Dual Photo‐ and pH‐Responsive Supramolecular Nanocarriers Based on Water‐Soluble Pillar[6]arene and Different Azobenzene Derivatives for Intracellular Anticancer Drug Delivery

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.     

Supramolecular Vesicles Coassembled from Disulfide‐Linked Benzimidazolium Amphiphiles and Carboxylate‐Substituted Pillar[6]arenes that Are Responsive to Five Stimuli

Novel supramolecular vesicles based on host–guest systems were coassembled from carboxylate‐substituted pillar[6]arene (CPA[6]) and disulfide‐linked benzimidazolium amphiphiles, and the microstructures of the CPA‐based supramolecular vesicles were clearly elaborated. The supramolecular vesicles showed controlled drug release in response to five stimuli, with glutathione, pH, CO₂, Zn²⁺ ions, and hexanediamine, leading to cleavage of the disulfide bonds, protonation of the carboxylate groups, metal chelation, and competitive binding. This is the first case of a smart pillararene‐based supramolecular vesicle being integrated with five stimuli‐responsive functions to meet the diverse requirements of controlled drug release. Importantly, each of the five stimuli is closely related to microenvironments of tumors and diseases of the human body. The smart stimuli‐responsive supramolecular vesicles have promising applications in drug therapy of tumors and relevant diseases.     

Aptamer-based self-assembled supramolecular vesicles for pH-responsive targeted drug delivery

Supramolecular vesicles have received great attention in biomedical application due to their inherent features, including simple synthesis and tunable amphiphilicity of the building blocks. Despite tremendous research efforts, developing supramolecular vesicles with targeted recognition and controlled release remains a major challenge. Herein, we constructed a novel aptamer-based self-assembled supramolecular vesicle by host-guest complexation of pyrene, viologen lipid, and cucurbit[8]urils for pH-responsive and targeted drug delivery. The proposed supramolecular vesicles are easy to be assembled and offer simple drug loading. Based on confocal fluorescence microscopy and cytotoxicity experiments, the drug-loaded supramolecular vesicles were shown to possess highly efficient internalization and apparent cytotoxic effect on target cancer cells, but not control cells. Furthermore, through simple aptamer or drug substitution, supramolecular vesicles can be applied to a variety of target cell lines and drugs, making it widely applicable. Taking advantage of the easy preparation, good stability, rapid pH response, and cell targeting ability, the aptamer-based self-assembled supramolecular vesicles hold great promise in controlled-release biomedical applications and targeted cancer therapy.     

Cyclodextrin/polyethylenimine-based supramolecular nanoparticles for loading and sustained release of ATP

A new supramolecular nanoparticle PEI/SCD was successfully constructed, showing the loading/sustained release abilities towards ATP.     

An integrated supramolecular fungicide nanoplatform based on pH-sensitive metal–organic frameworks

The construction of an integrated nanoplatform with controlled fungicide delivery features in the specific microenvironment produced by fungal pathogens is a highly desirable strategy to improve the utilization of fungicides. Herein, we report a supramolecular fungicide delivery system based on benzimidazole-modified NH₂-MIL-101(Fe) metal–organic frameworks (B-MIL-101(Fe) MOFs) as carriers loaded with osthole (OS), and β-cyclodextrin (β-CD) as nanovalves to form β-CD@B-MIL-101(Fe)-OS. The nanoplatform can release the loaded OS for fungus control through self-degradation of the MOFs skeleton in an oxalic acid microenvironment produced by Botrytis cinerea. The experimental results exhibit that the constructed supramolecular fungicide delivery system could effectively inhibit mycelial growth and protect the tomatoes from infection by B. cinerea during the ripening stage. This strategy constructs a facile and integrated supramolecular drug delivery system for B. cinerea control and opens up a new avenue for the sustainable development of modern agriculture.     

pH-Responsive supramolecular DOX-dimer based on cucurbit[8]uril for selective drug release

A supramolecular dimer of doxorubicin (DOX) was constructed via ternary host-guest interactions between cucurbit[8]uril (CB[8]) and tryptophan modified DOX (DOX-Trp, connected with an acid-labile bond) and we demonstrate for the first time that a supramolecular dimer of DOX can be formed upon homo-dimerization by CB[8], which may act as a stimuli pH-responsive, supramolecular DOX dimer prodrug system. This supramolecular DOX dimer transported DOX efficiently and selectively to cancer cells, thereby exhibiting significantly minimized cytotoxicity against noncancerous cells while maintaining effective cytotoxicity against cancer cells. Under this strategy, many other anticancer drugs could be chemically modified and loaded as a dimeric “ammunition” into CB[8] as supramolecular dimer prodrug systems (or a “jet fighter”) for improved cancer therapy.     

UV‐Responsive Supramolecular Vesicles with Double Hydrophobic Chains

In order to improve the stability of polymeric vesicles, supramolecular vesicles are developed via self‐assembly of the inclusion of γ‐cyclodextrin (γ‐CD) and 1‐pyrenemethyl palmitate (Py‐pal). The inclusion has one hydrophilic head and double hydrophobic tails, which looks like the phospholipid. From the transmission electron microscopy (TEM) image, it can be observed that the average diameter of supramolecular vesicles is approximately 55 nm and there is a huge cavity in supramolecular vesicles. Due to the photo‐breakable ester of Py‐pal, supramolecular vesicles are broken under UV irradiation. Supramolecular vesicles are used as UV‐responsive drug carriers to release the hydrophilic drug such as doxorubicin hydrochloride (DOX•HCl).

     

Supramolecular hydrogels for enzymatically triggered self-immolative drug delivery

For the first time the combination of self-immolative spacers and supramolecular hydrogels has been tested in enzyme triggered drug release. Low-molecular weight drug-gelator conjugates have been prepared, which contain a gel forming lysine moiety linked to model drugs (benzylamine and phenethylamine) through a self-immolating spacer (p-aminobenzyloxycarbonyl). In the presence of trypsin the amide linkage between the gelator moiety and the spacer is hydrolyzed leading to the release of the model drug. This approach provides with distinct advantages, such as sustained release or versatility associated to the use of supramolecular hydrogels and self-immolative spacers, respectively.     

Enzyme‐Responsive Polymeric Vesicles for Bacterial‐Strain‐Selective Delivery of Antimicrobial Agents

Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain‐selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and β‐lactamase (Bla), which are closely associated with drug‐resistant bacterial strains, antibiotic‐loaded polymeric vesicles undergo self‐immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain‐selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to β‐lactam antibiotic drugs, as a further validation, we demonstrate methicillin‐resistant S. aureus (MRSA)‐triggered release of antibiotics from Bla‐degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model.     

Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles,as a Potential New Nanocarrier for Oral Delivery of Tamoxifen

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL⁻¹) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.     

pH-Responsive supramolecular micelle based on host-guest interaction of poly(β-amino ester) derivatives and adamantyl-terminated poly(ethylene glycol) for cancer inhibition

A pH-responsive supramolecular micelle consisting of β-cyclodextrin-contained poly(β-amino ester) and adamantyl-terminated poly(ethylene glycol) was prepared through host-guest interaction. The micelle can encapsulate curcumin to achieve significant inhibition effect against sarcoma 180 in vivo.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Self‐Assembled Supramolecular Nanogels as a Safe and Effective Drug Delivery Vector for Cancer Therapy

Simple construction and manipulation of low‐molecular‐weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)‐polypropylene glycol containing self‐complementary multiple hydrogen‐bonded Cy moieties is developed, which undergoes spontaneous self‐assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase‐transition temperature and temperature‐induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug‐entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX‐loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 °C, DOX‐loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature‐responsive nanocarrier has highly promising potential for controlled release drug delivery systems.

     

Transformative Supramolecular Vesicles Based on Acid-Degradable Acyclic Cucurbit[n]uril and a Prodrug for Promoted Tumoral-Cell Uptake

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.     

pH‐responsive polymer core–shell nanospheres for drug delivery

Stimuli‐responsive polymer nanoparticles are playing an increasingly more important role in drug delivery applications. However, limited knowledge has been accumulated about processes which use stimuli‐responsive polymer nanospheres (matrix nanoparticles whose entire mass is solid) to carry and deliver hydrophobic therapeutics in aqueous solution. In this research, pyrene was selected as a model hydrophobic drug and a pyrene‐loaded core‐shell structured nanosphere named poly(DEAEMA)‐poly(PEGMA) was designed as a drug carrier where DEAEMA and PEGMA represent 2‐(diethylamino)ethyl methacrylate and poly(ethylene glycol) methacrylate, respectively. The pyrene‐loaded core‐shell nanospheres were prepared via an in situ two‐step semibatch emulsion polymerization method. The particle size of the core‐shell nanosphere can be well controlled through adjusting the level of surfactant used in the polymerization where an average particle diameter of below 100 nm was readily achieved. The surfactant was removed via a dialysis operation after polymerization. Egg lecithin vesicles (liposome) were prepared to mimic the membrane of a cell and to receive the released pyrene from the nanosphere carriers. The in vitro release profiles of pyrene toward different pH liposome vesicles were recorded as a function of time at 37 °C. It was found that release of pyrene from the core‐shell polymer matrix can be triggered by a change in the environmental pH. In particular the pyrene‐loaded nanospheres are capable of responding to a narrow window of pH change from pH = 5, 6, to 7 and can achieve a significant pyrene release of above 80% within 90 h. The rate of release increased with a decrease in pH. A first‐order kinetic model was proposed to describe the rate of release with respect to the concentration of pyrene in the polymer matrix. The first‐order rate constant of release k was thus determined as 0.049 h^?1 for pH = 5; 0.043 h^?1 for pH = 6; and 0.035 h^?1 for pH = 7 at 37 °C. The release of pyrene was considered to follow a diffusion‐controlled mechanism. The synthesis and encapsulation process developed herein provides a new approach to prepare smart nanoparticles for efficient delivery of hydrophobic drugs. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4440–4450     

LHRH/TAT dual peptides-conjugated polymeric vesicles for PTT enhanced chemotherapy to overcome hepatocellular carcinoma

Combination therapy such as photothermal therapy (PTT) enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Herein, we developed redox-responsive polymeric vesicles based on the amphiphilic triblock copolymer PCL-ss-PEG-ss-PCL. To avoid the limited therapeutic effect of chemotherapeutic drugs caused by systemic exposures and drug resistance, the redox-sensitive polymeric vesicles were cargoed with two chemotherapeutics: doxorubicin (DOX) and paclitaxel (PTX). Besides, indocyanine green (ICG) was encapsulated, and cell-penetrating peptides and LHRH targeting molecule were modified on the surface of polymeric vesicles. The results indicated that the polymeric vesicles can load different kinds of drugs with high drug loading content, trigger drug release in responsive to the reductive environment, realize high cellular uptake via dual peptides and laser irradiation, and achieve higher cytotoxicity via chemo-photothermal combination therapy. Hence, the redox-responsive LHRH/TAT dual peptides-conjugated PTX/DOX/ICG co-loaded polymeric micelles exhibited great potential in tumor-targeting and chemo-photothermal therapy.     

Functionalized mesoporous silica nanoparticle-based visible light responsive controlled release delivery system

A supramolecular assembly for visible light responsive release of cargo molecules is presented. Sulforhodamine 101 was loaded inside the mesopores of mercaptopropyl-functionalized mesoporous silica nanoparticles (MP-MSN) and entrapped by mercaptopropyl-coordinated Ru(bpy)(2)(PPh(3))-moieties. Irradiation with visible light triggers the release of capping species and loaded molecules.     

Active loading and tunable release of doxorubicin from block copolymer vesicles

Vesicles are spherical bilayers that offer a hydrophilic reservoir, suitable for the incorporation of water-soluble molecules, as well as a hydrophobic wall that protects the loaded molecules from the external solution. The permeability of a vesicle wall made from polystyrene can be enhanced by adding a plasticizer such as dioxane. Tuning the wall permeability allows loading and release of molecules from vesicles to be controlled. In this study, vesicles are prepared from polystyrene(310)-b-poly(acrylic acid)(36) and used as model carriers for doxorubicin (DXR), a weak amine and a widely used anticancer drug. To increase the wall permeability, different amounts of dioxane are added to the vesicle solution. A pH gradient is created across the vesicle wall (inside acidic) and used as an active loading method to concentrate the drug inside the vesicles. The results show that a pH gradient of ca. 3.8 units can enhance the loading level up to 10-fold relative to loading in the absence of the gradient. After loading, the release of DXR from vesicles is followed as a function of the wall permeability. The diffusion coefficient of doxorubicin through polystyrene (D) is evaluated from the initial slope of the release curves; the value of D ranges from 8 x 10(-17) to 6 x 10(-16) cm(2)/s, depending on the degree of plasticization of the vesicle wall.     

Cargo Encapsulation in Photochromic Supramolecular Hydrogels Depends on Specific Guest-Gelator Supramolecular Interactions

Photochromic supramolecular hydrogels are prospective materials for light-triggered drug release and bionanotechnology. Here we present a structural analysis of peptide-derived photochromic supramolecular hydrogels, which were physically loaded with a selection of biologically related compounds, using advanced techniques of nuclear magnetic resonance. The results enable detailed and correct understanding of the loading process and will allow for correct design of pharmacologically relevant systems for phototriggered drug delivery.     

Supramolecular nano drug delivery systems mediated via host-guest chemistry of cucurbit[n]uril (n = 6 and 7)

As a novel family of macrocyclic molecules,cucurbit[n]urils(CB[n]s) have emerged as promising building blocks of supramolecular nano drug delivery systems(SNDDS) in recent years.Direct encapsulation of amphiphilic guests by CB[6] and CB[7] can modulate their amphiphilicity,resulting in formation of supramolecular amphiphiles that self-assemble into supramolecular nanoparticles for drug delivery.Additionally,CB[n]'s host-guest chemistry on the surface of mesoporous nanoparticles makes CB[n] an ideal blocking agent to control drug release from delivery vehicles.These SNDDS possess intrinsic stimuli responsiveness towards external guest or host,which can further incorporate re s ponsiveness to a variety of other stimuli including pH,thermal,redox,photo and enzyme,to realize multiple stimuli-responsive drug release.Moreover,the recent breakthrough in direct functionalization of CB[n]s has provided a feasible method for preparing superior CB[6] and CB[7] derivatives that can be employed to build multifunctional SNDDS with unoccupied macrocycles located on surface,which could be decorated with various functional "tags" through host-guest chemistry.In this review,we summarized the recent progress of CB[6] and CB[7] based SNDDS through formation of supramolecular amphiphiles,supramolecular nanovalves as well as supramolecularly tailorable surface,which we hope to further promote the development of CB[n]s family as building blocks for advanced SNDDS.