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The delivery of therapeutic agents faces significant hurdles posed by the endo-lysosomal pathway, a bottleneck that hampers clinical effectiveness. This comprehensive review addresses the urgent need to enhance cellular delivery mechanisms to overcome these obstacles. It focuses on the potential of smart nanomaterials, delving into their unique characteristics and mechanisms in detail. Special attention is given to their ability to strategically evade endosomal entrapment, thereby enhancing therapeutic efficacy. The manuscript thoroughly examines assays crucial for understanding endosomal escape and cellular uptake dynamics. By analyzing various assessment methods, we offer nuanced insights into these investigative approaches' multifaceted aspects. We meticulously analyze the use of smart nanocarriers, exploring diverse mechanisms such as pore formation, proton sponge effects, membrane destabilization, photochemical disruption, and the strategic use of endosomal escape agents. Each mechanism's effectiveness and potential application in mitigating endosomal entrapment are scrutinized. This paper provides a critical overview of the current landscape, emphasizing the need for advanced delivery systems to navigate the complexities of cellular uptake. Importantly, it underscores the transformative role of smart nanomaterials in revolutionizing cellular delivery strategies, leading to a paradigm shift towards improved therapeutic outcomes.
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Endosomas , Lisosomas , Lisosomas/metabolismo , Humanos , Endosomas/metabolismo , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Nanoestructuras/química , Animales , Nanopartículas/químicaRESUMEN
The application of nanotechnology has significantly advanced the development of novel platforms that enhance disease treatment and diagnosis. A key innovation in this field is the creation of antitoxin nanoparticles (ATNs), designed to address toxin exposure. These precision-engineered nanosystems have unique physicochemical properties and selective binding capabilities, allowing them to effectively capture and neutralize toxins from various biological, chemical, and environmental sources. In this review, we thoroughly examine their therapeutic and diagnostic potential for managing toxin-related challenges. We also explore recent advancements and offer critical insights into the design and clinical implementation of ATNs.
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Nanopartículas , Humanos , Animales , Antitoxinas/uso terapéutico , Antitoxinas/química , Antitoxinas/farmacología , Nanotecnología/métodos , Diseño de FármacosRESUMEN
Genome editing involves precise modification of specific nucleotides in the genome using nucleases like CRISPR/Cas, ZFN, or TALEN, leading to increased efficiency of homologous recombination (HR) for gene editing, and it can result in gene disruption events via non-homologous end joining (NHEJ) or homology-driven repair (HDR). Genome editing, particularly CRISPR-Cas9, revolutionizes vaccine development by enabling precise modifications of pathogen genomes, leading to enhanced vaccine efficacy and safety. It allows for tailored antigen optimization, improved vector design, and deeper insights into host genes' impact on vaccine responses, ultimately enhancing vaccine development and manufacturing processes. This review highlights different types of genome editing methods, their associated risks, approaches to overcome the shortcomings, and the diverse roles of genome editing.
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Sistemas CRISPR-Cas , Edición Génica , Edición Génica/métodos , Humanos , Animales , Vacunas/inmunología , Vacunas/genética , Desarrollo de VacunasRESUMEN
This study explores a novel approach to address the challenges of delivering highly water-soluble drug molecules by employing hydrophobic ion-pairing (HIP) complexes within poly (lactic-co-glycolic acid) (PLGA) microspheres. The HIP complex, formed between doxycycline hyclate (DH) and docusate sodium (DS), renders the drug hydrophobic. The development of the microspheres was done using the QbD approach, namely, Box-Behnken Design (BBD). A comprehensive characterization of the HIP complex confirmed the successful conversion of DH. DH and the HIP complex were effectively loaded into PLGA microspheres using the oil-in-water (O/W) emulsion solvent evaporation method. Results demonstrated significant improvements in percentage entrapment efficiency (% EE) and drug loading (% DL) for DH within the HIP complex-loaded PLGA microspheres compared to DH-loaded microspheres alone. Additionally, the initial burst release of DH reduced to 3% within the initial 15 min, followed by sustained drug release over 8 days. The modified HIP complex strategy offers a promising platform for improving the delivery of highly water-soluble small molecules. It provides high % EE, % DL, minimal initial burst release, and sustained release, thus having the potential to enhance patient compliance and drug delivery efficiency.
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Ácido Láctico , Ácido Poliglicólico , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ácido Poliglicólico/química , Liberación de Fármacos , Ácido Láctico/química , Doxiciclina , Microesferas , Agua/química , Emulsiones/química , Tamaño de la PartículaRESUMEN
Ocular inserts offer distinct advantages, including a preservative-free drug delivery system, the ability to provide tailored drug release, and ease of administration. The present research paper delves into the development of an innovative ocular insert using CaliCut technology. Complementing the hot melt extrusion (HME) process, CaliCut, an advanced technology in ocular insert development, employs precision laser gauging to achieve impeccable cutting of inserts with desired dimensions. Its intelligent control over the stretching process through auto feedback-based belt speed adjustment ensures unparalleled accuracy and consistency in dosage form manufacturing. Dry eye disease (DED) poses a significant challenge to ocular health, necessitating innovative approaches to alleviate its symptoms. In this pursuit, castor oil has emerged as a promising therapeutic agent, offering beneficial effects by increasing the thickness of the lipid layer in the tear film, thus improving tear film stability, and reducing tear evaporation. To harness these advantages, this study focuses on the development and comprehensive characterization of castor oil-based ocular inserts. Additionally, in-vivo irritancy evaluation in rabbits has been undertaken to assess the inserts' safety and biocompatibility. By harnessing the HME and CaliCut techniques in the formulation process, the study demonstrates their instrumental role in facilitating the successful development of ocular inserts.
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Aceite de Ricino , Ojo , Animales , Conejos , Sistemas de Liberación de Medicamentos/métodosRESUMEN
INTRODUCTION: With the increase in the elderly population and the prevalence of multiple medical conditions, medication adherence, and efficacy have become crucial for the effective management of their health. The aging population faces unique challenges that need to be addressed through advancements in drug delivery systems and formulation technologies. AREAS COVERED: The current review highlights the recent advances in dosage form design for older individuals, with consideration of their specific physiological and cognitive changes. Various dosage forms, such as modified-release tablets/capsules, chewable tablets, and transdermal patches, can be tailored to meet the specific needs of elderly patients. Advancements in drug delivery systems, such as nanotherapeutics, additive manufacturing (three-dimensional printing), and drug-food combinations, improve drug delivery and efficacy and overcome challenges, such as dysphagia and medication adherence. EXPERT OPINION: Regulatory guidelines and considerations are crucial in ensuring the safe utilization of medications among older adults. Important factors to consider include geriatric-specific guidelines, safety considerations, labeling requirements, clinical trial considerations, and adherence and accessibility considerations.
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Sistemas de Liberación de Medicamentos , Humanos , Anciano , Comprimidos , Cápsulas , Formas de DosificaciónRESUMEN
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.
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Collagen-based hydrogels have emerged as a highly promising platform for diverse applications in ophthalmology, spanning from drug delivery systems to biomedical interventions. This review explores the diverse sources of collagen, which give rise to different types of collagen protein. The critical isolation and purification steps are discussed, emphasizing their pivotal role in preparing collagen for biomedical use. To ensure collagen quality and purity, and the suitability of collagen for targeted applications, a comprehensive characterization and quality control are essential, encompassing assessments of its physical, chemical, and biological properties. Also, various cross-linking collagen methods have been examined for providing insight into this crucial process. This comprehensive review delves into every facet of collagen and explores the wide-ranging applications of collagen-based hydrogels, with a particular emphasis on their use in drug delivery systems and their potential in diverse biomedical interventions. By consolidating current knowledge and advancements in the field, this review aims to provide a detailed overview of the utilization of engineered collagen-based hydrogels in ocular therapeutics.
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Cyclosporine (CsA) stays the most intangible molecule holding a good history for treating several ophthalmic conditions and it even attributes to multiple off-label uses. Topical delivery of CsA is the most preferred route but owing to the molecule's physicochemical properties such as poor aqueous solubility and high molecular weight as well as its encounter with multiple barriers of eye causes hindrance for proper delivery of the molecule to the site of action. However, Restasis®, Cequa®, and Verkazia® are the marketed formulations that have been approved by U.S. Food and Drug Administration, whereas Cyclokat® and Ikervis® by the European Medicines Agency. Although these medications are in use, they are associated with severe discomfort and poor patient compliance. This review gives an overview regarding current formulations available in the market, the products in pipeline and the recent advances undertaken for improving ocular delivery of CsA for various ophthalmic indications.
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Ciclosporina , Oftalmopatías , Humanos , Ciclosporina/química , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Ojo , Oftalmopatías/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Excipientes , Administración OftálmicaRESUMEN
Osteoporosis is a bone incapacitating malady which globally accounts for over hundred million fractures annually. Therapeutic interventions for management of osteoporosis are divided as antiresorptive agents and osteoanabolic agents. Teriparatide is the only osteoana-bolic peptide which is available world-wide for the treatment of osteoporosis. It is administered as a daily subcutaneous injection for the treatment of osteoporosis which results in both poor patient compliance and increase in the cost of the therapy. Even after 20 years of clinical use of teriparatide, no formulation of teriparatide has yet been translated from lab to clinic which can be delivered by non-invasive route The present review critically discusses attempts made by the researchers for efficient delivery of teriparatide through various non-invasive routes such as oral, nasal, pulmonary, and transdermal route. It also discusses long-acting injectable formulations of teriparatide to improve patient compliance. Understanding on the pharmacology of teriparatide highlights the enhanced effectiveness of intermittent/pulsatile mode of teriparatide delivery which has also been elaborated. In addition, targeted delivery of teriparatide using different bone specific targeting moieties has been also discussed.
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Achieving precise cancer theranostics necessitates the rational design of smart nanosystems that ensure high biological safety and minimize non-specific interactions with normal tissues. In this regard, "bioinspired" membrane-coated nanosystems have emerged as a promising approach, providing a versatile platform for the development of next-generation smart nanosystems. This review article presents an in-depth investigation into the potential of these nanosystems for targeted cancer theranostics, encompassing key aspects such as cell membrane sources, isolation techniques, nanoparticle core selection, approaches for coating nanoparticle cores with the cell membrane, and characterization methods. Moreover, this review underscores strategies employed to enhance the multi-functionality of these nanosystems, including lipid insertion, membrane hybridization, metabolic engineering, and genetic modification. Additionally, the applications of these bioinspired nanosystems in cancer diagnosis and therapeutics are discussed, along with the recent advances in this field. Through a comprehensive exploration of membrane-coated nanosystems, this review provides valuable insights into their potential for precise cancer theranostics.
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Nucleic acid therapeutics, specifically antisense oligonucleotides (ASOs), can effectively modulate gene expression and protein function, leading to long-lasting curative effects. The hydrophilic nature and large size of oligonucleotides present translational challenges, which have led to the exploration of various chemical modifications and delivery systems. The present review provides insights into the potential role of liposomes as a drug delivery system for ASOs. The potential benefits of liposomes as an ASO carrier, along with their method of preparation, characterization, routes of administration, and stability aspects, have been thoroughly discussed. A novel perspective in terms of therapeutic applications of liposomal ASO delivery in several diseases such as cancer, respiratory disease, ophthalmic delivery, infectious diseases, gastrointestinal disease, neuronal disorders, hematological malignancies, myotonic dystrophy, and neuronal disorders remains the major highlights of this review.
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The management of chronic conditions often requires patients to take daily medication for an extended duration. However, the need for daily dosing can lead to nonadherence to the therapy, which can result in the recurrence of the disease. Long-acting parenteral drug delivery systems have the potential to improve the treatment of chronic conditions. These systems use various technologies, such as oil-based injectables, PLGA-based microspheres, and in situ forming gel-based depots, to deliver different types of drugs. The use of long-acting parenteral formulations for the treatment of chronic infections such as HIV/AIDS and tuberculosis is a recent development in the field. Researchers are also exploring the use of long-acting parenteral formulations for the treatment of malaria, with the aim of reducing dosing frequency and improving adherence to treatment. This review discusses various aspects of long-acting formulation development, including the impact of the physicochemical properties of the drug, the type of long-acting formulation, and the route of administration. The clinical significance of long-acting formulations and recent advances in the field, such as long-acting nanoformulations and long-acting products currently in clinical trials, have also been highlighted.
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Sistemas de Liberación de Medicamentos , Humanos , Preparaciones de Acción Retardada , Enfermedad CrónicaRESUMEN
Chitosan, a biocompatible and biodegradable polysaccharide derived from chitin, has surfaced as a material of promise for drug delivery and biomedical applications. Different chitin and chitosan extraction techniques can produce materials with unique properties, which can be further modified to enhance their bioactivities. Chitosan-based drug delivery systems have been developed for various routes of administration, including oral, ophthalmic, transdermal, nasal, and vaginal, allowing for targeted and sustained release of drugs. Additionally, chitosan has been used in numerous biomedical applications, such as bone regeneration, cartilage tissue regeneration, cardiac tissue regeneration, corneal regeneration, periodontal tissue regeneration, and wound healing. Moreover, chitosan has also been utilized in gene delivery, bioimaging, vaccination, and cosmeceutical applications. Modified chitosan derivatives have been developed to improve their biocompatibility and enhance their properties, resulting in innovative materials with promising potentials in various biomedical applications. This article summarizes the recent findings on chitosan and its application in drug delivery and biomedical science.
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Lipid-based vaccine delivery systems such as the conventional liposomes, virosomes, bilosomes, vesosomes, pH-fusogenic liposomes, transferosomes, immuno-liposomes, ethosomes, and lipid nanoparticles have gained a remarkable interest in vaccine delivery due to their ability to render antigens in vesicular structures, that in turn prevents its enzymatic degradation in vivo. The particulate form of lipid-based nanocarriers confers immunostimulatory potential, making them ideal antigen carriers. Facilitation in the uptake of antigen-loaded nanocarriers, by the antigen-presenting cells and its subsequent presentation through the major histocompatibility complex molecules, leads to the activation of a cascade of immune responses. Further, such nanocarriers can be tailored to achieve the desired characteristics such as charge, size, size distribution, entrapment, and site-specificity through modifications in the composition of lipids and the selection of the appropriate method of preparation. This ultimately adds to its versatility as an effective vaccine delivery carrier. The current review focuses on the various lipid-based carriers that have been investigated to date as potential vaccine delivery systems, the factors that affect their efficacy, and their various methods of preparation. The emerging trends in lipid-based mRNA vaccines and lipid-based DNA vaccines have also been summarized.
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Bone-specific functionalization strategies on liposomes are promising approaches to delivering the drug in osteoporotic conditions. This approach delivers the drug to the bone surface specifically, reduces the dose and off-target effects of the drug, and thereby reduces the toxicity of the drug. The purpose of the current research work was to fabricate the bone-specific peptide conjugated pegylated nanoliposomes to deliver anabolic drug and its physicochemical evaluations. For this, a bone-specific peptide (SDSSD) was synthesized, and the synthesized peptide was conjugated with a linker (DSPE-PEG2000-COOH) to obtain a bone-specific conjugate (SDSSD-DSPE). Purified SDSSD-DSPE was characterized by HPLC, Maldi-TOF, NMR, and Scanning Electron Microscope/Energy Dispersive Spectroscopy (SEM/EDS). Further, peptide-conjugated and anabolic drug-encapsulated liposomes (SDSSD-LPs) were developed using the ethanol injection method and optimized by Central Composite Design (CCD) using a statistical approach. Optimized SDSSD-LPs were evaluated for their physicochemical properties, including surface morphology, particle size, zeta potential, in vitro drug release, and bone mineral binding potential. The obtained results from these studies demonstrated that SDSSD-DSPE conjugate and SDSSD-LPs were optimized successfully. The particle size, % EE, and zeta potential of SDSSD-LPs were observed to be 183.07 ± 0.85 nm, 66.72 ± 4.22%, and -25.03 ± 0.21 mV, respectively. SDSSD-LPs demonstrated a sustained drug release profile. Further, the in vitro bone mineral binding assay demonstrated that SDSSD-LPs deliver the drug to the bone surface specifically. These results suggested that SDSSD-LPs could be a potential targeting approach to deliver the anabolic drug in osteoporotic conditions.
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Migraine headaches are usually intolerable, and a quick-relief treatment remains an unmet medical need. Almotriptan malate is a serotonin (5-HT1B/1D) receptor agonist approved for the treatment of acute migraine in adults. It is currently available in an oral tablet dosage form and has a Tmax of 1-3 h, and therefore, there is a medical need to develop a non-invasive rapidly acting formulation. We have developed an intranasal formulation of almotriptan malate using the quality-by-design (QbD) approach. A 2-factor 3-level full factorial design was selected to build up the experimental setting. The developed formulation was characterized for pH, viscosity, in vitro permeation, ex vivo permeation, and histopathological tolerance. To assess the potential of the developed formulation to produce a rapid onset of action following intranasal delivery, a pharmacokinetic study was performed in the Sprague-Dawley rat model and compared to the currently available marketed oral tablet formulation. For this, the LC-MS/MS bioanalytical method was developed and used for the determination of plasma almotriptan malate concentrations. Results of a pharmacokinetic study revealed that intranasal administration of optimized almotriptan malate formulation enabled an almost five-fold reduction in Tmax and about seven-fold increase in bioavailability in comparison to the currently available oral tablet formulation, suggesting the potential of developed almotriptan malate intranasal formulation in producing a rapid onset of action as well as enhanced bioavailability.
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Trastornos Migrañosos , Agonistas de Receptores de Serotonina , Animales , Ratas , Administración Intranasal , Cromatografía Liquida , Agonistas de Receptores de Serotonina/farmacocinética , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Triptaminas/farmacocinética , Trastornos Migrañosos/tratamiento farmacológico , Serotonina/uso terapéutico , ComprimidosRESUMEN
Glioblastoma is one of the most devastating central nervous system disorders. Being a highly vascular brain tumor, it is distinguished by aberrant vessel architecture. This lends credence to the idea that endothelial cells (ECs) linked with glioblastoma vary fundamentally from ECs seen in the healthy human brain. To effectively design an antiangiogenic treatment, it is crucial to identify the functional and phenotypic characteristics of tumor-associated ECs. The ECs associated with glioblastoma are less prone to apoptosis than control cells and are resistant to cytotoxic treatments. Additionally, ECs associated with glioblastoma migrate more quickly than control ECs and naturally produce large amounts of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor (VEGF). For designing innovative antiangiogenic drugs that particularly target tumor-related ECs in gliomas, it is critical to comprehend these distinctive features of ECs associated with gliomas. This review discusses the process of angiogenesis, other factors involved in the genesis of tumors, and the possibility of ECs as a potential target in combating glioblastoma. It also sheds light on the association of tumor microenvironment and ECs with immunotherapy. This review, thus gives us the hope that neuro endothelial targeting with growth factors and angiogenesis regulators combined with gene therapy would open up new doorways and change our traditional perspective of treating cancer.
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The objective of the present work was to develop PTH (1-34)-loaded stealth nanoliposomes (PTH-LPs) by employing the use of the Quality by Design (QbD) approach. Risk identification was carried out using the Ishikawa fishbone diagram. PTH-LPs were optimized using Box Behnken Design, a type of response surface methodology to examine the effect of independent variables on dependent variables such as particle size and percentage entrapment efficiency (%EE). Design space was generated for PTH-LPs to reduce interbatch variability during the formulation development process. Furthermore, a cytotoxicity assay, cell proliferation assay, calcium calorimetric assay, mineralized nodule formation, and cellular uptake assay were carried out on MG-63 osteoblast-like cells. The results obtained from these procedures demonstrated that lipid concentration had a significant positive impact on particle size and %EE, whereas cholesterol concentration showed a reduction in %EE. The particle size and %EE of optimized formulation were found to be 147.76 ± 2.14 nm and 69.18 ± 3.62%, respectively. Optimized PTH-LPs showed the sustained release profile of the drug. In vitro cell evaluation studies showed PTH-LPs have good biocompatibility with MG-63 cells. The cell proliferation study revealed that PTH-LPs induced osteoblast differentiation which improved the formation of mineralized nodules in MG-63 cells. The outcome of the present study conclusively demonstrated the potential of the QbD concept to build quality in PTH-LPs with improved osteoanabolic therapy in osteoporosis.
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Osteoporosis is characterised by a major public health burden, particularly taking into account the ageing global population. Therapeutic modalities for osteoporosis are categorised on the basis of their effect on bone remodeling: antiresorptive agents and anabolic agents. Anabolic drugs are favoured as they promote the formation of new bone, whereas antiresorptive drugs terminate the further deterioration of bone. Non-specific delivery of anabolic agents results in prolonged kidney exposure causing malignant hypercalcemia, whereas antiresorptive agents and bisphosphonates may produce osteonecrosis of the jaw. Several clinical trials have been reported for combinational therapy of anabolic agents and antiresorptive agents for osteoporosis. However, none of them have proven their cumulative effectiveness in the treatment of disease. The present work emphasizes on dual-targeting drug delivery approach comprising of bone anabolic and antiresorptive agents that would deliver the therapeutic agents to both the zones of bone simultaneously. The anticipated pioneering delivery approach will intensify the explicit interaction between the therapeutic agent and bone surfaces separately without developing severe adverse effects and improve the osteoporotic therapy effectively compared to non-targeted drug delivery.