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Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance. Ge Zhishen,Liu Shiyong Chemical Society reviews Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (~pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9-6.2 in early endosomes and pH 5.0-5.5 in late endosomes and lysosomes) and redox and H2O2 gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of "active targeting" strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, β-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity. 10.1039/c3cs60048c
Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Alvarez-Lorenzo Carmen,Blanco-Fernandez Barbara,Puga Ana M,Concheiro Angel Advanced drug delivery reviews Polysaccharides are gaining increasing attention as components of stimuli-responsive drug delivery systems, particularly since they can be obtained in a well characterized and reproducible way from the natural sources. Ionic polysaccharides can be readily crosslinked to render hydrogel networks sensitive to a variety of internal and external variables, and thus suitable for switching drug release on-off through diverse mechanisms. Hybrids, composites and grafted polymers can reinforce the responsiveness and widen the range of stimuli to which polysaccharide-based systems can respond. This review analyzes the state of the art of crosslinked ionic polysaccharides as components of delivery systems that can regulate drug release as a function of changes in pH, ion nature and concentration, electric and magnetic field intensity, light wavelength, temperature, redox potential, and certain molecules (enzymes, illness markers, and so on). Examples of specific applications are provided. The information compiled demonstrates that crosslinked networks of ionic polysaccharides are suitable building blocks for developing advanced externally activated and feed-back modulated drug delivery systems. 10.1016/j.addr.2013.04.016
Physical triggering strategies for drug delivery. Sun Tao,Dasgupta Anshuman,Zhao Zongmin,Nurunnabi Md,Mitragotri Samir Advanced drug delivery reviews Physically triggered systems hold promise for improving drug delivery by enhancing the controllability of drug accumulation and release, lowering non-specific toxicity, and facilitating clinical translation. Several external physical stimuli including ultrasound, light, electric fields and magnetic fields have been used to control drug delivery and they share some common features such as spatial targeting, spatiotemporal control, and minimal invasiveness. At the same time, they possess several distinctive features in terms of interactions with biological entities and/or the extent of stimulus response. Here, we review the key advances of such systems with a focus on discussing their physical mechanisms, the design rationales, and translational challenges. 10.1016/j.addr.2020.06.010
Electric field-responsive nanoparticles and electric fields: physical, chemical, biological mechanisms and therapeutic prospects. Kolosnjaj-Tabi Jelena,Gibot Laure,Fourquaux Isabelle,Golzio Muriel,Rols Marie-Pierre Advanced drug delivery reviews Electric fields are among physical stimuli that have revolutionized therapy. Occurring endogenously or exogenously, the electric field can be used as a trigger for controlled drug release from electroresponsive drug delivery systems, can stimulate wound healing and cell proliferation, may enhance endocytosis or guide stem cell differentiation. Electric field pulses may be applied to induce cell fusion, can increase the penetration of therapeutic agents into cells, or can be applied as a standalone therapy to ablate tumors. This review describes the main therapeutic trends and overviews the main physical, chemical and biological mechanisms underlying the actions of electric fields. Overall, the electric field can be used in therapeutic approaches in several ways. The electric field can act on drug carriers, cells and tissues. Understanding the multiple effects of this powerful tool will help harnessing its full therapeutic potential in an efficient and safe way. 10.1016/j.addr.2018.10.017
Environment-sensitive hydrogels for drug delivery. Qiu Y,Park K Advanced drug delivery reviews 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. 10.1016/s0169-409x(01)00203-4
A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications. Pillay Viness,Tsai Tong-Sheng,Choonara Yahya E,du Toit Lisa C,Kumar Pradeep,Modi Girish,Naidoo Dinesh,Tomar Lomas K,Tyagi Charu,Ndesendo Valence M K Journal of biomedical materials research. Part A Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. 10.1002/jbm.a.34869