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•PEG12KL4 peptide is a promising mRNA delivery vector for pulmonary delivery.•Inhalable mRNA dry powder can be prepared by spray drying and spray freeze drying.•PEG12KL4/mRNA ...formulations did not cause significant toxicity and inflammatory response.
Pulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG12KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG12KL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEG12KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG12KL4 /mRNA complexes at a dose of 5μg mRNA resulted in luciferase expression in the deep lung region of mice 24h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEG12KL4 /mRNA complexes after single intratracheal administration. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEG12KL4 peptide as a mRNA delivery vector candidate for clinical applications.
Chitosan is a biodegradable and biocompatible natural polysaccharide that has a wide range of applications in the field of pharmaceutics, biomedical, chemical, cosmetics, textile and food industry. ...One of the most interesting characteristics of chitosan is its antibacterial and antifungal activity, and together with its excellent safety profile in human, it has attracted considerable attention in various research disciplines. The antimicrobial activity of chitosan is dependent on a number of factors, including its molecular weight, degree of deacetylation, degree of substitution, physical form, as well as structural properties of the cell wall of the target microorganisms. While the sole use of chitosan may not be sufficient to produce an adequate antimicrobial effect to fulfil different purposes, the incorporation of this biopolymer with other active substances such as drugs, metals and natural compounds in nanosystems is a commonly employed strategy to enhance its antimicrobial potential. In this review, we aim to provide an overview on the different approaches that exploit the antimicrobial activity of chitosan-based nanosystems and their applications, and highlight the latest advances in this field.
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Inhaled RNA Therapy: From Promise to Reality Chow, Michael Y.T.; Qiu, Yingshan; Lam, Jenny K.W.
Trends in pharmacological sciences,
10/2020, Letnik:
41, Številka:
10
Journal Article
Recenzirano
Odprti dostop
RNA-based medicine is receiving growing attention for its diverse roles and potential therapeutic capacity. The largest obstacle in its clinical translation remains identifying a safe and effective ...delivery system. Studies investigating RNA therapeutics in pulmonary diseases have rapidly expanded and drug administration by inhalation allows the direct delivery of RNA therapeutics to the target site of action while minimizing systemic exposure. In this review, we highlight recent developments in pulmonary RNA delivery systems with the use of nonviral vectors. We also discuss the major knowledge gaps that require thorough investigation and provide insights that will help advance this exciting field towards the bedside.
Inhaled RNA therapy has great potential for treating a range of lung diseases, including lung infections, cystic fibrosis and asthma.Although naked RNA is able to transfect in the lung following pulmonary administration, its efficiency may be subjected to variation due to the alteration of pulmonary surfactant composition between individuals and disease status, rendering it unfavorable for clinical application.Many delivery systems have been generated for delivery of RNA therapeutics in the lungs.Hybrid delivery systems that combine polymers, lipids, or peptides are increasingly popular for RNA delivery to enhance transfection efficiency.Delivery systems should be tailor-made for different RNA targets and lung diseases to overcome the specific set of delivery barriers associated with the different lung diseases.Only a few studies have evaluated the aerosol performance, integrity of RNA following aerosolization, dose–response relationship, pharmacokinetic profile, and long-term safety of inhaled RNA therapy formulations. More effort needs to be invested in these research areas for clinical translation.
Discovered a little over two decades ago, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are noncoding RNAs with important roles in gene regulation. They have recently been investigated as ...novel classes of therapeutic agents for the treatment of a wide range of disorders including cancers and infections. Clinical trials of siRNA- and miRNA-based drugs have already been initiated. siRNAs and miRNAs share many similarities, both are short duplex RNA molecules that exert gene silencing effects at the post-transcriptional level by targeting messenger RNA (mRNA), yet their mechanisms of action and clinical applications are distinct. The major difference between siRNAs and miRNAs is that the former are highly specific with only one mRNA target, whereas the latter have multiple targets. The therapeutic approaches of siRNAs and miRNAs are therefore very different. Hence, this review provides a comparison between therapeutic siRNAs and miRNAs in terms of their mechanisms of action, physicochemical properties, delivery, and clinical applications. Moreover, the challenges in developing both classes of RNA as therapeutics are also discussed.
RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic ...applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.
Abstract The presence of reactive primary amines in the backbone structure of chitosan, enables the derivatisation with different functional groups and thereby improving and expanding its properties, ...such as solubility and mucoadhesiveness, for biomedical applications. Such derivatives can be exploited with good results in a number of biomedical areas, including enhancement of nucleic acid transfection in gene therapy, as well as many other applications aiming to maximize drug delivery and aiding tissue engineering. The aim of this review is to provide an up to date overview of the methods used for derivatizing the chitosan with amino acids and to discuss the characteristics and potential biomedical application of the different amino acid derivatized chitosans described in the literature.
In the last decade, biological drugs have rapidly proliferated and have now become an important therapeutic modality. This is because of their high potency, high specificity and desirable safety ...profile. The majority of biological drugs are peptide- and protein-based therapeutics with poor oral bioavailability. They are normally administered by parenteral injection (with a very few exceptions). Pulmonary delivery is an attractive non-invasive alternative route of administration for local and systemic delivery of biologics with immense potential to treat various diseases, including diabetes, cystic fibrosis, respiratory viral infection and asthma, etc. The massive surface area and extensive vascularisation in the lungs enable rapid absorption and fast onset of action. Despite the benefits of pulmonary delivery, development of inhalable biological drug is a challenging task. There are various anatomical, physiological and immunological barriers that affect the therapeutic efficacy of inhaled formulations. This review assesses the characteristics of biological drugs and the barriers to pulmonary drug delivery. The main challenges in the formulation and inhalation devices are discussed, together with the possible strategies that can be applied to address these challenges. Current clinical developments in inhaled biological drugs for both local and systemic applications are also discussed to provide an insight for further research.
Introduction
The emergence of multidrug-resistant (MDR)
Mycobacterium tuberculosis
(
Mtb
) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line ...anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the
Mtb
membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria.
Aims
As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying.
Methods and Results
A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%.
Conclusions
Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.
The formulation of medicines for children remains a challenge. An ideal pediatric formulation must allow accurate dose administration and be in a dosage form that can be handled by the target age ...group. It is also important to consider the choices and the amount of excipients used in the formulation for this vulnerable age group. Although oral formulations are generally acceptable to most pediatric patients, they are not suitable for drugs with poor oral bioavailability or when a rapid clinical effect is required. In recent years, oral transmucosal delivery has emerged as an attractive route of administration for pediatric patients. With this route of administration, a drug is absorbed through the oral mucosa, therefore bypassing hepatic first pass metabolism and thus avoiding drug degradation or metabolism in the gastrointestinal tract. The high blood flow and relatively high permeability of the oral mucosa allow a quick onset of action to be achieved. It is a simple and non-invasive route of drug administration. However, there are several barriers that need to be overcome in the development of oral transmucosal products. This article aims to provide a comprehensive review of the current development of oral transmucosal delivery specifically for the pediatric population in order to achieve systemic drug delivery. The anatomical and physiological properties of the oral mucosa of infants and young children are carefully examined. The different dosage forms and formulation strategies that are suitable for young patients are discussed.
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