Improving drug delivery technology for treating neurodegenerative diseases

ABSTRACT

Introduction: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified.

Areas covered: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms.

Expert Opinion: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer’s disease and Parkinson’s disease. However, much work is still required in this field beyond the preclinical testing phase.     

Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate.

Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE.

Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.     

Biodegradable polymers: an update on drug delivery in bone and cartilage diseases

ABSTRACT

Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair.

Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering.

Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

The optimized drug delivery systems of treating cancer bone metastatic osteolysis with nanomaterials

Some cancers such as human breast cancer, prostate cancer, and lung cancer easily metastasize to bone, leading to osteolysis and bone destruction accompanied by a complicated microenvironment. Systemic administration of bisphosphonates (BP) or denosumab is the routine therapy for osteolysis but with non-negligible side effects such as mandibular osteonecrosis and hypocalcemia. Thus, it is imperative to exploit optimized drug delivery systems, and some novel nanotechnology and nanomaterials have opened new horizons for scientists. Targeted and local drug delivery systems can optimize biodistribution depending on nanoparticles (NPs) or microspheres (MS) and implantable biomaterials with the controllable property. Drug delivery kinetics can be optimized by smart and sustained/local drug delivery systems for responsive delivery and sustained delivery. These delicately fabricated drug delivery systems with special matrix, structure, morphology, and modification can minimize unexpected toxicity caused by systemic delivery and achieve desired effects through integrating multiple drugs or multiple functions. This review summarized recent studies about optimized drug delivery systems for the treatment of cancer metastatic osteolysis, aimed at giving some inspiration in designing efficient multifunctional drug delivery systems.     

Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases

With an increase in lifespan and changing population demographics, the incidence of central nervous system (CNS) diseases is expected to increase significantly in the 21st century. The most challenging of the CNS diseases are neurodegenerative diseases, characterized by age-related gradual decline in neurological function, often accompanied by neuronal death. Alzheimer's disease, Parkinson's disease and Huntington's disease are some examples of neurodegenerative diseases and have been well described in terms of disease mechanisms and pathology. However, successful treatment strategies for neurodegenerative diseases have so far been limited. Delivery of drugs into the CNS is one of the most challenging problems faced in the treatment of neurodegeneration. In this review, we describe the difficulties with CNS therapy, especially with the use of biological macromolecules, such as proteins and nucleic acid constructs. CNS therapeutics also represents a huge opportunity and examples of strategies that can enhance therapeutic delivery for the treatment of neurodegenerative diseases are emphasized. It is anticipated that with an increase in biological understanding of neurodegenerative diseases, there will be even more therapeutic opportunities. As such, these delivery strategies have a very important role to play in the future in the translation of CNS therapeutics from bench to bedside.     

线粒体靶向给药系统用于线粒体疾病治疗的研究进展

线粒体是细胞内具有一定结构和功能特性的细胞器,线粒体功能失调将导致机体疾病的发生,它在调节细胞凋亡方面也发挥着重要作用。为了修复线粒体功能的损伤,研究线粒体靶向给药系统显得尤为重要。本文对国内外的研究情况做简要综述。     

Carbon nanotubes in drug delivery: focus on infectious diseases

Carbon nanotubes have the potential to address the challenges of combating infectious agents by both minimizing toxicity by dose reduction of standard therapeutics and allowing a multiple payload capacity to achieve both targeted activity and combating infectious strains, resistant strains in particular. One of their unique characteristics is the network of carbon atoms in the nanometer scale, allowing the creation of nano-channels via cellular membranes. This review focuses on the characterization, development, integration and application of carbon nanotubes as nanocarrier-based delivery systems and their appropriate design for achieving the desired drug delivery results in the different areas of infectious diseases. While a more extensive toxicological and pharmacological profile must be obtained, this review will focus on existing research and pre-clinical data concerning the potential use of carbon nanotubes.     

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Introduction: Bisphosphonates (BPs) were introduced 45 years ago as anti-osteoporotic drugs and during the last decade have been utilized as bone-targeting groups in systemic treatment of bone diseases. Very recently, strategies of chemical immobilization of BPs in hydrogels and nanocomposites for bone tissue engineering emerged. These strategies opened new applications of BPs in bone tissue engineering.

Areas covered: Conjugates of BPs to different drug molecules, imaging agents, proteins and polymers are discussed in terms of specific targeting to bone and therapeutic affect induced by the resulting prodrugs in comparison with the parent drugs. Conversion of these conjugates into hydrogel scaffolds is also presented along with the application of the resulting materials for bone tissue engineering.

Expert opinion: Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs.     

Thermo-responsive systems for controlled drug delivery

Controlled drug delivery systems represent advanced systems that can be tightly modulated by stimuli in order to treat diseases in which sustained drug release is undesirable. Among the many different stimuli-sensitive delivery systems, temperature-sensitive drug delivery systems offer great potential over their counterparts due to their versatility in design, tunability of phase transition temperatures, passive targeting ability and in situ phase transitions. Thus, thermosensitive drug delivery systems can overcome many of the hurdles of conventional drug delivery systems in order to increase drug efficacies, drug targeting and decrease drug toxicities. In an effort to further control existing temperature-responsive systems, current innovative applications have combined temperature with other stimuli such as pH and light. The result has been the development of highly sophisticated systems, which demonstrate exquisite control over drug release and represent huge advances in biomedical research.     

脂质类纳米载体在难溶性药物递送中的应用

随着新技术在药物研发中的广泛应用,大量有活性的难溶性候选药物涌现出来,但水溶性差的问题又严重制约了此类药物的开发。目前纳米载体作为难溶性药物递送系统的研究日益增多。本文综述了微乳、脂肪乳、脂质体、固体脂质纳米粒、纳米脂质载体、脂质纳米混悬剂和仿生载体等脂质类纳米载体在难溶性药物递送中的应用,旨在为产品的开发提供新策略。     

Implantable microchip: the futuristic controlled drug delivery system

There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized.     

自组装药物传递系统

自组装药物传递系统（SADDS）是基于药质体提出的新概念和新给药系统,融合了前药、分子自组装和纳米技术,是两亲前药形成的自组装纳米体系。其突出的特点是自组装体几乎没有辅料的参与,载药量大,稳定性好,在体内可获得靶向、控释效果,特别适合于抗病毒和抗肿瘤治疗。SADDS是学科交叉的产物,是药剂学研究的新方向。本文阐述了SADDS概念的来源、特点和研究进展,并展望了SADDS的研究前景。     

Novel drug delivery systems for steroidal hormones

There are two main goals in the development of steroid containing drug delivery systems (DDS); firstly, to enhance the therapeutic value of the resulting systems versus standard dosage forms such as peroral tablets or injections. And secondly to manage the life cycle of drug substances which are going off patents. An example of an important development is patient friendly transdermal delivery systems (TDS) for oestrogen replacement therapy, which requires application intervals of once-a-week only, despite the fact that the biological half-life of the delivered oestradiol is ~ 20 min. Even more impressive are the achievements in the classes of intrauterine systems (IUS) and implants where the application intervals can be up to 5 years, throughout which low dosages of levonorgestrel are constantly released with high precision and reproducibility. Novel system developments also include steroid loaded vaginal rings for fertility control. On the basis of the technologies already available in the aforementioned areas of TDS, IUS, implants and vaginal rings, many efforts currently concentrate on expanding the therapeutic value of these system types via integrated technological and clinical development activities. Main targets are fertility control, hormone replacement therapy, treatment of gynaecological conditions (e.g. menorrhagia) and andropause (male hormone replacement therapy).     

Novel formulation and drug delivery strategies for the treatment of pediatric poverty-related diseases

Introduction: Due to a lack of approved drugs and formulations, children represent the most vulnerable patients. Magistral, unlicensed formulations obtained by the manipulation of solid forms should undergo clinical evaluation to ensure bioequivalence. The development of new pediatric medicines is complex and faces technological, economic and ethical challenges. This phenomenon has contributed to the emergence of an adult–children gap. To improve the situation, the World Health Organization launched the global campaign ‘Make medicines child size' and a number of international initiatives have been established. The situation is more critical in the case of poverty-related diseases (PRDs) that mainly affect poor countries.

Areas covered: This review critically discusses different strategies to develop pediatric formulations and drug delivery systems (DDS) in PRDs and their potential implementation in the current market. Readers will gain an updated perspective on the development of pediatric medicines for the treatment of PRDs and the proximate challenges and opportunities faced to ensure an effective pharmacotherapy.

Expert opinion: There is an urgent need for the development of innovative, scalable and cost-viable formulations to ensure pediatric patients have access to appropriate medications for PRDs. The guidelines of the International Conference on Harmonisation constitute a very good orientation tool, as they emphasize physiological and developmental aspects that need to be considered in pediatric research. It is important to consider cultural, economic and ethical aspects that make developing nations facing PRDs different from the developed world. Thus, the best strategy would probably be to conceive and engage similar initiatives in the developing world, to address unattended therapeutic niches.     

Controlled local drug delivery strategies from chitosan hydrogels for wound healing

Introduction: The main target of tissue engineering is the preparation and application of adequate materials for the design and production of scaffolds, that possess properties promoting cell adhesion, proliferation and differentiation. The use of natural polysaccharides, such as chitosan, to prepare hydrogels for wound healing and controlled drug delivery is a research topic of wide and increasing interest.

Areas covered: This review presents the latest results and challenges in the preparation of chitosan and chitosan-based scaffold/hydrogel for wound healing applications. A detailed overview of their behavior in terms of controlled drug delivery, divided by drug categories, and efficacy was provided and critically discussed.

Expert opinion: The need to establish and exploit the advantages of natural biomaterials in combination with active compounds is playing a pivotal role in the regenerative medicine fields. The challenges posed by the many variables affecting tissue repair and regeneration need to be standardized and adhere to recognized guidelines to improve the quality of evidence in the wound healing process. Currently, different methodologies are followed to prepare innovative scaffold formulations and structures. Innovative technologies such as 3D printing or bio-electrospray are promising to create chitosan-based scaffolds with finely controlled structures with customizable shape porosity and thickness. Chitosan scaffolds could be designed in combination with a variety of polysaccharides or active compounds with selected and reproducible spacial distribution, providing active wound dressing with highly tunable controlled drug delivery.     

Self-assembled filamentous nanostructures for drug/gene delivery applications

Importance of the field: Among many nanostructural shapes, filamentous shapes can have unique advantages over the others, including longer persistence in the bloodstream. With the advent of nanotechnology in recent years, a variety of shape-controlled nanostructures has been fabricated. As a wide variety of building blocks can self-assemble into filamentous nanostructures, there are many options available for biomaterial developments with filamentous nanostructures. Similarly to conventional spherical micelles, most filamentous nanostructures have hydrophobic cores where hydrophobic guest molecules can be encapsulated, which enable them to be used in drug delivery applications. Moreover, on suitable molecular design and self-assembly process control, filamentous nanostructures can also be made to deliver nucleic acids or even both drugs and nucleic acids simultaneously.

Areas covered in this review: This review describes the self-assembly process, current developments, and prospects of filamentous nanostructures in drug and gene delivery applications.

What the reader will gain: This review should be helpful in gaining insight into the self-assembly process and nanostructural shape control, the advantages of constructing filamentous nanostructures, and the design of more advanced nanobiomaterials.

Take home message: At present, the development of multifunctional nanostructures is one of the main focuses in nanobiomaterial developments. In this regard, filamentous nanostructures can be good initial targets for tailor-made nanostructure developments because they have more structural variables, as compared with spherical micelles.     

Targeted nanoparticle-based drug delivery and diagnosis

Nanotechnology, or systems/device manufacture at sizes generally ranging between 1 and 100 nm, is a multidisciplinary scientific field undergoing explosive development. The genesis of nanotechnology can be traced to advances in medicine, communications, genomics and robotics. One of the greatest values of nanotechnology will be in the development of new and effective medical treatments (i.e. nanomedicine). This review focuses on the potential of nanomedicine as it relates to the development of nanoparticles for enabling and improving the targeted delivery of therapeutic and diagnostic agents. We highlight the use of nanoparticles for specific intra-compartmental analysis using the examples of delivery to malignant cancers, to the central nervous system, and across the gastrointestinal barriers.     

Nanoparticulate drug delivery platforms for advancing bone infection therapies

Introduction: The ongoing surge of resistance of bacterial pathogens to antibiotic therapies and the consistently aging median member of the human race signal an impending increase in the incidence of chronic bone infection. Nanotechnological platforms for local and sustained delivery of therapeutics hold the greatest potential for providing minimally invasive and maximally regenerative therapies for this rare but persistent condition.

Areas covered: Shortcomings of the clinically available treatment options, including poly(methyl methacrylate) beads and calcium sulfate cements, are discussed and their transcending using calcium-phosphate/polymeric nanoparticulate composites is foreseen. Bone is a composite wherein the weakness of each component alone is compensated for by the strength of its complement and an ideal bone substitute should be fundamentally the same.

Expert opinion: Discrepancy between in vitro and in vivo bioactivity assessments is highlighted, alongside the inherent imperfectness of the former. Challenges entailing the cross-disciplinary nature of engineering a new generation of drug delivery vehicles are delineated and it is concluded that the future for the nanoparticulate therapeutic carriers belongs to multifunctional, synergistic and theranostic composites capable of simultaneously targeting, monitoring and treating internal organismic disturbances in a smart, feedback fashion and in direct response to the demands of the local environment.     

Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery

Importance of the field: Plasmonic nanoparticles provide a new route to treat cancer owing to their ability to convert light into heat effectively for photothermal destruction. Combined with the targeting mechanisms possible with nanoscale materials, this technique has the potential to enable highly targeted therapies to minimize undesirable side effects.

Areas covered in this review: This review discusses the use of gold nanocages, a new class of plasmonic nanoparticles, for photothermal applications. Gold nanocages are hollow, porous structures with compact sizes and precisely controlled plasmonic properties and surface chemistry. Also, a recent study of gold nanocages as drug-release carriers by externally controlling the opening and closing of the pores with a smart polymer whose conformation changes at a specific temperature is discussed. Release of the contents can be initiated remotely through near-infrared irradiation. Together, these topics cover the years from 2002 to 2009.

What the reader will gain: The reader will be exposed to different aspects of gold nanocages, including synthesis, surface modification, in vitro studies, intial in vivo data and perspectives on future studies.

Take home message: Gold nanocages are a promising platform for cancer therapy in terms of both photothermal destruction and drug delivery.