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Liposomes are versatile three-dimensional, biomaterial- based frameworks that can spatially enclose a variety of organic and inorganic biomaterials for advanced targeted-delivery applications. Implementation of external-stimulicontrolled release of their cargo will significantly augment their wide application for liposomal drug delivery. This paper presents the synthesis of a carbohydrate-derived lipid, capable of changing its conformation depending on the presence of Zn2+: an active state in the presence of Zn2+ ions and back to an inactive state in the absence of Zn2+ or when exposed to Na2EDTA, a metal chelator with high affinity for Zn2+ ions. This is the first report of a lipid triggered by the presence of a metal chelator. Total internal reflection fluorescence microscopy and a single-liposome study showed that it indeed was possible for the lipid to be incorporated into the bilayer of stable liposomes that remained leakage-free for the fluorescent cargo of the liposomes. On addition of EDTA to the liposomes, their fluorescent cargo could be released as a result of the membrane-incorporated lipids undergoing a conformational change. [ABSTRACT FROM AUTHOR]

In response to specific stimuli, dynamic covalent materials enable the generation of new structures by reversibly forming/breaking chemical bonds, thus showing great potential for application in controlled drug release. However, using dynamic covalent chemistry to program drug‐delivery kinetics remains challenging. Herein, an in situ polymerization‐generated DNA‐scaffolded disulfide redox network (DdiSRN) is reported in which nucleic acids are used as a scaffold for dynamic disulfide bonds. The constructed DdiSRN allows selective release of loading cargos inside cancer cells in response to redox stimuli. Moreover, the density of disulfide bonds in network can be tuned by precise control over their position and number on DNA scaffolds. As a result, drug‐delivery kinetics can be programmed with a half‐life, t1/2, decreasing from 8.3 to 4.4 h, thus facilitating keeping an adequate drug concentration within the therapeutic window. Both in vitro and in vivo studies confirm that co‐delivery of DOX and siRNA in combination with fast drug release inside cells using this DdiSRN enhances the therapeutic effect on multidrug‐resistant cancer. This nontrivial therapeutic platform enabling kinetic control provides a good paradigm for precision cancer medicine. [ABSTRACT FROM AUTHOR]

Keywords: antibodies; bioconjugation; drug delivery; multicomponent reactions; protein modifications EN antibodies bioconjugation drug delivery multicomponent reactions protein modifications 1 1 1 11/06/20 20201102 NES 201102 B Gemini reactions b : In their Full Paper on page 13797 ff., G. Chaubet et al. have investigated the potential of Ugi and Passerini multicomponent reactions for the site-selective conjugation of native trastuzumab. The conjugation proved to tolerate various aldehyde and isocyanide, and a plug-and-play approach was devised, allowing the facile generation of doubly labelled conjugates and antibody-drug conjugates. Antibodies, bioconjugation, drug delivery, multicomponent reactions, protein modifications. [Extracted from the article]

Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype. In the last years, navitoclax has emerged as a possible treatment for TNBC. Nevertheless, rapid navitoclax resistance onset has been observed thorough Mcl‐1 overexpression. As a strategy to overcome Mcl‐1‐mediated resistance, herein we present a controlled drug co‐delivery system based on mesoporous silica nanoparticles (MSNs) targeted to TNBC cells. The nanocarrier is loaded with navitoclax and the Mcl‐1 inhibitor S63845 and capped with a MUC1‐targeting aptamer (apMUC1‐MSNs(Nav/S63845)). The apMUC1‐capped nanoparticles effectively target TNBC cell lines and successfully induce apoptosis, overcoming navitoclax resistance. Moreover, navitoclax encapsulation protects platelets against apoptosis. These results point apMUC1‐gated MSNs as suitable BH3 mimetics nanocarriers in the targeted treatment of MUC1‐expressing TNBC. [ABSTRACT FROM AUTHOR]

In the continuous search for multimodal systems with combined diagnostic and therapeutic functions, several efforts have been made to develop multifunctional drug delivery systems. In this work, through a covalent approach, a new class of fluorinated poly(lactic‐co‐glycolic acid) co‐polymers (F‐PLGA) were designed that contain an increasing number of magnetically equivalent fluorine atoms. In particular, two novel compounds, F3‐PLGA and F9‐PLGA, were synthesized and their chemical structure and thermal stability were analyzed by solution NMR, DSC, and TGA. The obtained F‐PLGA compounds were proven to form in aqueous solution colloidal stable nanoparticles (NPs) displaying a strong 19F NMR signal. The fluorinated NPs also showed an enhanced ability to load hydrophobic drugs containing fluorine atoms compared to analogous pristine PLGA NPs. Preliminary in vitro studies showed high cell viability and the NP ability to intracellularly deliver and release a functioning drug. [ABSTRACT FROM AUTHOR]

An attractive nanoemulsion fluid system with a drop‐percolated network is depicted in the image, in which dipole–dipole interaction between phosphorylcholine groups of lecithin and methoxy end groups of poly(ethylene oxide)‐block‐poly(ϵ‐caprolactone) leads to a gel‐like rheological behavior. This intriguing emulsion system significantly enhances transdermal delivery efficiency due to its favorable attraction to the skin as well as high diffusivity of the nanoscale emulsion drops. More information can be found in the Full Paper by Y. Lee, A. Fernandez‐Nieves, J. W. Kim et al. on page 4292 ff. [ABSTRACT FROM AUTHOR]

This paper reports the facile design and synthesis of a series of lipidic organoalkoxysilanes with different numbers of triethoxysilane headgroups and hydrophobic alkyl chains linked by glycerol and pentaerythritol for the construction of cerasomes with regulated surface siloxane density and controlled release behavior. It was found that the number of triethoxysilane headgroups affected the properties of the cerasomes for encapsulation efficiency, drug loading capacity, and release behavior. For both water-soluble doxorubicin (DOX) and water-insoluble paclitaxel (PTX), the release rate from the cerasomes decreased as the number of triethoxysilane headgroups increased. The slower release rate from the cerasomes was attributed to the higher density of the siloxane network on the surface of the cerasomes, which blocks the drug release channels. In contrast to the release results with DOX, the introduction of one more hydrophobic alkyl chain into the cerasome-forming lipid resulted in a slower release rate of PTX from the cerasomes due to the formation of a more compact cerasome bilayer. An MTT viability assay showed that all of these drug-loaded cerasomes inhibited proliferation of the HepG2 cancer cell line. The fine tuning of the chemical structure of the cerasome-forming lipids would foster a new strategy to precisely regulate the release rate of drugs from cerasomes. [ABSTRACT FROM AUTHOR]

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell-targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof-of-concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase-1 (Hyal-1). Moreover, after receptor-mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site-selective, controlled-release delivery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Gram‐negative bacteria develop specific systems for the uptake of scarce nutrients, including vitamin B12. These uptake pathways may be utilized for the delivery of biologically relevant molecules into cells. Indeed, it was recently reported that vitamin B12 transported an antisense peptide nucleic acid (PNA) into Escherichia coli and Salmonella Typhimurium cells. The present studies indicate that the conjugation site of PNA to vitamin B12 has an impact on PNA transport into bacterial cells. Toward this end, a specifically designed PNA oligomer has been tethered at various positions of vitamin B12 (central Co, R5′‐OH, c and e amide chains, meso position, and at the hydroxy group of cobinamide) by using known or newly developed methodologies and tested for the uptake of the synthesized conjugates by E. coli. Compounds in which the PNA oligonucleotide was anchored at the R5′‐OH position were transported more efficiently than that of other compounds tethered at the peripheral positions around the corrin ring. Of importance is the fact that, contrary to mammalian organisms, E. coli also takes up cobinamide, which is an incomplete corrinoid. This selectivity opens up ways to fight bacterial infections. Open up! Gram‐negative bacteria develop specific systems for the uptake of scarce nutrients, for example, vitamin B12, which may be utilized for the delivery of biologically relevant molecules into cells (see figure). The conjugation site of a peptide nucleic acid (PNA) to vitamin B12 impacts on PNA transport into bacterial cells. Contrary to that in mammals, Escherichia coli also takes up cobinamide, which is an incomplete corrinoid; this selectivity opens up a way to fight bacterial infections. [ABSTRACT FROM AUTHOR]

The design, synthesis, and characterization of a new multifunctional supramolecular assembly based on a photoactive glycosylated porphyrin and covalently attached monofunctionalized cucurbit[7]uril (CB7) are reported. To obtain the target supramolecular assembly, azido‐functionalized tetraphenylporphyrin (TPP) was used as a building block. TPP was first glycosylated by copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction, then a monopropargyloxy‐functionalized‐CB7 unit was conjugated to glycosylated TPP with a second CuAAC reaction. The host–guest chemistry of the assembly was investigated by 1H NMR experiments to establish the availability of the CB7 as a host. The imidazole‐based guest, which is known to have high affinity toward CB7, was observed to form inclusion complex with CB7. It was also demonstrated that this supramolecular assembly can serve as an efficient photosensitizer for the generation of singlet oxygen. Sugar‐coated assemblies: A new multifunctional supramolecular assembly was synthesized by clicking an azide functionalized photoactive glycosylated porphyrin with monopropargyloxy functionalized cucurbit[7]uril (CB7). This supramolecular assembly can serve as a host to bind with guests and an efficient photosensitizer for the generation of singlet oxygen (see figure). [ABSTRACT FROM AUTHOR]

For better removal of excessive free radicals and harmful bacteria from the human body, the development of synergistic antioxidant and antibacterial agents is urgently required. Herein, we designed novel temperature-sensitive, curcumin (Cur)-loaded nanogels for the application of scavenging reactive oxygen species and killing pathogenic bacteria. Photothermal sterilization, different from traditional antibiotics, is a promising and effective treatment for pathogenic bacterial infection. The nanogels were fabricated by using poly(N-isopropylacrylamide) (a temperature-sensitive hydrogel) to encapsulate poly(3,4-ethylenedioxythiophene) nanoparticles (photothermal agents) and Cur through a reformative precipitation polymerization. When triggered by near-IR light, the Cur-loaded nanogels exhibited high (56.8 %), and excellent temperature-sensitive effects. Moreover, the light-induced temperature increase can also weaken the interaction between the networks of PNIPAAm and Cur, to show excellent antioxidant and antibacterial performance (90 % cell death) of the nanogels. [ABSTRACT FROM AUTHOR]

Fluorinated graphene (FG) possess distinctively novel properties different from graphene and is suitable for many biomedical applications. However, the hydrophobic nature and inert properties of FG limit its further application as a biological material. Here we show the preparation of nano-sized FG (ca. 60 nm) that exhibits high NIR absorbance for photothermal therapy. In order to make it stable in physiological solutions, the FG is enriched with oxygen and followed by covalent binding with chitosan as a novel pH-responsive nanocarrier. Furthermore, controlled loading of two anticancer drugs, doxorubicin (DOX) and camptothecin (CPT) has been realized and the functionalized ultrasmall FG shows remarkably high cytotoxicity toward Hela cancer cells compared to that loaded with either CPT or DOX only. This work established nano-sized FG as a novel photothermal agent due to its small size and can be used a stimulus-responsive nanocarrier for mixed drug delivery and combined therapy. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs currently used in clinical settings have high toxicity, low specificity, and short half-lives. Herein, polypyrrole-based anticancer drug nanocapsules were prepared by tailoring the size of the nanoparticles with a template method, controlling drug release by means of an aromatic imine, increasing nanoparticle stability through PEGylation, and improving tumor-cell selectivity by folate mediation. The nanoparticles were characterized by TEM and dynamic light scattering. α-Folate receptor expression levelsof tumor cells and normal cells were investigated by western blot and quantitative polymerase chain reaction analyses. Flow cytometry and fluorescence imaging were used to verify the cell uptake of the different-sized nanoparticles. From the different-sized polypyrrole nanoparticles, the optimally functionalized nanoparticles of 180 nm hydrodynamic diameter were chosen and further usedfor in vitroandin vivotests. The nanoparticles showed excellent biocompatibility and the drug-loaded nanoparticles exhibited effective inhibition of tumor cell growth in vitro. Moreover, the drug-loaded nanoparticles showed substantially enhanced accumulation in tumor regions and effectively inhibitedin vivotumor growth. Furthermore, the nanoparticles showed reduced doxorubicin-induced toxicity andno significant side effects in normal organs of tumor-bearing mice, as measured by body-weight shifts and evaluationof drug distribution. Overall, the functionalized nanoparticles are promising nanocarriers for tumor-targeting drug delivery. [ABSTRACT FROM AUTHOR]

With a view to developing a theranostic nanomedicine for targeted drug delivery systems visible by magnetic resonance (MR) imaging, robust metal-free magnetic nanoemulsions (mean particle size less than 20 nm) consisting of a biocompatible surfactant and hydrophobic, low molecular weight 2,2,5-trimethyl-5-(4-alkoxy)phenylpyrrolidine- N-oxyl radicals were prepared in pH 7.4 phosphate-buffered saline (PBS). The structure of the nanoemulsions was characterized by electron paramagnetic resonance spectroscopy, and dynamic light scattering and small-angle neutron-scattering measurements. The nanoemulsions showed high colloidal stability, low cytotoxicity, enough reduction resistance to excess ascorbic acid, and sufficient contrast enhancement in the proton longitudinal relaxation time ( T1) weighted MR images in PBS in vitro (and preliminarily in vivo). Furthermore, the hydrophobic anticancer drug paclitaxel could be encapsulated inside the nanoparticles, and the resulting paclitaxel-loaded nanoemulsions were efficiently incorporated into HeLa cells to suppress cell growth. [ABSTRACT FROM AUTHOR]

Exploration of yoctowell cavities on magnetic silica nanoparticles for encapsulation and controlled release of drug molecules has been performed by using naturally occurring stimuli, that is, pH. For more details see the Full Paper by S. V. Bhosale on page 5253 ff. [ABSTRACT FROM AUTHOR]

A vesicle-single walled carbon nanotube (CNT) conjugate was developed by a boronic acid-diol covalent linkage between a self-assembled vesicle and dispersed CNT. Trimesic acid based phenylboronic acid appended triple-tailed amphiphiles ( T1 and T1S) were synthesized that formed monolayered vesicles through H-aggregation in DMSO-water (2:1 v/v) and pure water, respectively. Aqueous CNT dispersion was prepared with cholesterol-based glucose-functionalized amphiphile ( D1). These two supramolecular self-assemblies were covalently linked by using a boronic acid-diol interaction between a phenylboronic acid based T1S vesicle and 1,2-diol moieties of glucose tethered dispersing agent ( D1) to develop a vesicle-CNT conjugate. Lewis acid-base chemistry was exploited to form this boronate-diol adduct between two supramolecular self-assemblies. The formation of vesicles, CNT dispersion, and the vesicle-CNT conjugate was characterized by microscopic and spectroscopic techniques. Anticancer drug doxorubicin was encapsulated within this T1S-vesicle- D1-CNT conjugate with a higher loading capacity compared to the individual cargo carrier (vesicle or CNT). This cytocompatible T1S-vesicle- D1-CNT conjugate successfully delivered loaded doxorubicin within a B16F10 melanoma cell and also exhibited better cellular transportation ability compared to the drug-loaded vesicle or CNT. This was further reflected in an enhanced killing efficiency of the cancer cells by the vesicle-CNT conjugate compared to the drug-loaded vesicle or CNT. [ABSTRACT FROM AUTHOR]

Dual stimuli-responsive nanoparticles capable of fine-tuning drug release to augment therapeutic efficacy have become a promising tool for anticancer drug delivery. However, the rational design of these 'smart' nanoparticles for a selective delivery and controlled release of multidrug combinations in cancer cells to achieve synergistic effects remain challenging. Here we report the pH/redox dual responsive nanoparticle FA-DOX-Ind-NP (FA=folic acid, DOX=doxorubicin, Ind=indomethacin, NP=nanoparticle) based on the novel tumor targeting and biodegradable poly(β-amino ester) polymer, and demonstrate its high ability to enter into cancer cells and release a combination of the anticancer drug doxorubicin and the non-steroidal anti-inflammatory drug indomethacin to achieve synergistic chemo-anti-inflammatory effects and overcome multidrug resistance. This study highlights the great potential of tumor targeting and dual stimuli-responsive nanoparticles for an efficient delivery of multidrug combination to improve the cancer therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Increased levels of intracellular prostaglandin E2 (PGE2) have been linked with the unregulated cancer cell migration that often leads to metastasis. Non-steroidal anti-inflammatory drugs (NSAIDs) are known inhibitors of cyclooxygenase (COX) enzymes, which are responsible for the increased PGE2 concentration in inflamed as well as cancer cells. Here, we demonstrate that NSAID-derived ZnII-based coordination polymers are able to inhibit cell migration of human breast cancer cells. Various NSAIDs were anchored to a series of 1D ZnII coordination polymers through carboxylate-Zn coordination, and these structures were fully characterized by single-crystal X-ray diffraction. Hand grinding in a pestle and mortar resulted in the first reported example of nanoscale coordination polymers that were suitable for biological studies. Two such hand-ground nanoscale coordination polymers NCP1 a and NCP2 a, which contained naproxen (a well-studied NSAID), were successfully internalized by the human breast cancer cells MDA-MB-231, as was evident from cellular imaging by using a fluorescence microscope. They were able to kill the cancer cells (MTT assay) more efficiently than the corresponding mother drug naproxen, and most importantly, they significantly inhibited cancer cell migration thereby displaying anticancer activity. [ABSTRACT FROM AUTHOR]

This study introduces an extremely stable attractive nanoscale emulsion fluid, in which the amphiphilic block copolymer, poly(ethylene oxide)- block-poly( ϵ-caprolactone) (PEO- b-PCL), is tightly packed with lecithin, thereby forming a mechanically robust thin-film at the oil-water interface. The molecular association of PEO- b-PCL with lecithin is critical for formation of a tighter and denser molecular assembly at the interface, which is systematically confirmed by T2 relaxation and DSC analyses. Moreover, suspension rheology studies also reflect the interdroplet attractions over a wide volume fraction range of the dispersed oil phase; this results in a percolated network of stable drops that exhibit no signs of coalescence or phase separation. This unique rheological behavior is attributed to the dipolar interaction between the phosphorylcholine groups of lecithin and the methoxy end groups of PEO- b-PCL. Finally, the nanoemulsion system significantly enhances transdermal delivery efficiency due to its favorable attraction to the skin, as well as high diffusivity of the nanoscale emulsion drops. [ABSTRACT FROM AUTHOR]

Graphene oxide (GO) enwrapped SiO2/TiO2 hollow nanoparticles (GO-HNP) are synthesized by the Stöber method and used as a nanocarrier for loading protoporphyrin IX (PpIX). The synthesized nanoparticle has high dispersibility and high uniformity in diameter (ca. 50 nm). Furthermore, this nanoparticle shows λ=808 nm laser induced PpIX release properties (photoinduced 'on-off' drug-release system). GO-HNP-PpIX is employed for inducing both photothermal therapy (PTT) and photodynamic therapy (PDT). The synergic effect of PTT and PDT exhibits powerful anticancer properties. When cancer cells are treated with GO-HNP-PpIX and irradiated with both visible light and a NIR laser, the cell viability drops dramatically to 2.5 %, which is an anticancer effect approximately 13 times higher than that obtained in a previous study. Moreover, no significant cell damage has been observed under λ=808 nm laser irradiation. The GO-HNP-PpIX system suggests an external stimuli-responsive efficient anticancer treatment effect toward human breast cancer cells. [ABSTRACT FROM AUTHOR]

The ability to reversibly cross-link proteins and peptides grants the amino acid cysteine its unique role in nature as well as in peptide chemistry. We report a novel class of S-alkylsulfonyl- l-cysteines and N-carboxy anhydrides (NCA) thereof for peptide synthesis. The S-alkylsulfonyl group is stable against amines and thus enables its use under Fmoc chemistry conditions and the controlled polymerization of the corresponding NCAs yielding well-defined homo- as well as block co-polymers. Yet, thiols react immediately with the S-alkylsulfonyl group forming asymmetric disulfides. Therefore, we introduce the first reactive cysteine derivative for efficient and chemoselective disulfide formation in synthetic polypeptides, thus bypassing additional protective group cleavage steps. [ABSTRACT FROM AUTHOR]

Both molecular and crystal-engineering approaches were exploited to synthesize a new class of multidrug-containing supramolecular gelators. A well-known nonsteroidal anti-inflammatory drug, namely, indomethacin, was conjugated with six different l-amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table-top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature-dependent 1H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single-crystal X-ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen-bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self-delivery) applications for future multidrug-containing injectable delivery vehicles. [ABSTRACT FROM AUTHOR]

C−H bond activation of 2-methoxyethylamino-bis(phenolate)-yttrium catalysts allowed the synthesis of BAB block copolymers comprised of 2-vinylpyridine (2VP; monomer A) and diethylvinylphosphonate (DEVP; monomer B) as the A and B blocks, respectively, by rare-earth-metal-mediated group-transfer polymerization (REM-GTP). The inherent multi-stimuli-responsive character and drug-loading and -release capabilities were observed to be dependent on the chain length and monomer ratios. Cytotoxicity assays revealed the biocompatibility and nontoxic nature of the obtained micelles toward ovarian cancer (HeLa) cells. The BAB block copolymers effectively encapsulated, transported, and released doxorubicin (DOX) within HeLa cells. REM-GTP enables access to previously unattainable vinylphosphonate copolymer structures, and thereby unlocks their full potential as nanocarriers for stimuli-responsive drug delivery in HeLa cells. The self-evident consequence is the application of these new micelles as potent drug-delivery vehicles with reduced side effects in future cancer therapies. [ABSTRACT FROM AUTHOR]

Drug binding to human serum albumin (HSA) has been characterized by a spin-labeling and continuous-wave (CW) EPR spectroscopic approach. Specifically, the contribution of functional groups (FGs) in a compound on its albumin-binding capabilities is quantitatively described. Molecules from different drug classes are labeled with EPR-active nitroxide radicals (spin-labeled pharmaceuticals (SLPs)) and in a screening approach CW-EPR spectroscopy is used to investigate HSA binding under physiological conditions and at varying ratios of SLP to protein. Spectral simulations of the CW-EPR spectra allow extraction of association constants ( KA) and the maximum number ( n) of binding sites per protein. By comparison of data from 23 SLPs, the mechanisms of drug-protein association and the impact of chemical modifications at individual positions on drug uptake can be rationalized. Furthermore, new drug modifications with predictable protein binding tendency may be envisaged. [ABSTRACT FROM AUTHOR]

The construction and application of a unique monodisperse closomer drug-delivery system (CDDS) integrating three different functionalities onto an icosahedral closo-dodecaborane [B12]2− scaffold is described. Eleven B-OH vertices of [ closo-B12(OH)12]2− were used to attach eleven copies of the anticancer drug chlorambucil and the targeting vector glucosamine through a bifurcating lysine linker. The remaining twelfth vertex was used to attach a fluorescent imaging probe. The presence of multiple glucosamine units offered a monodisperse and highly water-soluble CDDS with a high payload of therapeutic cargo. This array enhanced the penetration of the drug into cancer cells by exploiting the overexpression of GLUT-1 receptors present on cancer cells. About 15-fold enhancement in cytotoxicity was observed for CDDS-1 against Jurkat cells, compared to CDDS-2, which lacks the GLUT-1 targeting glucosamine. A cytotoxicity comparison of CDDS-1 against colorectal RKO cells and its GLUT-1 knock-out version confirmed that GLUT-1 mediates endocytosis. Using fluorescent markers both CDDS-1 and -2 were traced to the mitochondria, a novel target for alkylating agents. [ABSTRACT FROM AUTHOR]

Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM-based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation. [ABSTRACT FROM AUTHOR]

A new series of MnII coordination polymers, namely, [{Mn(L)(H2O)2} ⋅2 Nap]∞ ( CP1), [{Mn(L)(Ibu)2(H2O)2}]∞ ( CP2), [{Mn(L)(Flr)2(H2O)2}]∞ ( CP3), [{Mn(L)(Ind)2(H2O)2} ⋅H2O]∞ ( CP4), [{Mn2(L)2(μ-Flu)4(H2O)} ⋅L]∞ ( CP5), [{Mn2(L)2(μ-Tol)4(H2O)2}]∞ ( CP6) and [{Mn2(L)2(μ-Mef)4(H2O)2}]∞ ( CP7) (Nap=naproxen, Ibu=ibuprofen, Flr=flurbiprofen, Ind=indometacin, Flu=flufenamic acid, Tol=tolfenamic acid and Mef=mefenamic acid) derived from various non-steroidal anti-inflammatory drugs (NSAIDs) and the organic linker 1,2-bis(4-pyridyl)ethylene (L) have been synthesized with the aim of being used for cell imaging and drug delivery. Single-crystal X-ray diffraction (SXRD) studies revealed that the NSAID molecules were part of the coordination polymeric network either through coordination to the metal center (in the majority of the cases) or through hydrogen bonding. Remarkably, all the MnII coordination polymers were found to be soluble in DMSO, thereby making them particularly suitable for the desired biological applications. Two of the coordination polymers (namely, CP1 and CP3) reported herein, were found to be photoluminescent both in the solid as well as in the solution state. Subsequent experiments (namely, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and PGE2 (prostaglandin E2) assays) established their biocompatibility and anti-inflammatory response. In vitro studies by using a macrophage cell line (i.e., RAW 264.7) revealed that both CP1 and CP3 were excellent cell imaging agents. Finally, biodegradability studies under simulated physiological conditions in phosphate-buffered saline (PBS) at pH 7.6 showed that slow and sustained release of the corresponding NSAID was indeed possible from both CP1 and CP3. [ABSTRACT FROM AUTHOR]

Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual-responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the PtIV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt-HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the PtIV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells. [ABSTRACT FROM AUTHOR]

Towards ultrathin rare ‐ earth nanomaterials A general and facile wet ‐ chemistry strategy for the synthesis of ultrathin rare ‐ earth oxide nanosheets has been established. The ultrathin Sm2O3 and Gd2O3 nanosheets demonstrate promising pH ‐ controlled anticancer drug ‐ delivery behavior. For more details, see the Full Paper by B. Lei, Y. Du et al. on page 11954 ff. [ABSTRACT FROM AUTHOR]

A combination therapy using a neuroprotective drug, N ‐ (4 ‐ hydroxylphenylacetyl) spermine, and an anticancer drug, doxorubicin, integrated with functional mesoporous silica nanoparticles as carriers has been developed for improved treatment of metastatic melanoma cancer, as reported by Y. Zhao et al. in their Full Paper on page 6123 ff. [ABSTRACT FROM AUTHOR]

Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host-guest inclusion complex formed from water-soluble pillar[6]arene ( WP6) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1, which gradually transform into layered structures with liquid-crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2, which exhibit dual photo- and pH-responsiveness. Notably, the resulting WP6⊃ G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ-loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ-loaded vesicles is associated with apoptosis. Therefore, the dual pH- and UV-responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery. [ABSTRACT FROM AUTHOR]

Cyclodextrins are widely deployed in the pharmaceutical industry. The cover features Mount Etna and represents a recent “eruption” in research activity on metal dyshomeostasis in disease models. In their Full Paper on page 8954, G. Vecchio et. al show cyclodextrins to be novel inhibitors of metal‐induced protein aggregation. [ABSTRACT FROM AUTHOR]

DNA nanostructures have recently attracted increasing interest in biological and biomedical applications by virtue of their unique properties, such as structural programmability, multi‐functionality, stimuli‐responsive behaviors, and excellent biocompatibility. In particular, the intelligent responsiveness of smart DNA nanostructures to specific stimuli has facilitated their extensive development in the field of high‐performance biosensing and controllable drug delivery. This minireview begins with different self‐assembly strategies for the construction of various DNA nanostructures, followed by the introduction of a variety of stimuli‐responsive functional DNA nanostructures for assembling metastable soft materials and for facilitating amplified biosensing. The recent achievements of smart DNA nanostructures for controllable drug delivery are highlighted. Finally, the current challenges and possible developments of this promising research are discussed in the fields of intelligent nanomedicine. [ABSTRACT FROM AUTHOR]

Drug delivery vectors based on amphiphiles have important features such as versatile physicochemical properties and stimuli‐responsiveness. Amino acid‐based surfactants are especially promising amphiphiles due to their enhanced biocompatibility compared to conventional surfactants. They can self‐organize into micelles, vesicles and complex hierarchical structures, such as fibers, twisted and coiled ribbons, and tubules. In this work, we investigated the self‐assembly and drug loading properties of a family of novel anionic double‐tailed lysine‐derived surfactants, with variable degree of tail length mismatch, designated as mLys10 and 10Lysn, where m and n are the number of carbon atoms in the tails. These surfactants form tubular aggregates with assorted morphologies in water that undergo gelation due to dense entanglement, as evidenced by light and electron microscopy. Lysozyme (LZM), an enzyme with antimicrobial properties, was selected as model protein for loading. After the characterization of the interfacial properties and phase behavior of the amphiphiles, the LZM‐loading ability of the tubules was investigated, under varying experimental conditions, to assess the efficiency of the aggregates as pH‐ and temperature‐sensitive nanocarriers. Further, the toxicological profile of the surfactants per se and surfactant/LZM hydrogels was obtained, using human skin fibroblasts (BJ‐5ta cell line). Overall, the results show that the tubule‐based hydrogels exhibit very interesting properties for the transport and controlled release of molecules of therapeutic interest. [ABSTRACT FROM AUTHOR]

Maleimides are essential compounds for drug conjugation reactions via thiols to antibodies, peptides and other targeting units. However, one main drawback is the occurrence of thiol exchange reactions with, for example, glutathione resulting in loss of the targeting ability. A new strategy to overcome such retro‐Michael exchange processes of maleimide–thiol conjugates by stabilization of the thiosuccinimide via a transcyclization reaction is presented. This reaction enables the straightforward synthesis of stable maleimide–thiol adducts essential in drug‐conjugation applications. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene‐containing (Fc‐CH2‐OXA), ruthenocene‐containing (Rc‐CH2‐OXA) and benzene‐containing (Ph‐CH2‐OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in‐depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite. [ABSTRACT FROM AUTHOR]

Enzyme‐powered micro‐ and nanomotors are tiny devices inspired by nature that utilize enzyme‐triggered chemical conversion to release energy stored in the chemical bonds of a substrate (fuel) to actuate it into active motion. Compared with conventional chemical micro‐/nanomotors, these devices are particularly attractive because they self‐propel by utilizing biocompatible fuels, such as glucose, urea, glycerides, and peptides. They have been designed with functional material constituents to efficiently perform tasks related to active targeting, drug delivery and release, biosensing, water remediation, and environmental monitoring. Because only a small number of enzymes have been exploited as bioengines to date, a new generation of multifunctional, enzyme‐powered nanorobots will emerge in the near future to selectively search for and utilize water contaminants or disease‐related metabolites as fuels. This Minireview highlights recent progress in enzyme‐powered micro‐ and nanomachines. [ABSTRACT FROM AUTHOR]

PEG is the gold standard polymer for pharmaceutical applications, however it lacks degradability. Degradation under physiologically relevant pH as present in endolysosomes, cancerous and inflammatory tissues is crucial for many areas. The authors present anionic ring‐opening copolymerization of ethylene oxide with 3,4‐epoxy‐1‐butene (EPB) and subsequent modification to introduce acid‐degradable vinyl ether groups as well as methacrylate (MA) units, enabling radical cross‐linking. Copolymers with different molar ratios of EPB, molecular weights (Mn) up to 10 000 g mol−1 and narrow dispersities (Đ<1.05) were prepared. Both the P(EG‐co‐isoEPB)MA copolymer and the hydrogels showed pH‐dependent, rapid hydrolysis at pH 5–6 and long‐term storage stability at neutral pH (pH 7.4). By designing the degree of polymerization and content of degradable vinyl ether groups, the release time of an entrapped protein OVA‐Alexa488 can be tailored from a few hours to several days (hydrolysis half‐life time t1/2 at pH 5: 13 h to 51 h). [ABSTRACT FROM AUTHOR]

One of the major goals in systems chemistry is to create molecular assemblies with emergent properties that are characteristic of life. An interesting approach toward this goal is based on merging different biological building blocks into synthetic systems with properties arising from the combination of their molecular components. The covalent linkage of nucleic acids (or their constituents: nucleotides, nucleosides and nucleobases) with lipids in the same hybrid molecule leads, for example, to the so‐called nucleolipids. Herein, we describe nucleolipids with a very short sequence of two nucleobases per lipid, which, in combination with hydrophobic effects promoted by the lipophilic chain, allow control of the self‐assembly of lipidic amphiphiles to be achieved. The present work describes a spectroscopic and microscopy study of the structural features and dynamic self‐assembly of dinucleolipids that contain adenine or thymine moieties, either pure or in mixtures. This approach leads to different self‐assembled nanostructures, which include spherical, rectangular and fibrillar assemblies, as a function of the sequence of nucleobases and chiral effects of the nucleolipids involved. We also show evidence that the resulting architectures can encapsulate hydrophobic molecules, revealing their potential as drug delivery vehicles or as compartments to host interesting chemistries in their interior. [ABSTRACT FROM AUTHOR]

The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well‐known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions). [ABSTRACT FROM AUTHOR]

Nanoparticle‐based drug formulations have been impeded by a series of physiological barriers in achieving therapeutic outcomes, including opsonization and sequestration by the mononuclear phagocyte system, elevated interstitial fluid pressure and dense interstitial matrix, endo‐lysosomal trapping and drug efflux pumps. To address this issue, this work develops size‐controllable stealth doxorubicin‐loaded nanodrug coated with CD47 peptides based on supramolecular chemistry. The frontispiece graphic shows the smart nanodrug efficiently decrease macrophage sequestration, disassemble into smaller drugs in the tumor microenvironment, enters into tumor cell nucleus and overcoming drug resistance. For more information see the Communication by X. Zhang, W. Tan et al. on page 1895. [ABSTRACT FROM AUTHOR]

Smart supramolecular vesicles constructed by host–guest interactions between "acid‐degradable" acyclic cucurbit[n]uril (CB[n]) and a doxorubicin prodrug are reported. "Acid‐degradable" acyclic CB[n] is a high‐affinity host for several common antitumor drugs, and its degradation leads to a more dramatic decrease in binding affinity than that observed for "acid‐sensitive" hosts. Supramolecular complexation between acid‐degradable acyclic CB[n] and a doxorubicin prodrug resulted in the formation of negatively charged supramolecular vesicles. The prodrug strategy allowed doxorubicin to be conjugated to vesicles in a stable manner with a high drug‐loading ratio of 20 %. The resulting supramolecular vesicles were responsive to tumor acidity (pH 6.5). Induced by mildly acidic conditions (pH 6.5–5.5), acid‐degradable acyclic CB[n] could be degraded, and this led to a vesicle‐to‐micelle transition to form positively charged micelles. This transition resulted in a pH‐dependent change in size and surface charge, which improved tumoral‐cell uptake for doxorubicin. Improved uptake: Smart supramolecular vesicles were constructed by host–guest interactions between "acid‐degradable" acyclic cucurbit[n]uril (CB[n]) and a doxorubicin prodrug. Under mildly acidic conditions (pH 6.5–5.5), CB[n] degraded, which led to a vesicle‐to‐micelle transition. This transition resulted in a pH‐dependent change in size and surface charge, which improved the uptake of doxorubicin by tumor cells (see figure). [ABSTRACT FROM AUTHOR]

A series of physiological barriers have impeded nanoparticle‐based drug formulations (NDFs) from reaching their targeted sites and achieving therapeutic outcomes. In this study, we develop size‐controllable stealth doxorubicin‐loaded nanodrug coated with CD47 peptides (DOX/sNDF‐CD47) based on supramolecular chemistry to overcome multiple biological barriers. The smart DOX/sNDF‐CD47 can efficiently decrease sequestration by macrophages and disassemble into poly(amidoamine) dendrimers with nuclear localization sequences (DOX/PAMAM‐NLS) in the presence of matrix metalloproteinase‐2 (MMP‐2). Such structure transformation endows DOX/sNDF‐CD47 with the ability of deep penetration in multicellular tumor spheroid, lysosomal escape, and nucleus localization, resulting in excellent cytotoxicity and drug resistance combating. In vivo experiments further confirmed that DOX/sNDF‐CD47 has good tumor‐targeting ability and can significantly improve therapeutic efficacy of DOX on xenograft tumor model. The ability to overcome multiple biological barriers makes sNDF‐CD47 a promising NDFs to treat cancer expressing MMP‐2 and combating drug resistance. Smart nanodrug DOX/sNDF‐CD47, prepared via supramolecular assembly, can efficiently decrease macrophages sequestration, and disassemble into smaller nanodrug in the presence of MMP‐2. Such structural transformation makes it efficiently overcome various biological barriers and drug resistance. In vivo experiments further confirmed that DOX/sNDF‐CD47 has good tumor‐targeting ability and can significantly improve therapeutic efficacy of DOX on xenograft tumor model. [ABSTRACT FROM AUTHOR]

A new multifunctional supramolecular assembly was synthesized by clicking an azide‐functionalized photoactive glycosylated porphyrin with monopropargyloxy‐functionalized cucurbit[7]uril (CB7). This supramolecular assembly can serve as a host to bind with guests and an efficient photosensitizer for the generation of singlet oxygen. More information can be found in the Full Paper by D. Tuncel et al. on page 15550. [ABSTRACT FROM AUTHOR]

Therapeutic nanoreactors have been proposed as nanoplatforms to treat diseases through in situ production of therapeutic agents. When this treatment strategy is applied in cancer therapy, it can efficiently produce highly toxic anticancer drugs in situ from low‐toxic prodrugs or some biomolecules in tumor tissues, which can maximize the therapeutic efficacy with a significantly low systemic toxicity. An ideal therapeutic nanoreactor can provide the reaction space, protect the loaded fragile catalysts, target the desired pathological site, and be selectively activated. In this minireview, we highlight the recent advances concerning the applications of therapeutic nanoreactors as in vivo nanoplatforms particularly in cancer therapy. Herein, the therapeutic nanoreactors are discussed on the basis of treatment strategies and various nanoparticles. Specifically, the treatment strategies of nanoreactors including single enzyme, single enzyme with chemodrugs, and multienzymes, as well as varying types of engineered nanoparticle‐loaded active catalysts, primarily including liposomes, polymersomes, polymeric micelles, inorganic nanoparticles, and metal–organic framework (MOF) architectures, are documented and briefly discussed. Finally, we elucidate the current challenges to be addressed toward further development and translation into clinical applications of these therapeutic nanoreactors in cancer therapy. Small reactors for big medicine: This minireview summarizes the recent advances concerning the applications of therapeutic nanoreactors as in vivo nanoplatforms particularly for cancer therapy according to varying treatment strategies and types of nanoparticles. [ABSTRACT FROM AUTHOR]

Abstract: Herein a new class of iminoboronates obtained from 2‐acetylbenzene boronic acids and aminophenols is presented. The N,O‐ligand topology enabled the formation of an additional B−O bond that locks the boron center in a tetrahedral geometry. This molecular arrangement decisively contributes to improve the construct′s stability in biocompatible conditions and retaining the iminoboronate reversibility in more acidic environments. 2‐Acetylbenzene boronic acid was reacted with a fluorescent amino‐coumarin to yield a stable and non‐fluorescent N,O‐iminoboronate. This mechanism was further used to assemble a folate receptor targeting conjugate that selectively delivered the fluorescent amino‐coumarin to MDA‐MB‐231 human breast cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia in solid tumors facilitates the progression of the disease, develops resistance to chemo and radiotherapy, and contributes to relapse. Due to the lack of tumor penetration, most of the reported drug carriers are unable to reach the hypoxic niches of the solid tumors. We have developed tissue‐penetrating, hypoxia‐responsive echogenic polymersomes to deliver anticancer drugs to solid tumors. The polymersomes are composed of a hypoxia‐responsive azobenzene conjugated and a tissue penetrating peptide functionalized polylactic acid‐polyethylene glycol polymer. The drug‐encapsulated, hypoxia‐responsive polymersomes substantially decreased the viability of pancreatic cancer cells in spheroidal cultures. Under normoxic conditions, polymersomes were echogenic at diagnostic ultrasound frequencies but lose the echogenicity under hypoxia. In‐vivo imaging studies with xenograft mouse model further confirmed the ability of the polymersomes to target, penetrate, and deliver the encapsulated contents in hypoxic pancreatic tumor tissues. [ABSTRACT FROM AUTHOR]

Abstract: The elucidation of the mechanism by which the reduction of coordinatively saturated PtIV prodrugs occurs, leading to the release of the two axial ligands, is of foremost importance, being the key step for the activation of these anticancer compounds, and addressing their synthetic strategies. A systematic DFT computational analysis of the reduction process by small biomolecules, which is supposed to occur by inner‐ or outer‐sphere electron‐transfer mechanisms, has been undertaken using the recently synthesised Asplatin PtIV complex, c,c,t‐[PtCl2(NH3)2(OH)(aspirin)], as model system and l‐ascorbic acid as reducing agent. Further calculations have been carried out on Asplatin analogues that should be obtained replacing the OH− ligand with Cl− and Br−. The most accredited inner‐sphere mechanistic suggestions have been explored and a recently proposed computational methodology has been applied to estimate the corresponding standard redox potentials, which cannot be directly obtained from voltammetric experiments due to the irreversibility of the platinum(IV)‐to‐platinum(II) reduction process. [ABSTRACT FROM AUTHOR]

Abstract: In this study, the influence of metals (Mg, Al, and Ca) and reaction conditions (time, temperature, and metal grain size) on the metallothermic reduction of Stöber silica nanoparticles (NPs) to form porous Si has been explored. Mg metal was found to be an effective reducing agent even at temperatures below its melting point; however, it also induced a high degree of structural damage and morphology change. Al was effective in reducing silica NPs only at its melting point or above, but the resulting particles retained a higher degree of structural morphology as compared to those reduced using Mg. Ca was found to be ineffective in reducing silica. A new reductant, a mixture of 70 % Mg and 30 % Al, was found to induce the least amount of morphology change, and the reactions proceeded at a temperature (450 °C) lower than those required with Mg or Al individually. Furthermore, porous Si NPs obtained using Mg, Al, and the mixture of 70 % Mg and 30 % Al as reductants have been investigated as carriers for ibuprofen loading and release. Porous Si obtained from reductions with Mg and the Mg/Al mixture showed higher drug loading and a sustained drug release profile, whereas porous Si obtained from Al reduction had lower loading and showed a conventional release profile over 24 h. [ABSTRACT FROM AUTHOR]

A series of multifunctional shape-controlled nonspherical hollow mesoporous silica nanoparticles (HMSNs) drug carriers have been prepared by employing Fe2O3 with four morphologies (capsule, cube, rice, and rhombus) as a sacrificial template and a multifunctional cap as the encapsulating shell. The resulting shape-controlled nonspherical HMSNs perfectly replicate the original morphology of the Fe2O3 templates, which possess a high specific surface area, good monodispersity, perpendicular mesoporous channels, and excellent biocompatibility. After modification of polyethylene glycol (PEG) and folic acid (FA), the shape-controlled HMSN core and functional shell can then be integrated into a single device (HMSNs-PEG-FA) to provide an efficient and tumor-cell-selective drug-delivery system. The shape-controlled HMSNs and HMSNs-PEG-FA all show controlled pH-responsive release behavior for the anticancer drug doxorubicin hydrochloride (DOX). The in vitro results indicate that HMSNs-PEG-FA is biocompatible and selectively targets HeLa cells (overexpressed folate receptors). Fluorescence images show that desirable surface modification and the nonspherical shape effectively facilitate cellular internalization of HMSNs. It is expected that the construction of these unique nanomaterials with controlled morphology through the hard-templating technique may also provide useful information for the design of nanoscale multifunctional systems. [ABSTRACT FROM AUTHOR]