The importance of drug delivery to chemists, medicinal and otherwise, has increased since the advent of integrated drug discovery processes. Physicochemical and biological barriers, pathways for drug delivery, formulation, pharmacokinetic and pharmacodynamic issues, metabolism, and cell culture models used in studying drug delivery are just some of the topics that make drug delivery an exciting field for researchers.
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New inroads in theranostics: The grafting of fluorescent ZnS:Mn-doped nanocrystals and the anticancer drug doxorubicin onto graphene oxide can be used for cell labeling and drug delivery applications. The nanocomposite particles exhibit drug entrapment efficiency of 100% and cancer cell killing efficiency of 85%. The particles label the perinuclear region of HeLa cells with yellow fluorescence (see figure).
Through the tube: A versatile strategy has been developed to control the derivatisation of carbon nanotubes with an anticancer drug, a targeting ligand and a fluorophore for the design of a multimodal drug delivery system for anticancer therapy (see scheme).
Color me pretty: Highly porous metal–organic frameworks with uniform topological networks were constructed by isoreticular extension through click reactions. The accessibility of their pores to large molecules make them highly promising materials for size-dependent large-molecule capture and separation, as demonstrated visually by the selective capture of dye molecules (see picture; MeB=methylene blue, R6G=rhodamine 6G, BBR=brilliant blue R).
A chemoenzymatic conjugation method that is based on enzymatic prenylation and oxime ligation is a simple and efficient means for generating highly stable and homogeneous protein–drug conjugates in a site-specific manner. It can be generally applied to the conjugation of drugs to a wide range of protein binders, facilitating the development of targeted therapies with high efficacies and low off-target effects.
All rolled into one: A biologically inspired delivery vehicle for CRISPR–Cas9 is based on yarn-like DNA nanoparticles that are synthesized by rolling circle amplification. The DNA nanoclews were efficiently loaded with Cas9 protein/single guide RNA complexes and delivered them into human cells, enabling targeted gene disruption.
A cleavable amphiphilic peptide (CAP) nanocarrier transforms from self-assembled nanofibers to spherical nanoparticles (NPs) by loading hydrophobic drugs, and cleavage by the tumor-specific protease, FAP-α, resulted in specific and efficient release of the encapsulated drugs at tumor sites. This Transformers-like drug nanocarrier could disrupt the stromal barrier, and enhance local drug accumulation.
Prodrugs enlarged: An unprecedented synthesis of enzymatically cleavable siRNA prodrugs (“siRNN”) has recently been reported. Targeting domain (TD)-functionalized siRNN released the parent siRNA after cellular uptake and triggered the RNA interference mechanism both in vitro and in vivo. The highlighted report could pave the way for prodrug-based approaches to overcome delivery-related limitations of nucleic acid therapeutics.
Responding well to silica: Mesoporous silica nanoparticles represent one of the most promising nanocarriers for drug delivery (see figure). This concept article describes how their functionalization has allowed the design of more efficient systems by improving their specific retention and uptake with targeted and stimuli-responsive properties.
Nanospace: Self-assembled boronic ester cavitand capsules (see scheme) show unique properties that depend on the characteristics of the bis(catechol) linkers.
Multi-compartmental hydrogel microparticles were fabricated by combining electrospinning and photopatterning processes. Each compartment was made of a fiber matrix with different composition. the resultant microparticles have a potential for various biomedical applications such as bioassay, drug delivery, and tissue engineering.
Switch it on! The integration of pH-sensitive switchable lipids (see picture) into poly(ethylene glycol)-coated liposome formulations enabled the efficient cytoplasmic delivery of polar compounds through an endosomal-escape mechanism. The liposome formulations containing the switchable lipids were stable at pH 7.4 and upon storage but instantly destabilized at endosomal pH values (pH 5–5.5).
Tough gels for drug release: Amphiphilic Janus dendrimers with low molecular weights can readily form self-assembled fibers at very low mass proportion to create supramolecular hydrogels with outstanding mechanical properties (see figure). The gels can be efficiently loaded with different bioactive cargo, such as active enzymes, peptides, and drug molecules, to be used for sustained release in drug delivery.
Responding to change: Stimuli-responsive materials are of immense importance because of their ability to undergo alteration of their properties in response to their environment. The properties of such materials can be tuned by subtle adjustments in temperature, pH, light, and so forth. This review article provides an overview of multi-stimuli-responsive polymeric materials.
Breaking the rules: Thermoresponsive polymers with both dimethyldioxolane and hydroxyethyl side chains were hydrolyzed rapidly under slightly acidic conditions while being stable at pH 7.4 or during storage: important properties for biomedical applications. Thus, hydrolysis of the acid-labile cyclic-acetal groups was accelerated by the presence of hydroxy groups, which led to enhanced hydration of the collapsed copolymer globules (see picture).
Hybrid artificial cells: Over the last years, considerable effort has been devoted to the integration of functionalized synthetic membranes with biological systems, producing “hybrid” artificial cells. This Concept article fundamentally covers recent advances and the current state-of-the-art of such hybrid systems. Specifically, the design of minimal supramolecular constructs that can faithfully mimic or reconstruct the structure and/or function of living systems is described.
Double inhibition: A smart drug-delivery system, constructed by using antagomir-capped mesoporous silica nanoparticles (MSNs), is capable of simultaneous target-triggered release of an antagomir and a hydrophobic small-molecule microRNA inhibitor in Huh7 cells to achieve combination inhibition of endogenous miR-122.
Let's get organized: Docking of His-tagged proteins onto a soluble nickel-immobilized linear polymer enables formation of an efficient protein delivery system with a pyridylthiourea-grafted polyethylenimine carrier. Protein multimerization and the structural features of the multimers were studied.
Lanthanide oxide nanostructures (Sm2O3 and Gd2O3) with various morphologies (nanoflakes, nanowires, ultrathin nanosheets) were synthesized by a facile wet chemistry method. As a proof-of-concept, the Sm2O3 and Gd2O3 ultrathin nanosheets demonstrate promising pH-controlled anticancer drug-delivery behavior.
Two is better than one: A carrier system is developed that can generate NO bubbles in the acidic environment of tumor tissues to trigger localized drug release (specifically irinotecan, denoted CPT-11) and to reverse Pgp-mediated multidrug resistance (Pgp=P-glycoprotein). The combined system enhances intracellular drug accumulation in cancer cells so that the concentration exceeds the therapeutic threshold, eventually leading to antitumor activity.
A reduction-responsive drug delivery nanocarrier system derived from a linear polyester containing disulfide bonds in the main chain is reported. After conjugation to polyethylene glycol (PEG), the polymer self-assembles into nanoparticles capable of encapsulating dyes and anticancer drugs. The nanoparticles are highly sensitive to the concentration of an intracellular reducing agent and exhibit superior anticancer activity.
Get smart: A smart targeting gene carrier for cancer-specific delivery has been successfully prepared by a “multilayer bricks-and-mortar” strategy. Carriers produced by two different self-assembly schemes were investigated for their ability to compact pDNA into nanoparticles. Cell viability studies show that the most suitable (Method A) material has lower cytotoxicity than 25 kDa bPEI and that transfection efficiency is maintained.
Attractive interactions can arise between a fluorocarbon gas and a C2F5-labeled compound (red triangle with green tail) across a phospholipid monolayer, allowing recruitment and immobilization of the fluorinated compound in the phospholipid layer. This new phenomenon allowed preparation of microbubbles loaded with a C2F5-labeled hypoxia biomarker.
Get a response! pH-Responsive drug-delivery systems have promising applications because they are “smart” or “intelligent” in overcoming the shortcomings of conventional drug formulations and are able to deliver drugs in a controlled manner at specific sites and times, which results in high therapeutic efficacy. Recent progress obtained for pH-responsive drug-delivery systems and future perspectives is presented.
Nanotherapeutics are designed and constructed from mesoporous silica nanoparticles for the targeted treatment of cancer based on characteristics of tumor tissues. The picture shows drug delivery triggered by the acidic extracellular environment of cancer, endocytosis of the drug carrier, and intracellular release of cargo drugs.
Targeted & Specific: The applications of nucleic acid aptamers in cancer are reviewed. Single-stranded (ss) oligonucleotide (DNA or RNA)-based aptamers conjugated with drugs and nanomaterials are covered in detail, highlighting their therapeutic potential while acknowledging the challenges that remain to be overcome.
Bringing life from cell death: Stimuli-responsive polymeric nanoparticles can respond to the microenvironment of a particular disease and its cells. Internal triggers as well as external devices permit temporally and spatially controlled drug delivery. The development of well-defined nanomedicines is critical for their behavior in vivo.
On the way to nanomedicine: Considerable advances in the development of nanoparticles for cancer therapy have been made in recent years. Nanoparticle-based drug-delivery systems offer advantages with regard to multidrug resistance, systemic delivery, and clearance, and enable for example specific tumor targeting and controlled release of therapeutic agents.
Moving tracks from maleimide: New site-selective protein modification reactions at cysteine have been developed. Unlike conventional maleimide conjugation, which results in a labile thioether succinimide, the new bioconjugation reactions result in stable conjugates and provide opportunities to develop a new generation of homogeneous, stable, and therapeutically useful conjugates.
On target: Carbon-monoxide-releasing molecules (CORMs) are promising agents for the treatment of several diseases. CORMs are particularly good for enabling CO delivery in a controlled manner without affecting oxygen transport by hemoglobin. Significant progress in the methods for CO detection in live cells and the understanding of the reactivity of CORMs in vivo provides insights into CO biology and the design of safer, and more selective and efficient CORMs for clinical use.
Selective delivery: Active drug targeting enhances the efficacy and specificity of systemic therapeutics. Aptamers, artificial nucleic acid ligands, represent powerful targeting tools that can act as cell-specific drug carriers. The advancements from the past decade have provided various approaches that open new gateways for drug administration in cancer therapy.
PCMs on the rise: As a result of their sharp melting points and large heats of fusion during phase transition, phase-change materials (PCMs) have already found commercial use in thermal management. The vast potential of this class of fascinating materials has recently been tapped in a diverse array of high-tech applications such as controlled release, information storage, sensing/detection, and barcoding.
Release on demand: The pH gradients between extra- and intracellular regions can be utilized for the controlled release of drugs and biological cargos from delivery systems. Biocompatible carrier systems with pH-cleavable units must fulfill many other criteria as well, for example, a long blood circulation time. This can be achieved by tailored micro- and nanocarriers based on macromolecular architectures or stable self-assembled systems.
Missing a piece? We propose the idea of combining regular chemotherapy with radiation therapy to minimize side effects and to increase drug-delivery efficiency. The unfinished puzzle in the picture shows the Aesculapian snake—the symbol of pharmacy and cure—to remind us that there is still a gap between potent chemotherapeutics and radiotherapy. We hope the emerging research area summarized in this Focus Review can function as the connecting pieces to solve the puzzle of an effective and comprehensive treatment.