Synthetic polymer systems in drug delivery

The development of synthetic polymers for applications in drug delivery is reviewed, with particular reference to polymers that can be activated to release a medicinal agent in vivo or that can respond to changes in environment to enhance the effectiveness of therapy. The mechanisms by which these polymers are designed to deliver drugs are highlighted, along with the challenges facing synthetic chemists and pharmaceutical scientists in designing new and more active therapeutic vehicles. Currently, synthetic materials with biomimetic properties are attracting growing attention as possible new dosage formulations and the potential applications of these increasingly sophisticated polymers in cell-specific drug targeting and in the emerging field of gene therapy are also considered. Finally, the potential development issues for delivery of therapeutics using active or 'smart' polymers are discussed with an analysis of the future trends in this rapidly expanding area of research.     

Nanoparticles for delivery of chemotherapeutic agents to tumors

Despite decades of research, progress in cancer chemotherapy is relatively slow, hampered, in part, by the lack of appropriate mechanisms to deliver anticancer drugs selectively to tumor tissues. This is a challenging task, as various cellular, anatomical and physiological barriers impede effective delivery of drugs to tumors. Systemic or oral administration can cause severe toxicity, which limits the therapeutic potential of anticancer drugs. Therefore, the most important goal of drug delivery is to minimize the exposure of normal tissues to these drugs while maintaining their therapeutic concentration in tumors. Furthermore, the risk of subtherapeutic dosing of anticancer drugs is significant as tumors may develop drug resistance as a result of biochemical changes, drug export mechanisms, or limitations in mechanisms of cellular drug importation. As the field of cancer nanomedicine advances, it is anticipated that many drug delivery-related issues concerning cancer chemotherapeutics will be resolved. This review discusses the current status of nanoparticle-mediated cancer drug delivery, challenges to its utilization, and potential implications of its use in cancer therapy.     

Targeted multifunctional lipid-based nanocarriers for image-guided drug delivery

Lipid-based nanocarriers have proven successful in the delivery of mainly chemotherapeutic agents, and currently they are being applied clinically in the treatment of various types of cancer. These drug delivery systems achieve increased therapeutic efficacy by altering the pharmacokinetics and biodistribution of encapsulated drugs, resulting in decreased drug toxicity and enhanced accumulation in tumor tissue. This increased accumulation is due to the relatively leaky immature vasculature of a tumor. After the clinical relevance of such drug delivery systems was demonstrated, research in this area focused on optimization, both by cell specific targeting and including controlled and triggered release concepts within the carrier. These more advanced targeted nanocarriers in general have clearly shown their potential in various animal tumor models and await clinical application. The development of targeted nanocarriers in which therapeutic and imaging agents are merged into a single carrier will certainly be of importance in the near future. Indeed, scientists active in the field of imaging (e.g. nuclear and magnetic resonance imaging) have already started to exploit nanocarriers for molecular imaging. Image-guided drug delivery using these multifunctional nanocarriers, containing therapeutic and imaging agents, will ultimately allow for online monitoring of tumor location, tumor targeting levels, intratumoral localization and drug release kinetics prior and during radio- and/or chemotherapeutic treatment. This review describes the current status and challenges in the field of nanocarrier-aided drug delivery and drug targeting and discusses the opportunities of combining imaging probes with these drug carriers and the potential of these multifunctional lipid-based nanocarriers within image-guided drug delivery.     

The influence of pulmonary surfactant on nanoparticulate drug delivery systems

The pulmonary route is very attractive for drug delivery by inhalation. In this regard, nanoparticulate drug delivery systems, designed as multifunctional engineered nanoparticles, are very promising since they combine several opportunities like a rather uniform distribution of drug dose among all ventilated alveoli allowing for uniform cellular drug internalization. However, although the field of nanomedicine offers multiple opportunities, it still is in its infancy and the research has to proceed in order to obtain a specific targeting of the drug combined with minimum side effects. If inhaled nanoparticulate drug delivery systems are deposited on the pulmonary surfactant, they come into contact with phospholipids and surfactant proteins. It is highly likely that the interaction of nanoparticulate drug delivery systems with surfactant phospholipids and proteins will be able to mediate/modulate the further fate of this specific drug delivery system. In the present comment, we discuss the potential interactions of nanoparticulate drug delivery systems with pulmonary surfactant as well as the potential consequences of this interaction.     

载抗肿瘤药物纳米靶向给药系统的研究进展

利用纳米微粒作为小分子抗肿瘤药物靶向传递系统的研究正在快速的发展和进行中,将抗肿瘤药物用各种不同材料的纳米微粒包裹,可以有助于提高其水溶性,增加肿瘤组织中的药物分布,以及加强抗肿瘤活性,同时减小对其他组织器官的非特异性毒性。此类研究主要集中在如何使得抗肿瘤药物在靶向肿瘤组织部位释放传递以及限制其对健康组织器官的影响,本文从当今常见纳米载药系统的类型以及肿瘤细胞靶向、肿瘤微环境靶向以及肿瘤转移灶靶向等多方面综述载抗肿瘤药物纳米微粒传递系统的研究进展。     

Microneedles and their applications

Microneedle mediated microporation has proved its potential to enhance the delivery of therapeutic drug molecules through skin over the last one decade. Several patents have been granted and cutting edge research is going on particularly for the delivery of biopharmaceuticals (macromolecules like protein or peptides). The technology involves use of micron sized needles made of diverse materials to form microchannels into the stratum corneum (or deeper), outermost barrier layer of the skin. These microchannels are deep enough to facilitate efficient drug delivery through disrupted stratum corneum but short enough to avoid bleeding or pain. So far, the microneedle technology has been explored for drug and vaccine delivery through transcutaneous route. However, the miniaturized nature of these microneedles and anticipated minimal invasiveness has led the scientists to explore and patent its possible use for several other applications.The use of this technology in combination with other enhancement techniques has also gained recent attention. This review article focuses on the latest developments in the field of microneedles as described in patent and research literature. Comprehensive review of several topics including device design/fabrication, formulation development, safety/regulatory issues, therapeutic applications and major challenges in the commercialization of microneedles as medical devices has been presented here.     

Pharmacoepigenetic aspects of gene polymorphism on drug therapies: effects of DNA methylation on drug response

Our knowledge of epigenetics has increased in recent times and its role in various aspects of cellular physiology and disease cannot be overemphasized, even though many issues still need to be clarified. The role of epigenetics in drug therapy is one aspect that necessitates more work. Although a few epigenetic drugs are already being used clinically and others are being developed for such use, other aspects of drug therapy that are affected by epigenetic alterations need to be considered. We want to emphasize the role of environment as an important factor that modifies the epigenome, creating variation among individuals and that can ultimately affect how they respond to drug therapy. The numerous gene products that are being utilized as drug targets can likewise be affected epigenetically and would thus require special attention.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

Protein-based nanoparticles as a drug delivery system: chances,risks, perspectives

This review aims to provide a broad overview of the development of drug delivery nanoparticulate systems, their classification by basic material, preparation method and administration route while focusing on recent trends in the field of protein-based nanoparticles. Literature on drug delivery by nanotechnology was reviewed in the light of previous and ongoing research. Potentials and challenges including regulatory issues are discussed in the context of possible applications of the miscellaneous nanoparticle devices. Over the past years homogeneous and clearly size-defined nanoparticles have been successfully designed from a large variety of starting materials. These nanoparticles offered diverse targeting or imaging properties in order to either enhance pharmacodynamic efficiency or reduce side effects of the delivered drug substance or to monitor the system’s fate in vivo. The latter is considered especially crucial when it comes to finally guiding nanoparticulate formulations through the clinical phase and its use for the patient’s benefit in the end. If the clinical requirements can be met, the main promises of the new nanoparticulate formulations and associated new routes of drug delivery can be met (a) to enable new types of medicines to be carried to previously inaccessible sites within the body or (b) to reduce risks in delivering already established drugs.     

Nanocomposite thin films for triggerable drug delivery

Introduction: Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion.

Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape.

Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.     

Malaria treatment using novel nano-based drug delivery systems

We reside in an era of technological innovation and advancement despite which infectious diseases like malaria remain to be one of the greatest threats to the humans. Mortality rate caused by malaria disease is a huge concern in the twenty-first century. Multiple drug resistance and nonspecific drug targeting of the most widely used drugs are the main reasons/drawbacks behind the failure in malarial therapy. Dose-related toxicity because of high doses is also a major concern. Therefore, to overcome these problems nano-based drug delivery systems are being developed to facilitate site-specific or target-based drug delivery and hence minimizing the development of resistance progress and dose-dependent toxicity issues. In this review, we discuss about the shortcomings in treating malaria and how nano-based drug delivery systems can help in curtailing the infectious disease malaria.     

Magnetism in drug delivery: The marvels of iron oxides and substituted ferrites nanoparticles

In modern drug delivery, seeking a drug delivery system (DDS) with a modifiable skeleton for proper targeting of loaded actives to specific sites in the body is of extreme importance for a successful therapy. Magnetically guided nanosystems, where particles such as iron oxides are guided to specific regions using an external magnetic field, can provide magnetic resonance imaging (MRI) while delivering a therapeutic payload at the same time, which represents a breakthrough in disease therapy and make MNPs excellent candidates for several biomedical applications. In this review, magnetic nanoparticles (MNPs) along with their distinguishable properties, including pharmacokinetics and toxicity, especially in cancer therapy will be discussed. The potential perspective of using other elements within the MNP system to reduce toxicity, improve pharmacokinetics, increase the magnetization ability, improve physical targeting precision and/or widen the scope of its biomedical application will be also discussed.     

Sustained-release ophthalmic drug delivery systems for treatment of macular disorders: present and future applications

Macular disease currently poses the greatest threat to vision in aging populations. Historically, most of this pathology could only be dealt with surgically, and then only after much damage to the macula had already occurred. Current pathophysiological insights into macular diseases have allowed the development of effective new pharmacotherapies. The field of drug delivery systems has advanced over the last several years with emphasis placed on controlled release of drug to specific areas of the eye. Its unique location and tendency toward chronic disease make the macula an important and attractive target for drug delivery systems, especially sustained-release systems. This review evaluates the current literature on the research and development of sustained-release posterior segment drug delivery systems that are primarily intended for macular disease with an emphasis on age-related macular degeneration.Current effective therapies include corticosteroids and anti-vascular endothelial growth factor compounds. Recent successes have been reported using anti-angiogenic drugs for therapy of age-related macular degeneration. This review also includes information on implantable devices (biodegradable and non-biodegradable), the use of injected particles (microspheres and liposomes) and future enhanced drug delivery systems, such as ultrasound drug delivery. The devices reviewed show significant drug release over a period of days or weeks. However, macular disorders are chronic diseases requiring years of treatment. Currently, there is no 'gold standard' for therapy and/or drug delivery. Future studies will focus on improving the efficiency and effectiveness of drug delivery to the posterior chamber. If successful, therapeutic modalities will significantly delay loss of vision and improve the quality of life for patients with chronic macular disorders.     

Advances in mesoporous silica nanoparticles for targeted stimuli-responsive drug delivery: an update

Introduction: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered.

Areas covered: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy.

Expert opinion: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.     

Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging

Drug delivery is an interdisciplinary and independent field of research and is gaining the attention of pharmaceutical researchers, medical doctors and industry. A safe and targeted drug delivery could improve the performance of some classic medicines already on the market, and moreover, will have implications for the development and success of new therapeutic strategies such as anticancer drug delivery, peptide and protein delivery and gene therapy. In the last decade, several drug-delivery technologies have emerged and a fascinating part of this field is the development of nanoscale drug delivery devices. Nanoparticles (NPs) have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs and other colloidal drug-delivery systems modify the kinetics, body distribution and drug release of an associated drug. This review article focuses on the potential of nanotechnology in medicine and discusses different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging. FROM THE CLINICAL EDITOR: This comprehensive review focuses on different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging.     

MRI-Guided Monitoring of Thermal Dose and Targeted Drug Delivery for Cancer Therapy

Application of localized hyperthermia treatment for solid tumor therapy is under active clinical investigation. The success of this treatment methodology, whether for tumor ablation or drug delivery, requires accurate target localization and real-time temperature mapping of the targeted region. Magnetic Resonance Imaging (MRI) can monitor temperature elevations in tissues in real-time during tumor therapy. MRI can also be applied in concert with methods such as High Intensity Focused Ultrasound (HIFU) to enable image-guided drug delivery (IGDD) from temperature sensitive nanocarriers, by exploiting not only its anatomic resolution, but its ability to detect and measure drug release using markers co-loaded with drugs within the nanocarriers. We review this rapidly emerging technology, providing an overview of MRI-guided tissue thermal dose monitoring for HIFU and Laser therapy, its role in targeted drug delivery and its future potential for clinical translation.     

Non-oral drug delivery in Parkinson’s disease: a summary from the symposium at the 7th International Congress of Parkinson’s Disease and Movement Disorders

This symposium reviewed the issues of non-oral therapy in the late stage Parkinson’s disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy.     

Nano-emulsions and Micro-emulsions: Clarifications of the Critical Differences

Much research has been done over the past years on self-emulsifying drug delivery systems, their main interest being the simplicity of the formulation processes, the great stability of the systems and their high potential in pharmaceutical applications and industrial scaling-up. Self-emulsifying drug delivery systems are generally described in the literature indiscriminately as either nano-emulsions or micro-emulsions. Although this misconception appears to be common, these two systems are fundamentally different, based on very different physical and physicochemical concepts. Their differences result in very different stability behaviors, which can have significant consequences regarding their applications and administration as nanomedicines. This paper aims at clarifying the problem, first by reviewing all the physical and physicochemical fundamentals regarding these two systems, using a quantitative thermodynamic approach for micro-emulsions. Following these clarifications, we show how the confusion between nano-emulsions and micro-emulsions appears in the literature and how most of the micro-emulsion systems referred to are actually nano-emulsion systems. Finally, we illustrate how to clear up this misconception using simple experiments. Since this confusion is well established in the literature, such clarifications seem necessary in order to improve the understanding of research in this important field.     

Brain-Targeted Drug Delivery

Because the brain is tightly segregated from the circulating blood by a unique membranous barrier, the blood-brain barrier (BBB), many pharmaceuticals cannot be efficiently delivered to, or sustained within the brain; hence, they are ineffective in treating cerebral diseases. Therefore, drug delivery methods that can provide brain delivery, or eventually preferential brain delivery (i.e. brain targeting), are of particular interest. To achieve successful delivery, an understanding of the major structural, enzymatic, and active transport aspects related to the BBB, and of the issues related to lipophilicity and its role in CNS entry, is critical. During the last years, considerable effort was focused in the field of brain-targeted drug delivery. Various more or less sophisticated approaches, such as intracerebral delivery, intracerebroventricular delivery, intranasal delivery, BBB disruption, nanoparticles, receptor mediated transport (vector-mediated transport or ‘chimeric’ peptides), cell-penetrating peptides, prodrugs, and chemical delivery systems, have been attempted. These approaches may offer many intriguing possibilities for brain delivery and targeting, but only some have reached the phase where they can provide safe and effective human applications. Site-target indexing and the use of targeting enhancement factors can be used to quantitatively assess the site-targeting effectiveness from a pharmacokinetic perspective of chemical delivery systems.     

Carbon nanomaterials combined with metal nanoparticles for theranostic applications

Among targeted delivery systems, platforms with nanosize dimensions, such as carbon nanomaterials (CNMs) and metal nanoparticles (NPs), have shown great potential in biomedical applications. They have received considerable interest in recent years, especially with respect to their potential utilization in the field of cancer diagnosis and therapy. The many functions of nanomaterials provide opportunities to use them as multimodal agents for theranostics, a combination of therapy and diagnosis. Carbon nanotubes and graphene are some of the most widely used CNMs because of their unique structural and physicochemical properties. Their high specific surface area allows for efficient drug loading and the possibility of functionalization with various bioactive molecules. In addition, CNMs are ideal platforms for the attachment of NPs. In the biomedical field, NPs have also shown tremendous potential for use in drug delivery, non-invasive tumour imaging and early detection due to their optical and magnetic properties. NP/CNM hybrids not only combine the unique properties of the NPs and CNMs but they also exhibit new properties arising from interactions between the two entities. In this review, the preparation of CNMs conjugated to different types of metal NPs and their applications in diagnosis, imaging, therapy and theranostics are presented.