Morphology-tunable and pH-responsive supramolecular self-assemblies based on AB2-type host-guest-conjugated amphiphilic molecules for controlled drug delivery.
ABSTRACT: Although stimuli-responsive supramolecular self-assemblies have been constructed, the controlled drug delivery induced by morphology transitions of these supramolecular self-assemblies on the basis of host-guest-conjugated monomers (HGCMs) are few reported. In this paper, the self-assembly behaviors of AB2-type HGCMs, e.g., β-cyclodextrin-benzimidazole2 (β-CD-BM2), were investigated at neutral and acidic pH conditions, respectively. Specifically, β-CD-BM2 first self-assembled into fan-shaped supramolecular self-assemblies with a hydrodynamic diameter of 163 nm at neutral pH, whereas they were further dissociated into spherical supramolecular self-assemblies with a size of 52 nm under acidic conditions. This morphology transition process was utilized to conduct a two-stage DOX delivery under neutral and acidic pH. Basic cell experiments demonstrated that the drug-loaded β-CD-BM2-based supramolecular self-assemblies with varied morphology could inhibit cancer cell proliferation, indicating their potential application in the field of drug delivery.
Project description:Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic chemotherapies. The H6-based nanofiber assemblies encapsulated camptothecin (CPT) with up to 60% efficiency, a 7-fold increase in CPT encapsulation relative to spherical micelles. Additionally, pH-sensitive nanofibers showed improved tumor accumulation over both spherical micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines.
Project description:Background:Doxorubicin (DOX) is one of the most effective treatments for hepatocellular carcinoma (HCC), but is restricted by its poor pharmacokinetics. Herein, we exploited efficient targeted drug delivery systems and they have been found to be a worthy strategy for liver cancer therapy. Materials and methods:We investigated polymeric nanoparticles which were synthesized based on host-guest interaction between β-cyclodextrin and benzimidazole. The properties of nanoparticles with regard to size/shape, encapsulation efficiency, and drug release were investigated using conventional experiments. Cell proliferation assay in vitro, cell uptake assay, and cell apoptosis analysis were used to investigate cytotoxicity, uptake, and mechanism of targeted supramolecular prodrug complexes (TSPCs)-based self-assemblies and supramolecular prodrug complexes (SPCs)-based self-assemblies. Results:The pH-sensitive lactobionic acid (LA)-modified pH-sensitive self-assemblies were synthesized successfully. The results of in vitro released assay showed that the accelerated released of DOX from TSPCs-based self-assemblies with the decrease of pH value. When TSPCs-based self-assemblies were taken up by HepG2 cells, they demonstrated a faster release rate under acidic conditions and proved to have higher cytotoxicity than in the presence of LA. A mechanistic study revealed that TSPCs-based self-assemblies inhibited liver cell proliferation by inducing cell apoptosis. Conclusion:The pH-sensitive nanocomplex, as liver-targeted nanoparticles, facilitated the efficacy of DOX in HepG2 cells, offering an appealing strategy for the treatment of HCC.
Project description:The interaction between gold sub-nanometer clusters composed of ten atoms (Au10) and tetrakis(4-sulfonatophenyl)porphyrin (TPPS) was investigated through various spectroscopic techniques. Under mild acidic conditions, the formation, in aqueous solutions, of nanohybrid assemblies of porphyrin J-aggregates and Au10 cluster nanoparticles was observed. This supramolecular system tends to spontaneously cover glass substrates with a co-deposit of gold nanoclusters and porphyrin nanoaggregates, which exhibit circular dichroism (CD) spectra reflecting the enantiomorphism of histidine used as capping and reducing agent. The morphology of nanohybrid assemblies onto a glass surface was revealed by atomic force microscopy (AFM), and showed the concomitant presence of gold nanoparticles with an average size of 130 nm and porphyrin J-aggregates with lengths spanning from 100 to 1000 nm. Surface-enhanced Raman scattering (SERS) was observed for the nanohybrid assemblies.
Project description:The development of stimuli-responsive amphiphilic supramolecular nanostructures is an attractive target for systems based on light-absorbing chromophores that can function as photosensitizers in water. We report here on a water soluble supramolecular carboxylated perylene monoimide system in which charge can be switched significantly by a change in pH. This was accomplished by substituting the perylene core with an ionizable hydroxyl group. In acidic environments, crystalline supramolecular nanoribbons with dimensions on the order of 500 × 50 × 2 nm form readily, while in basic solution the additional electrostatic repulsion of the ionized hydroxyl reduces assemblies to very small dimensions on the order of only several nanometers. The HOMO/LUMO levels were also found to be sensitive to pH; in acidic media the HOMO/LUMO levels are -5.65 and -3.70 eV respectively versus vacuum, whereas is in basic conditions they are -4.90 and -3.33 eV, respectively. Utilizing the assemblies as photosensitizers in photocatalytic production of hydrogen with [Mo3S13]2- as a catalyst at a pH of 4, H2 was generated with a turnover number of 125 after 18 hours. Charge switching the assemblies at a pH of 9-10 and using an iron porphyrin catalyst, protons could again be reduced to hydrogen and CO2 was reduced to CO with a turnover number of 30. The system investigated offers an example of dynamic photosensitizing assemblies that can drive reactions in both acidic and basic media.
Project description:Together with the influenza A virus, influenza B virus causes seasonal flu epidemics. The M2 protein of influenza B (BM2) forms a tetrameric proton-conducting channel that is important for the virus lifecycle. BM2 shares little sequence homology with AM2, except for a conserved HxxxW motif in the transmembrane (TM) domain. Unlike AM2, no antiviral drugs have been developed to block the BM2 channel. To elucidate the proton-conduction mechanism of BM2 and to facilitate the development of BM2 inhibitors, we have employed solid-state NMR spectroscopy to investigate the conformation, dynamics, and hydration of the BM2 TM domain in lipid bilayers. BM2 adopts an ?-helical conformation in lipid membranes. At physiological temperature and low pH, the proton-selective residue, His19, shows relatively narrow (15)N chemical exchange peaks for the imidazole nitrogens, indicating fast proton shuttling that interconverts cationic and neutral histidines. Importantly, pH-dependent (15)N chemical shifts indicate that His19 retains the neutral population to much lower pH than His37 in AM2, indicating larger acid-dissociation constants or lower pKa's. We attribute these dynamical and equilibrium differences to the presence of a second titratable histidine, His27, which may increase the proton-dissociation rate of His19. Two-dimensional (1)H-(13)C correlation spectra probing water (1)H polarization transfer to the peptide indicates that the BM2 channel becomes much more hydrated at low pH than at high pH, particularly at Ser12, indicating that the pore-facing serine residues in BM2 mediate proton relay to the proton-selective histidine.
Project description:In this work, we prepared color-changing colloids by using the electrostatic self-assembly approach. The supramolecular structures are composed of a pH-responsive polymeric surfactant and the water-soluble porphyrin 5,10,15,20-tetrakis-(sulfonatophenyl)porphyrin (TPPS). The pH-responsive surfactant polymer was achieved by the chemical modification of an alternating aliphatic polyketone (PK) via the Paal-Knorr reaction with N-(2-hydroxyethyl)ethylenediamine (HEDA). The resulting polymer/dye supramolecular systems form colloids at the submicron level displaying negative zeta potential at neutral and basic pH, and, at acidic pH, flocculation is observed. Remarkably, the colloids showed a gradual color change from green to pinky-red due to the protonation/deprotonation process of TPPS from pH 2 to pH 12, revealing different aggregation behavior.
Project description:The strategy of using Fe3O4 amphiphilic Janus nanoparticles (Fe3O4@AJNPs) bearing ?-cyclodextrin (?-CD) and aminopyridine (APD) functionalized polymethyl methacrylate (PGMA) to construct pH-stimuli responsive co-assemblies through host-guest interactions between ?-CD and APD was proposed. The spherical co-assemblies with an average diameter about 210?nm were excellent magnetic responsive and quite stable even up to 2 months in deionized water. The pH-liable capability of these co-assemblies was revealed by disassembly of the formed superstructures with destruction of the built inclusion complexes. The disassembly process was monitored by SEM, TEM, DLS and fluorescent molecules probe. After disassembly of the co-assemblies caused by protonation of nitrogens in APD, hydrophobic PGMA-APD lacking of interactions with the Fe3O4@AJNPs chains was precipitated, and the remained Fe3O4@AJNPs turned to re-assemble to self-assemblies. Besides, the recyclable Fe3O4@APJNs could reassembly with additional PGMA-APD to build co-assemblies with a uniform morphology for several times. These pH-sensitive co-assemblies with high stability, good magnetic responsiveness and cytocompatibility could be used as pH-responsive vehicles within which to encapsulate drugs for subsequent controlled release.
Project description:Peptide amphiphiles are molecules containing a peptide segment covalently bonded to a hydrophobic tail and are known to self-assemble in water into supramolecular nanostructures with shape diversity ranging from spheres to cylinders, twisted ribbons, belts, and tubes. Understanding the self-assembly mechanisms to control dimensions and shapes of the nanostructures remains a grand challenge. We report here on a systematic study of peptide amphiphiles containing valine-glutamic acid dimeric repeats known to promote self-assembly into belt-like flat assemblies. We find that the lateral growth of the assemblies can be controlled in the range of 100 nm down to 10 nm as the number of dimeric repeats is increased from two to six. Using circular dichroism, the degree of ?-sheet twisting within the supramolecular assemblies was found to be directly proportional to the number of dimeric repeats in the PA molecule. Interestingly, as twisting increased, a threshold is reached where cylinders rather than flat assemblies become the dominant morphology. We also show that in the belt regime, the width of the nanostructures can be decreased by raising the pH to increase charge density and therefore electrostatic repulsion among glutamic acid residues. The control of size and shape of these nanostructures should affect their functions in biological signaling and drug delivery.
Project description:We demonstrate a strategy to trigger and finely control the assembly of supramolecular DNA nanostructures with pH. Control is achieved via a rationally designed strand displacement circuit that responds to pH and activates a downstream DNA tile self-assembly process. We observe that the DNA structures form under neutral/basic conditions, while the self-assembly process is suppressed under acidic conditions. The strategy presented here demonstrates a modular approach toward building systems capable of processing biochemical inputs and finely controlling the assembly of DNA-based nanostructures under isothermal conditions. In particular, the presented architecture is relevant for the development of complex DNA devices able to sense and respond to molecular markers associated with abnormal metabolism.
Project description:Magnetic resonance imaging (MRI) is a noninvasive imaging modality that provides excellent spatial and temporal resolution. The most commonly used MR probes face significant challenges originating from the endogenous (1)H background signal of water. In contrast, fluorine MRI ((19)F MRI) allows quantitative probe imaging with zero background signal. Probes with high fluorine content are required for high sensitivity, suggesting nanoscale supramolecular assemblies containing (19)F probes offer a potentially useful strategy for optimum imaging as a result of improved payload. We report here on supramolecular nanostructures formed by fluorinated peptide amphiphiles containing either glutamic acid or lysine residues in their sequence. We identified molecules that form aggregates in water which transition from cylindrical to ribbon-like shape as pH increased from 4.5 to 8.0. Interestingly, we found that ribbon-like nanostructures had reduced magnetic resonance signal, whereas their cylindrical counterparts exhibited strong signals. We attribute this drastic difference to the greater mobility of fluorinated tails in the hydrophobic compartment of cylindrical nanostructures compared to lower mobility in ribbon-like assemblies. This discovery identifies a strategy to design supramolecular, self-assembling contrast agents for (19)F MRI that can spatially map physiologically relevant changes in pH using changes in morphology.