Potential use of non-classical pathways for the transport of macromolecular drugs

Since an increasing number of drug delivery strategies utilising proteins and peptides exhibiting 'non-classical' transport activities have been proposed, studies have begun to establish underlying functional relationships between different vectors. These attempts to find common factors have been hampered by a lack of biophysical data for the various potential protein and peptide transporters, as well as by the structural and functional diversity of the group as a whole. We describe the various types of vectors being considered for use and the preliminary therapeutic successes that have been achieved. Additionally, the various models that have been proposed for non-classical import and export are outlined and discussed in relation to therapeutic delivery. Possible future developments are also discussed.     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.     

Local strategies and delivery systems for the treatment of malignant gliomas

Abstract

Glioma is one of the most common type of malignant tumours with high morbidity and mortality rates. Due to the particular features of the brain, such as blood–brain barrier or blood–tumour barrier, therapeutic agents are ineffective by systemic administration. The tumour inevitably recurs and devitalises patients. Herein, an overview of the localised gliomas treatment strategies is provided, including direct intratumoural/intracerebral injection, convection-enhanced delivery, and the implant of biodegradable polymer systems. The advantages and disadvantages of each therapy are discussed. Subsequently, we have reviewed the recent developments of therapeutic delivery systems aimed at transporting sufficient amounts of antineoplastic drugs into the brain tumour sites while minimising the potential side effects. To treat gliomas, localised and controlled delivery of drugs at their desired site of action is preferred as it reduces toxicity and increases treatment efficiency. Simultaneously, various drug delivery systems (DDS) have been used to enhance drug delivery to the brain. Use of non-conventional DDS for localised therapy has greatly expanded the spectrum of drugs available for the treatment of malignant tumours. Use smart DDS via localised delivery strategies, in combination with radiotherapy and multiple drug loading would serve as a promising approach to treat gliomas.     

Drug Delivery by Phonophoresis

Phonophoresis is defined as the migration of drug molecules, contained in a contact agent, through the skin under the influence of ultrasound. Several drugs have been introduced into the body by this technique. The design of a phonophoretic drug delivery system is in developmental stages in various research laboratories. Parameters affecting the delivery of drugs by this technique and devices available for drug delivery purposes are discussed in this review.     

Recent progress in drug delivery systems for anticancer agents

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.     

The future perspectives of natural materials for pulmonary drug delivery and lung tissue engineering

Introduction: Search for new, functional biomaterials that can be used to synergistically deliver a drug, enhance its adsorption and stimulate the post-injury recovery of tissue function, is one of the priorities in biomedicine. Currently used materials for drug delivery fail to satisfy one or more of these functionalities, thus they have limited potential and new classes of materials are urgently needed.

Areas covered: Natural materials, due to their origin, physical and chemical structure can potentially fulfill these requirements and there is already strong evidence of their usefulness in drug delivery. They are increasingly utilized in various therapeutic applications due to the obvious advantages over synthetic materials. Particularly in pulmonary drug delivery, there have been limitations in the use of synthetic materials such as polymers and lipids, leading to an increase in the use of natural and protein-based materials such as silk, keratin, elastin and collagen. Literature search in each specialized field, namely, silk, keratin and collagen was conducted, and the benefits of each material for future application in pulmonary drug delivery are highlighted.

Expert opinion: The natural materials discussed in this review have been well established in their use for other applications, yet further studies are required in the application of pulmonary drug delivery. The properties exhibited by these natural materials seem positive for their application in lung tissue engineering, which may allow for more extensive testing for validation of pulmonary drug delivery systems.     

Recent advances in the role of supramolecular hydrogels in drug delivery

Introduction: Supramolecular hydrogels, formed by noncovalent crosslinking of polymeric chains in water, constitute an interesting class of materials that can be developed specifically for drug delivery and biomedical applications. The biocompatibility, stimuli responsiveness to various external factors, and powerful functionalization capacity of these polymeric networks make them attractive candidates for novel advanced dosage form design.

Areas covered: This review summarizes the significance of supramolecular hydrogels in various biomedical and drug delivery applications. The recent advancement of these hydrogels as potential advanced drug delivery systems (for gene, protein, anticancer and other drugs) is discussed. The importance of these hydrogels in biomedical applications, particularly in tissue engineering, biosensing, cell-culture research and wound treatment is briefly described.

Expert opinion: The use of supramolecular hydrogels in drug delivery is still in very early stages. However, the potential of such a system is undeniably important and very promising. A number of recent studies have been conducted, which mainly focus on the use of cyclodextrin-based host–guest complex as well as other supramolecular motifs to form supramolecular hydrogels for delivery of various classes of drugs, therapeutic agents, proteins and genes. However, there are still plenty of opportunities for further development in this area for drug delivery and other biomedical applications.     

Albumin corona on nanoparticles – a strategic approach in drug delivery

Nanomaterials have been used widely for delivery of therapeutic agents. Protein–nanoparticle (NP) complexes have gained importance as vehicles for targeted drug delivery due to increased ease of administration, stability and half-life of drug, and reduced toxic side effects. Designing of phospholipid–bovine serum albumin (BSA) complexes and stealth NPs with BSA has paved the way for drug delivery carriers with prolonged blood circulation times. Preformed albumin corona has shown to decrease non-specific association and thereby reduce the clearance rate. Albumin corona has enabled the localization of drug carriers in specific tissues such as liver and heart, thus regulating biodistribution. Tailored albumin–NP conjugates have also enabled controlled degradation of NP and drug release. However, the binding of albumin with NP is associated with conformational and functional modulations in protein as observed with silver, gold and superparamagnetic iron oxide NPs. In this review, we highlight the various potential albumin–NP hybrids as nano drug carriers.     

“Programmed Polymeric Devices” for Pulsed Drug Delivery

Pharmaceutical research strives to design drug delivery systems that respond to therapeutic needs. Considering the facts that physiologic parameters (e.g., heart rate, blood pressure, and plasma concentration of hormones, plasma proteins, and enzymes) display constancy over time, drug delivery systems with a constant release profile have been designed. However, because of circadian rhythms in physiologic parameters and pathologic conditions (e.g., asthma, angina pectoris), the conventional paradigm concerning drug concentrations "the flatter the better" may not be what the organism may need. Instead, to correlate with our biological needs, "precisely timed drug delivery," which could be accomplished with "programmable dosage forms," is required. Precisely timed drug delivery may maximize therapeutic efficacy, may minimize dose frequency, and may reduce toxicity by avoiding side effects and drug tolerance. This paper outlines the concepts that have been proposed to release drugs in a pulsed manner from pharmaceutical devices.     

Controlled release of heparin-binding growth factors using heparin-containing particulate systems for tissue regeneration

The strategy of growth factor delivery to specific sites for therapeutic applications has been considered an essential process in biomedical fields despite some obstacles, such as a non-controlled release with initial burst. This article focuses on particulate systems using heparin for the controlled delivery of heparin-binding growth factors (HBGFs), an emerging area in the tissue engineering field. Since heparin has been widely utilized for growth factor delivery due to its electrostatic nature and specific affinity with HBGFs, heparin-containing polymeric particulates can be utilized as functional carriers to deliver growth factors in a controlled manner. In particular, examples of the HBGF delivery systems containing heparin, perspectives and potential applications are described and discussed.     

Chitosan-based gastroretentive floating drug delivery technology: an updated review

Introduction: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care.

Areas covered: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed.

Expert opinion: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future.     

Superparamagnetic iron oxide nanoparticle ‘theranostics’ for multimodality tumor imaging,gene delivery,targeted drug and prodrug delivery

The superparamagnetic iron oxide nanoparticle (SPIO) ‘theranostics’, which contain imaging probes for tumor diagnosis and therapeutic compounds for therapy in a single nanoparticle, might provide significant benefits compared with exiting tumor imaging and therapeutic strategies. In this review, we summarize the progress of SPIO ‘theranostics’ that integrate tumor targeting, multimodality imaging, and gene delivery or targeted drug and prodrug delivery. This review describes various methods of SPIO synthesis, surface coating and characterization. Different tumor-targeting strategies, such as antibody fragments, nucleotides and receptor ligands, are discussed to improve SPIO delivery for multimodality imaging. We also examine the utility of SPIOs for gene delivery, siRNA delivery and imaging. Several methods for drug encapsulation and conjugation onto SPIOs are compared for targeted drug delivery, site-specific release and imaging-guided drug delivery. Finally, we also review the pharmacokinetics (including biodistribution) of SPIOs based on their characteristics.     

Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Potential of the bioflavonoids in the prevention/treatment of ocular disorders

Objectives Flavonoids are a common group of plant polyphenols that give colour and flavour to fruits and vegetables. In recent years, flavonoids have gained importance in the pharmaceutical field through their beneficial effects on human health and are widely available as nutritional supplements. Several pharmacological actions of the bioflavonoids may be useful in the prevention or treatment of ocular diseases responsible for vision loss such as diabetic retinopathy, macular degeneration and cataract. This review aims to summarize the potential therapeutic applications of various bioflavonoids in different ocular diseases and also discusses delivery of these agents to the ocular tissues. Key findings It is apparent that the flavonoids are capable of acting on various mechanisms or aetiological factors responsible for the development of different sight threatening ocular diseases. From a drug delivery perspective, ocular bioavailability depends on the physicochemical and biopharmaceutical characteristics of the selected flavonoids and very importantly the route of administration. Summary The potential therapeutic applications of various bioflavonoids in ocular diseases is reviewed and the delivery of these agents to the ocular tissues is discussed. Whereas oral administration of bioflavonoids may demonstrate some pharmacological activity in the outer sections of the posterior ocular segment, protection of the retinal ganglionic cells in vivo may be limited by this delivery route. Systemic or local administration of these agents may yield much higher and effective concentrations of the parent bioflavonoids in the ocular tissues and at much lower doses.     

外泌体作为药物载体在中枢神经系统疾病中的研究进展

外泌体作为细胞间通讯的重要信使，在正常和病理条件下通过转运蛋白质、核酸等物质参与多种生物学功能的调控过程。治疗药物难以跨越血脑屏障（BBB）致使脑内药物浓度过低，无法达到预期治疗效果一直是中枢神经系统（CNS）疾病的治疗瓶颈。考虑到外泌体具有良好的生物相容性、较好的渗透性、能够穿越血脑屏障、天然的稳定性以及低免疫原性和毒性等优点，研究者们开始将其作为新型药物递送系统（DDS）来提升药物在脑内的生物利用度，为临床治疗CNS疾病提供一种新兴治疗策略。本文就外泌体DDS治疗CNS疾病的研究进展进行综述，概述了目前外泌体的载药方式和作为脑部递送载体的特性，重点介绍了外泌体作为核酸、蛋白质和化学药物的递送载体在CNS疾病中的治疗应用。     

Chitosan-based delivery systems for protein therapeutics and antigens

Therapeutic peptides/proteins and protein-based antigens are chemically and structurally labile compounds, which are almost exclusively administered by parenteral injections. Recently, non-invasive mucosal routes have attracted interest for administration of these biotherapeutics. Chitosan-based delivery systems enhance the absorption and/or cellular uptake of peptides/proteins across mucosal sites and have immunoadjuvant properties. Chitosan is a mucoadhesive polysaccharide capable of opening the tight junctions between epithelial cells and it has functional groups for chemical modifications, which has resulted in a large variety of chitosan derivatives with tunable properties for the aimed applications. This review provides an overview of chitosan-based polymers for preparation of both therapeutic peptides/protein and antigen formulations. The physicochemical properties of these carrier systems as well as their applications in protein and antigen delivery through parenteral and mucosal (particularly nasal and pulmonary) administrations are summarized and discussed.     

Ultrasound targeted microbubble destruction for drug and gene delivery

Background: Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. Objective: This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. Methods: All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. Conclusion: Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.     

Layer-by-Layer assembled nano-drug delivery systems for cancer treatment

Nano-drug delivery systems (NDDS) are functional drug-loaded nanocarriers widely applied in cancer therapy. Recently, layer-by-layer (LbL) assembled NDDS have been demonstrated as one of the most promising platforms in delivery of anticancer therapeutics. Here, a brief review of the LbL assembled NDDS for cancer treatment is presented. The fundamentals of the LbL assembled NDDS are first interpreted with an emphasis on the formation mechanisms. Afterwards, the tailored encapsulation of anticancer therapeutics in LbL assembled NDDS are summarized. The state-of-art targeted delivery of LbL assembled NDDS, with special attention to the elaborately control over the passive and active targeting delivery, are represented. Then the controlled release of LbL assembled NDDS with various stimulus responsiveness are systematically reviewed. Finally, conclusions and perspectives on further advancing the LbL assembled NDDS toward more powerful and versatile platforms for cancer therapy are discussed.     

Extended ocular drug delivery systems for the anterior and posterior segments: biomaterial options and applications

Introduction: The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues.

Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed.

Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.     

Nasal-nanotechnology: revolution for efficient therapeutics delivery

Context: In recent years, nanotechnology-based delivery systems have gained interest to overcome the problems of restricted absorption of therapeutic agents from the nasal cavity, depending upon the physicochemical properties of the drug and physiological properties of the human nose.

Objective: The well-tolerated and non-invasive nasal drug delivery when combined with the nanotechnology-based novel formulations and carriers, opens the way for the effective systemic and brain targeting delivery of various therapeutic agents. To accomplish competent drug delivery, it is imperative to recognize the interactions among the nanomaterials and the nasal biological environment, targeting cell-surface receptors, drug release, multiple drug administration, stability of therapeutic agents and molecular mechanisms of cell signaling involved in patho-biology of the disease under consideration.

Methods: Quite a few systems have been successfully formulated using nanomaterials for intranasal (IN) delivery. Carbon nanotubes (CNTs), chitosan, polylactic-co-glycolic acid (PLGA) and PLGA-based nanosystems have also been studied in vitro and in vivo for the delivery of several therapeutic agents which shown promising concentrations in the brain after nasal administration.

Results and conclusion: The use of nanomaterials including peptide-based nanotubes and nanogels (NGs) for vaccine delivery via nasal route is a new approach to control the disease progression. In this review, the recent developments in nanotechnology utilized for nasal drug delivery have been discussed.