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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The pH low insertion peptide (pHLIP) allows drugs to be delivered selectively to the cytoplasm of cancer cells based on tumor extracellular acidity (pHe). Incorporation of noncanonical amino acids into pHLIP can increase the pH at which it inserts into membranes, thus better matching tumor pHe, without compromising the sharpness of transition.
Light release: The use of a photoswitch to control the release of a reactive chemical entity (drug or tag) with light under physiological conditions has been demonstrated. A water-soluble furyl-substituted diarylethene derivative was used in the reversible Diels–Alder reactions with maleimides to yield photoswitchable Diels–Alder adducts. Employing bioorthogonal visible light, the release of therapeutically effective concentrations of maleimide-based reactive inhibitors or labels from these “prodrugs” or “protags” could be photoreversibly triggered (see figure). A thorough investigation of the release dynamics is also presented.
Biocompatible vesicles: Cationic and anionic surfactants derived from serine are mixed in water to yield robust vesicles of varying size, charge, and pH (see figure). The structures show long-term stability and thus offer high potential as biocompatible nanocarriers.
Smart device: Poly(AAm-co-AN)-g-PEG micelles were used as a temperature-triggered drug delivery system based on their upper critical solution temperature. The polymeric micelles displayed a good drug release profile both in vitro and in vivo. Additionally, an excellent antitumor efficiency was achieved. DOX=doxorubicin.
Double up: A gold nanorod (GNR)–photosensitizer (PS) complex, which was prepared by using the LbL method, exhibits high anticancer activity in vitro using a synergistic therapy of photothermal therapy (PTT) followed by photodynamic therapy (PDT). In this system, PTT controls the PS release to maximize 1O2 photogeneration for PDT.
Building on solid foundations: A hetero-bifunctional linker joining a “cleavable” disulfide moiety and a “clickable” terminal acetylene group was synthesized and used to decorate carbon nanotubes (CNTs). When used in combination with other selected terminal acetylene molecules, the linker can impart multimodality through a controlled click reaction to give carbon nanohybrids (see figure).
A novel 3D gold-DNA superstructure based on DNA growing and origami folding on gold nanoparticles had been fabricated. The new 3D superstructures exhibit great potential for high-efficiency molecule transport for use in cellular imaging and drug delivery.
Deliver the goods: A preliminary study of the cellular uptake of a nanoconstruct obtained by loading poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a tetrathiahelicene conjugated to a fluorescent rhodamine probe has been carried out. The ability to internalize the tetrathiahelicene and deliver it intracellularly has been investigated by means of cytotoxicity and cell uptake tests on Balb/3T3 clone A31 fibroblasts (see figure).
Drugs included: The antitumor drug cis–trans–cis-[PtCl2(CH3CO2)2(adamantlyamine)(NH3)] (LA-12) co-administered with 3- or 6-functionalised β-cyclodextrin conjugated with γ-folate (βCyD3-FAγ or βCyD6-FAγ) as an inclusion complex showed IC50 values significantly lower than that of LA-12 alone or LA-12 co-administered with βCyD in folate receptor-overexpressing cancer cells (see figure).
An open and shut case: A pH-responsive free-blockage release system was achieved through controlling the hydrophobic/hydrophilic conversion of mesoporous silica nanopores (see figure). This system could have the ability of continuous infection to tumor cells with high drug-delivery efficiency and few side effects.
siRNA dendrimers with an anandamide receptor ligand are accessible through a click-chemistry approach, and are taken up even by sensitive neural cells. Silencing of two key proteins of the rabies virus was achieved, allowing the suppression of the viral titer in infected neurons below the detection limit.
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.
Delivery on demand: New stimuli-responsive lipidic cubic phases (LCPs) made up of designer host–guest systems are presented (see scheme). These biocompatible nanomaterials exhibit efficient pH- and light-induced binding, release and sequestration of hydrophilic dyes, while preserving a cubic symmetry, as was evidenced by small-angle X-ray scattering.
Site-specific: An activated platelet-specific antibody and antithrombotic protein were site-specifically conjugated to the corona of protein nanomicelles for efficient detection and inhibition of thrombus formation. These multifunctional protein micelles provide a promising approach to the site-specific delivery of a potent antithrombotic agent, thus reducing the dose and bleeding risk. aPC=activated protein C, Th=thrombin.
Precise release of doxorubicin (DOX) in the weakly acidic microenvironment of cancer cells has been achieved with an amorphous calcium carbonate/doxorubicin@silica (ACC–DOX@silica) nanoreactor. Only low drug leakage occurs in physiological and lysosomal/endosomal environments, but at pH 6.5 the drug is specifically released and results in efficient cell death.
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.