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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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).
Hitting the mark: An anticancer theranostic platform with a high drug-loading capacity, termed an aptamer-functionalized calcium carbonate (CaCO3) nanostructure (apt-CCN), is reported (see picture). This smart nanostructure selectively reaches the lysosomes through receptor-mediated endocytosis and is responsive to the relatively low lysosome pH (4.5–5.5), which facilitates the release of doxorubicin.
On the double: Two types of nanocarriers are fabricated: supramolecular micelles formed from water-soluble pillararene (WP6) and azobenzene derivative G1, which gradually transform into layered structures, and supramolecular vesicles formed by WP6 and guest G2, which exhibit dual photo- and pH-responsive behavior (see figure). Mitoxantrone (MTZ)-loaded vesicles show a similar therapeutic effect for cancer cells to free MTZ and reduced damage to normal cells.
A nanotheranostic agent: A ZnO-functionalized upconverting nanotheranostic platform for multi-modality bioimaging (UCL/CT/MRI) and pH-triggered on-demand drug release has been successfully fabricated (see picture). Nontoxic ZnO can play the role of a “gatekeeper” to block the drug in the mesopores of the as-prepared agents until ZnO is dissolved in the acidic environment around tumors.
Formulation control: Dendrimer derivatives for in vivo siRNA delivery to liver endothelial cells, hepatocellular carcinoma cells, and/or hepatocytes are prepared from poly(amido amine) and poly(propylenimine) dendrimers substituted with alkyl chains of different lengths. Through formulation changes, these materials have the ability to broaden or narrow their targeted cellular subpopulation within the liver.
Open on delivery: Cyclic-disulfide-based prodrugs are especially suitable for the highly efficient intracellular delivery of antiviral and antimetabolic nucleoside monophosphates. The key feature of this design is a reduction-triggered charge-dissipating cyclodeesterification of an alicyclic disulfide, followed by facile intramolecular self-quenching of the transient thiirane (see scheme; GSH=glutathione).
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.
Let it go! Targeted drug delivery to the malaria parasite is demonstrated with next-generation 1,2,4-trioxolanes closely related to antimalarial agents arterolane and OZ439. The new systems are prepared by an improved synthetic route and exhibit superior drug-like properties compared with their progenitors. Efficient release of a small-molecule payload is demonstrated with the aminonucleoside puromycin, which becomes incorporated into the Plasmodium falciparum proteome when released from a competent trioxolane conjugate.
Delivering the goods: Encapsulating liposomes are widely used for controlled drug delivery. Nano-impact experiments are employed for the electrochemical attomolar quantification of the contents of a vitamin C encapsulated liposome at the single liposome level. Liposome sizing and their picomolar concentration are also determined in biological buffer in real time.
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.
Reversible protein function modulation was achieved by a convenient chemical approach. RNase A was equipped with a boronic acid group (RNase A–NBC) that responds to reactive oxygen species (ROS). This complex shows cytotoxicity in the presence of ROS as, e.g., in cancer cells, whereas healthy cells are only affected at significantly higher concentrations.
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.
Chemical Trojan horses: Can they rescue antiviral activity? Nucleoside mono- and diphosphate prodrugs of d4U and ddU were prepared by applying the cycloSal and DiPPro approaches. These compounds underwent successful delivery, but surprisingly showed weak or no antiviral activity. Phosphorylation studies with nucleoside diphosphate kinase showed that this enzyme is practically unable to convert ddUDP and d4DUP to the triphosphate form.
Signed, sealed, and delivered: Efficient trans-to-cis photoisomerization of fumaramic acid derivatives with successive pH-dependent degradation under mild acidic conditions was observed. Fumaramic acid derivatives can show pH-responsive degradability only after the preceding photoisomerization.
A supramolecular synthon approach enables an easy access (through salt formation) to a series of supramolecular gelators derived from nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine. Biocompatibility and anti-inflammatory response of the gelator salts indicate their plausible use in biomedical applications (see figure).
Multifunctional CPPs: Robust and biocompatible coordination polymer nanoparticles (CPPs) with enhanced thermal and colloidal stabilities were obtained by incorporation of carboxyl groups on the amorphous structure. The surface carboxyl groups can be subsequently functionalized, generating a multifunctional nanoplatform for theranostic applications such as drug delivery and imaging (see scheme; EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; NHS=N-hydroxysuccinimide).
The incredible shrinking gel: A shrinkable supramolecular metallo-hydrogel was developed (see figure) that could serve as a matrix to efficiently separate ionic dye mixtures or as an intelligent drug vehicle for stepwise release of two-component ionic drugs.
Au gets carried away: Cancer-targeted mesoporous silica nanoparticles for delivery of cytotoxic gold(III) porphyrin complexes are prepared. Encapsulation of the metal complex minimizes its toxic side effects on normal human cells and enhances its anticancer efficacy through inhibition of thioredoxin reductase activity and activation of signaling pathways mediated by reactive oxygen species.
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.
Better together: Upconverting nanoparticles with a mesoporous TiO2 shell (MTUNs) have been synthesized for light-triggered drug delivery and synergistic cancer therapy. Cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or photodynamic therapy (see figure; Dox=doxorubicin, HA=hyaluronic acid, Hyal=hyaluronidase).
Lipophilicity enhancement of a chemotherapeutic agent was achieved by the introduction of a variety of hydrophobic moieties. This allows the self-assembly of the generated prodrugs with block copolymers into amphiphilic polymeric nanoparticles, which exhibited excellent antitumor activity compared to a clinically approved prodrug in a colorectal tumor xenograft model.
Molecular Trojan horses: In organometallic B12–DNA conjugates, such as the herein presented B12-octadecanucleotide, the natural B12 moiety may assist in vivo delivery of oligonucleotides to cellular targets in humans and animals. Binding of the B12–DNA conjugate to human transcobalamin indicates the B12 moiety to be a potential vector for oligonucleotide delivery from blood into cells (see figure).
On target: A synthetic glycopeptide (P) that contains six mannose-6-phosphate residues was covalently attached to a fluorescent activity-based probe for cathepsins. The construct was internalized in live cells through binding to the mannose-6-phosphate receptor (MPR), thus validating the cluster as an MPR-targeting ligand that can be used to deliver cargo into the endolysosomal pathway.
Camptothecine core: Polylysine dendrimers with the conjugated drug in the core were synthesized for cancer therapy. The release rates of the camptothecine conjugates were easily tunable by adjusting the dendrimer generation and the peripheral functional groups as well as the pH. Conjugates showing a fast drug release also exhibited a high anticancer activity against intraperitoneal and subcutaneous tumors.
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.