal vaccines against influenza type A and B and hepatitis B have been approved by health authorities. This comprehensive literature review aims to summarize the critical aspects of these formulations and highlight their potential for the future establishment of nasal vaccination. Both preclinical (in vitro and in vivo) and clinical studies are incorporated, summarized, and critically discussed, as well as the limitations of nasal immunization.

Advanced CaCO3-derived delivery systems for bioactive compounds.

Calcium carbonate (CaCO3) has long been used as a delivery system owing to its wide availability, biocompatibility, and degradability. However, it often suffers from many challenges toward rapid dissolution at stomach acid environment, low retention ability, and lack of sustained release. Many of these issues can be addressed by modifying the CaCO3 particles or integrating them with other encapsulation systems, generating advanced CaCO3-derived systems. This review article presents a recent progress (2015-2022) in the utilization of CaCO3 particles in the exploration of various advanced delivery systems, including polymer-doped CaCO3, surface-coated CaCO3, CaCO3-stabilized Pickering emulsions, CaCO3-in-hydrogels, and liposomal CaCO3. Some emerging systems templated on CaCO3 sacrificial cores, such as hollow capsules, matrix-type capsules, and core-shell capsules, are also reviewed. A brief description of each system is given, and then their formation, structure, and properties are described. Particular emphasis is given to the applications and challenges of these advanced systems for the protection and controlled delivery of bioactive compounds in the biological, pharmaceutical, and functional food fields.

Advancements in Skin Delivery of Natural Bioactive Products for Wound Management: A Brief Review of Two Decades.

Application of modern delivery techniques to natural bioactive products improves their permeability, bioavailability, and therapeutic efficacy. Many natural products have desirable biological properties applicable to wound healing but are limited by their inability to cross the stratum corneum to access the wound. Over the past two decades, modern systems such as microneedles, lipid-based vesicles, hydrogels, composite dressings, and responsive formulations have been applied to natural products such as curcumin or aloe vera to improve their delivery and efficacy. This article reviews which natural products and techniques have been formulated together in the past two decades and the success of these applications for wound healing. Many cultures prefer natural-product-based traditional therapies which are often cheaper and more available than their synthetic counterparts. Improving natural products' effect can provide novel wound-healing therapies for those who trust traditional compounds over synthetic drugs to reduce medical inequalities.

PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulation: Applications in Rheumatic Autoimmunity.

BACKGROUND: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity. METHODS: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm. RESULTS: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm. CONCLUSION: This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.

Recent advances in cyclosporine drug delivery: challenges and opportunities.

Cyclosporine has been established as a gold standard for its immunosuppressant action. Apart from this, the molecule is boon in treating broad spectrum of diseases like rheumatoid arthritis, psoriasis, and dry eye syndrome. The broad spectrum of cyclosporine demands efficient delivery systems by several routes. Neoral® and Sandimmune® are currently available formulations for oral route, whereas Restasis® is used for ocular delivery of cyclosporine. The available formulations serve the purpose only to a limited extent due to constraints like high molecular weight, low solubility, low permeability, bitter taste, and narrow therapeutic index of cyclosporine. Therefore, several novel formulations like microemulsion, self-emulsifying systems, nanoparticles, and microspheres were developed to overcome these constraints, exploring different routes like oral, ocular, and topical for cyclosporine. Additionally, iontophoresis and ultrasound-mediated delivery has also been studied to improve its poor permeability in topical delivery, whereas biodegradable implants were reported to increase the retention time in cornea and prolonged the release of cyclosporine by ocular route. Although these recent advances in cyclosporine delivery look promising, its clinical translation require in depth studies to deliver safe, efficacious, and stable formulation of cyclosporine. This review focuses on challenges of cyclosporine delivery and the recent advancements for overcoming the constraints.

Ultrasound focuser: A multi-cylindrical source configuration and entrapped particles dynamics.

We aim to introduce the proof of concept of a 3D ultrasound Focuser with possible advanced applications in living-matter/cell entrapment, particle focusing, transportation through virtual channel and drug, agent or material delivery systems. The proposed mechanism is assumed to be fully submerged in a fluidic environment and composed of three parallel acoustic line sources which are located in such a way that form a triangular right prism. By approximating the wave field of each cylindrical source as a progressive plane wave field whose amplitude decreases with respect to the travelling distance from the source, the acoustic radiation force exerted on a single particle is analytically derived. It is shown that when each source has a π/3 phase different from other sources, an attracting zone around the axis of the triangular prism is formed for wavelengths in the order of the size scale, λ/l∼O(1), where l denotes the distance between each two sources. The optimal operating situation (the largest attracting zone) is found for the case where λ≈l. The theoretical study is supported by stability analysis of dynamics of the entrapped particle which located on the axis of the prism; and validated by computing the trajectories of migration of the test particle. The stability analysis is performed by considering the unsteady solution of Stokes equations and the possible flow of environmental fluid medium. In addition, the required settling time and required length scales to focus the particle to the center line of the prism for different size scale ratios are estimated and discussed. Compared to other 3D focusing techniques, this method is non-invasive, robust, easy to implement, applicable to nearly all types of micro-particles and does not need any specific pre-designed channel for focusing process.

Exploring recent developments to improve antioxidant, anti-inflammatory and antimicrobial efficacy of curcumin: A review of new trends and future perspectives.

Curcumin derivatives have been well-documented due to their natural antioxidant, antimicrobial and anti-inflammatory activities. Curcuminoids have also gained widespread recognition due to their wide range of other activities which include anti-infective, anti-mutagenic, anticancer, anti-coagulant, antiarthrititc, and wound healing potential. Despite of having a wide range of activities, the inherent physicochemical characteristics (poor water solubility, low bioavailability, chemical instability, photodegradation, rapid metabolism and short half-life) of curcumin derivatives limit their pharmaceutical significance. Aiming to overcome these pharmaceutical issues and improving therapeutic efficacy of curcuminoids, newer strategies have been attempted in recent years. These advanced techniques include polymeric nanoparticles, nanocomposite hydrogels, nanovesicles, nanofibers, nanohybrid scaffolds, nanoconjugates, nanostructured lipid carriers (NLCs), nanoemulsion, polymeric micelles and polymeric blend films. Incorporation of curcumin in these delivery systems has shown improved solubility, transmembrane permeability, long-term stability, improved bioavailability, longer plasma half-life, target-specific delivery, and upgraded therapeutic efficacy. In this review, a range of in vitro and in vivo studies have been critically discussed to explore the pharmaceutical significance and therapeutic viability of the advanced delivery systems to improve antioxidant, anti-inflammatory and antimicrobial efficacies of curcumin and its derivatives.

Nanoencapsulation, an efficient and promising approach to maximize wound healing efficacy of curcumin: A review of new trends and state-of-the-art.

Wound healing is a multifarious and vibrant process of replacing devitalized and damaged cellular structures, leading to restoration of the skin's barrier function, re-establishment of tissue integrity, and maintenance of the internal homeostasis. Curcumin (CUR) and its analogs have gained widespread recognition due to their remarkable anti-inflammatory, anti-infective, anticancer, immunomodulatory, antioxidant, and wound healing activities. However, their pharmaceutical significance is limited due to inherent hydrophobic nature, poor water solubility, low bioavailability, chemical instability, rapid metabolism and short half-life. Owing to their pharmaceutical limitations, newer strategies have been attempted in recent years aiming to mitigate problems related to the effective delivery of curcumanoids and to improve their wound healing potential. These advanced strategies include nanovesicles, polymeric micelles, conventional liposomes and hyalurosomes, nanocomposite hydrogels, electrospun nanofibers, nanohybrid scaffolds, nanoconjugates, nanostructured lipid carriers (NLCs), nanoemulsion, nanodispersion, and polymeric nanoparticles (NPs). The superior wound healing activities achieved after nanoencapsulation of the CUR are attributed to its target-specific delivery, longer retention at the target site, avoiding premature degradation of the encapsulated cargo and the therapeutic superiority of the advanced delivery systems over the conventional delivery. We have critically reviewed the literature and summarize the convincing evidence which explore the pharmaceutical significance and therapeutic feasibility of the advanced delivery systems in improving wound healing activities of the CUR and its analogs.