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.     

Tumor microenvironment responsive drug delivery systems

Conventional tumor-targeted drug delivery systems (DDSs) face challenges, such as unsatisfied systemic circulation, low targeting efficiency, poor tumoral penetration, and uncontrolled drug release. Recently, tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas. With the introduction of several additional functionalities, the properties of these smart DDSs including size, surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting, and eventually achieve desired drug release for an optimized therapeutic efficiency. This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery. Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli, including pH, glutathione, adenosine-triphosphate, reactive oxygen species, enzyme and inflammatory factors are summarized. Special emphasis of this review is placed on their responsive mechanisms, drug loading models, drawbacks and merits. Several typical multi-stimuli responsive DDSs are listed. And the main challenges and potential future development are discussed.     

Advance in oral delivery systems for therapeutic protein

Abstract

Oral delivery is the most common method of drug administration with high safety and good compliance for patients. However, delivering therapeutic proteins to the target site via oral route involves tremendous challenge due to unfavourable conditions like biochemical barrier, mucus barrier and epithelial barriers. According to the functional differences of various protein drug delivery systems, the recent advances in pH responsive polymer-based drug delivery system, mucoadhesive polymer-based drug delivery system, absorption enhancers-based drug delivery system and composite polymer-based delivery system all were briefly summarised in this review, which not only clarified the clinic potential of these novel drug delivery systems, but also described the way for increasing oral bioavailability of therapeutic protein.     

Responsive polymeric delivery systems

This paper discusses the state of the art in a relatively new approach in the field of controlled drug delivery–responsive polymeric drug delivery systems. Such systems are capable of adjusting drug release rates in response to a physiological need. The fundamental principles of externally and self-regulated delivery systems are examined. Special attention is paid to specific clinical settings such as diabetes, presenting the advantages and disadvantages of different approaches.     

Smart drug delivery systems for precise cancer therapy

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.     

Silica materials in drug delivery applications

In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.     

国外上市新型注射剂的研究进展

纳米粒、微球、脂质体、原位凝胶和微乳或亚微乳等给药系统能减少药物在体内外的降解,实现药物的控制释放.基于上述给药系统的新型注射剂已成为药物研发的关注热点.本文综述了近年国外上市的新型注射剂的剂型特点及其临床应用概况,并介绍了几种新型注射装置.     

Smart polymers for the controlled delivery of drugs – a concise overview

Smart polymers have enormous potential in various applications. In particular, smart polymeric drug delivery systems have been explored as “intelligent” delivery systems able to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties. The responses vary widely from swelling/contraction to disintegration. Synthesis of new polymers and crosslinkers with greater biocompatibility and better biodegradability would increase and enhance current applications. The most fascinating features of the smart polymers arise from their versatility and tunable sensitivity. The most significant weakness of all these external stimuli-sensitive polymers is slow response time. The versatility of polymer sources and their combinatorial synthesis make it possible to tune polymer sensitivity to a given stimulus within a narrow range. Development of smart polymer systems may lead to more accurate and programmable drug delivery. In this review, we discuss various mechanisms by which polymer systems are assembled in situ to form implanted devices for sustained release of therapeutic macromolecules, and we highlight various applications in the field of advanced drug delivery.KEY WORDS: Smart polymers, Temperature responsive polymers, pH responsive polymers, Field sensitive polymers, Glucose responsive polymers     

智能材料在药剂学中的分类与应用

目的为智能材料在药剂学中的应用提供理论依据。方法通过查阅近年国内外文献,对物理、化学和生物化学刺激敏感型智能材料的分类、各类材料构建相应智能给药系统的设计原理及其在药剂学中的应用进行详细的阐述。结果应用智能材料可制备出各种智能给药系统,通过感应病变部位各种环境信息的变化,实现药物的定点、定时、定量释放。结论虽然智能材料的应用迄今为止多数仍停留在实验研究阶段,但可以预见智能材料在药剂学领域中的应用会显现出更大的优势。     

Pulsatile drug release control using hydrogels.

Current research in the field of drug delivery devices, by which pulsed and/or pulsatile release is achieved, has been intensified. In this article several types of drug delivery systems using hydrogels are discussed that showed pulsed and/or pulsatile drug delivery characteristics. As is frequently found in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, while minimizing undesired side effects. Special attention has been given to the thermally responsive poly(N-isopropylacrylamide) and its derivative hydrogels. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery devices, hydrogels, and micelles. Development of modified alginate gel beads with pulsed drug delivery characteristic is also described in this article.     

Classification of stimuli–responsive polymers as anticancer drug delivery systems

Abstract

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli–responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli–responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.     

Zinc-based metal–organic frameworks as nontoxic and biodegradable platforms for biomedical applications: review study

Abstract

Development of biomedical systems for controllable drug delivery systems and construction of biosensors is imperative to reduce side effects of common treatment techniques and enhance the therapeutic efficacy. To address this issue, metal–organic frameworks (MOFs) as hybrid porous polymeric structures have attracted worldwide attention due to their unprecedented opportunities in vast range of applications in diverse fields including chemistry, biological, and medicinal science as gas storage/separation, sensing, and drug delivery systems. Recently, biomedical application has become an interesting and promising issue for development and usage of multi-functional MOFs. Flexible chemical composition and versatile porous structure of MOFs enable the engineering and enhancement of their medical formulation and functionality as practical carriers for whether therapeutic or imaging agents. One important point in this domain is the efficient delivery of drugs in the body using nontoxic and biodegradable carriers. This review brings together the literatures that addressing the biomedical applications of Zinc-based MOFs (i.e. as drug delivery systems or nontoxic agent in matter of therapeutic applications) to present recent achievements in this interesting field.     

Environment-sensitive hydrogels for drug delivery.

Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.     

Environment-sensitive hydrogels for drug delivery

Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.     

Electronic MEMS for triggered delivery

Implantable electronic devices such as pacemakers and neural implants are often used for electrical stimulation. The usage of microfabrication techniques to produce microelectromechanical systems (MEMS) has allowed engineers to address a wider range of clinical indications. A new direction in the area of MEMS technology is the goal of achieving pulsatile drug delivery. The digital capabilities of MEMS may allow greater temporal control over drug release compared to traditional polymer-based systems, while the batch-processing techniques used in the microelectronics industry can lead to greater device uniformity and reproducibility than is currently available to the pharmaceutical industry. A repertoire of structures, including microreservoirs, micropumps, valves, and sensors, is being developed that will provide a strong foundation for the design of integrated, responsive MEMS for drug delivery.     

Ordered mesoporous silicates as matrices for controlled release of drugs

Interest in and thereby also development of ordered mesoporous silicates as drug delivery devices have grown immensely over the past few years. On hand selected cases from the literature, the power of such systems as delivery devices has been established. Specifically, it is shown how it is possible to enhance the release kinetics of poorly soluble drugs by embedding them in mesoporous silicates. Further critical factors governing the structure and release of the model drug itraconazole incorporated in an SBA-15 matrix are briefly reviewed. The possibility of functionalizing the surface of mesoporous matrices also under harsher conditions offers a broad platform for the design of stimuli-responsive drug release, including pH responsive systems and systems which respond to the presence of specific ions, reducing agents, magnetic field or UV light, whose efficiency and biocompatibility has been established in vitro.     

Smart Polymers in Nasal Drug Delivery

Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones.     

Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs

Introduction: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently.

Areas covered: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials.

Expert opinion: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic.     

Environmentally responsive ophthalmic gel formulation of carteolol hydrochloride

Environmentally responsive gel formulation for ocular controlled delivery of carteolol hydrochloride (HCl) was developed in an attempt to improve ocular bioavailability and hence decrease its systemic absorption and side effects. The viscosity and the ability of the prepared formulations to deliver carteolol HCl in vitro and in vivo were monitored and compared with an aqueous commercial solution. The effect of polymer concentration and drug concentration on the in vitro release of carteolol HCl was examined. Gelrite formulations showed pseudoplastic behavior with thixotropic characteristics and the viscosity of the prepared systems increased as the concentration of the polymer increased. At fixed drug concentrations, as the Gelrite concentration increased, the drug release decreased. At fixed polymer concentrations, as the drug concentration increased the release of drug increased. Gelrite formulation (0.4% w/w) containing 1% drug showed significantly improved bioavailability compared with the commercial aqueous solution (Arteoptic® 1%). The developed in situ gel formulation showed potential for use as delivery systems with superior ocular bioavailability of carteolol HCl.