Stimuli-responsive nanocarriers for drug delivery
TL;DR: Recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
Abstract: Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
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TL;DR: By successively addressing each of the biological barriers that a particle encounters upon intravenous administration, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
Abstract: Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
4,457 citations
TL;DR: Novel engineering approaches are discussed that capitalize on the growing understanding of tumour biology and nano–bio interactions to develop more effective nanotherapeutics for cancer patients.
Abstract: The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.
3,800 citations
1,837 citations
TL;DR: It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.
Abstract: In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.
1,603 citations
TL;DR: A brief introduction to the applications of MOFs in controlled drug/cargo delivery and cancer therapy that have been reported in recent years is provided here.
Abstract: Metal-organic frameworks (MOFs)-an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers-have attracted increasing attention in recent years. The superior properties of MOFs, such as well-defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, make them promising candidates as drug delivery hosts. Furthermore, scientists have made remarkable achievements in the field of nanomedical applications of MOFs, owing to their facile synthesis on the nanoscale and alternative functionalization via inclusion and surface chemistry. A brief introduction to the applications of MOFs in controlled drug/cargo delivery and cancer therapy that have been reported in recent years is provided here.
1,475 citations
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TL;DR: This work develops a platform based on the photothermal effect of gold nanocages that works well with various effectors without involving sophiscated syntheses, and is well-suited for in vivo studies due to the high transparency of soft tissue in NIR.
Abstract: Photosensitive caged compounds have enhanced our ability to address the complexity of biological systems by generating effectors with remarkable spatial/temporal resolutions. The caging effect is typically removed by photolysis with ultraviolet light to liberate the bioactive species. Although this technique has been successfully applied to many biological problems, it suffers from a number of intrinsic drawbacks. For example, it requires dedicated efforts to design and synthesize a precursor compound for each effector. The ultraviolet light may cause damage to biological samples and is suitable only for in vitro studies because of its quick attenuation in tissue. Here we address these issues by developing a platform based on the photothermal effect of gold nanocages. Gold nanocages represent a class of nanostructures with hollow interiors and porous walls. They can have strong absorption (for the photothermal effect) in the near-infrared while maintaining a compact size. When the surface of a gold nanocage is covered with a smart polymer, the pre-loaded effector can be released in a controllable fashion using a near-infrared laser. This system works well with various effectors without involving sophisticated syntheses, and is well suited for in vivo studies owing to the high transparency of soft tissue in the near-infrared region.
1,305 citations
TL;DR: A tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.
Abstract: Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake Herein, we have designed a tailor-made dual pH-sensitive polymer–drug conjugate nanoparticulate system to overcome the challenges The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (∼68) to facilitate cell internalization Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (∼50) further promotes doxorubicin release from the endocytosed drug carriers This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy
1,027 citations
TL;DR: Liposomes can be designed to release an entrapped drug preferentially at temperatures attainable by mild local hyperthermia, suggesting possible applications in the treatment of tumors or local infection.
Abstract: Liposomes can be designed to release an entrapped drug preferentially at temperatures attainable by mild local hyperthermia. In a test system in vitro, protein synthesis by Escherichia coli is inhibited and killing of the cells is enhanced by heating neomycin-containing liposomes to their phase transition temperature to maximize drug release. In the presence of serum the ratio of release at 44 degrees C to that at 37 degrees C can be made greater than 100:1, suggesting possible applications in the treatment of tumors or local infection.
860 citations
TL;DR: A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized and could lead to a new generation of self-regulated insulin-releasing devices.
Abstract: A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system (BA-MSN) for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized Fluorescein isothiocyanate-labeled, gluconic acid-modified insulin (FITC-G-Ins) proteins were immobilized on the exterior surface of BA-MSN and also served as caps to encapsulate cAMP molecules inside the mesopores of BA-MSN The release of both G-Ins and cAMP was triggered by the introduction of saccharides The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose > glucose > other saccharides The unique feature of this double-release system is that the decrease of FITC-G-Ins release with cycles can be balanced by the release of cAMP from mesopores of MSN, which is regulated by the gatekeeper effect of FITC-G-Ins In vitro controlled release of cAMP was studied at two pH conditions (pH 74 and 85) Furthermore, the cytotoxicity of cAMP-loade
694 citations
TL;DR: The mesopores of MSN could be efficiently capped by the photoresponsive AuNPs without leaking the toxic drug, paclitaxel, inside of live human cells, and the cargo-release property could be easily controlled by low-power photoirradiation under biocompatible and physiological conditions.
Abstract: A gold nanoparticle (AuNP)-capped mesoporous silica nanosphere (MSN)-based intracellular drug delivery system (PR-AuNPs-MSN) for the photoinduced controlled release of an anticancer drug, paclitaxel, inside of human fibroblast and liver cells was synthesized and characterized. We found that the mesopores of MSN could be efficiently capped by the photoresponsive AuNPs without leaking the toxic drug, paclitaxel, inside of live human cells. This “zero premature release” characteristic is of importance for delivery of toxic drugs in chemotherapy. Furthermore, we demonstrated that the cargo-release property of this PR-AuNPs-MSN system could be easily controlled by low-power photoirradiation under biocompatible and physiological conditions. We envision that our results would play a significant role in designing new generations of carrier materials for intracellular delivery of a variety of hydrophobic toxic drugs.
599 citations